Awareness of knowledge or awareness of processing? Implications for sleep-related memory consolidation.
The present study assessed the effects of awareness at encoding on off-line learning during sleep. A new framework is suggested according to which two aspects of awareness are distinguished: awareness of task information, and awareness of task processing. The number reduction task (NRT) was employed because it has two levels of organization, an overt one based on explicit knowledge of task instructions, and a covert one based on hidden abstract regularities of task structure (implicit knowledge). Each level can be processed consciously (explicitly) or non-consciously (implicitly). Different performance parameters were defined to evaluate changes between two sessions for each of the four conditions of awareness arising from whether explicit or implicit task information was processed explicitly or implicitly. In two groups of subjects, the interval between the pre-sleep and post-sleep sessions was filled either with early-night sleep, rich in slow wave sleep (SWS), or late-night sleep, rich in rapid eye movement (REM) sleep. Results show that implicit processing of explicit information was improved in the post-sleep relative to the pre-sleep session only in the early-night group. Independently of sleep stage, changes between sessions occurred for explicit processing of implicit information only in those subjects who gained insight into the task regularity after sleep. It is concluded that SWS but not REM sleep specifically supports gains in computational skills for the processing of information that was accessible by consciousness before sleep.


Oxygen Passivation Mediated Tunability of Trion and Excitons in MoS_{2}.
Using wide spectral range in situ spectroscopic ellipsometry with systematic ultrahigh vacuum annealing and in situ exposure to oxygen, we report the complex dielectric function of MoS_{2} isolating the environmental effects and revealing the crucial role of unpassivated and passivated sulphur vacancies. The spectral weights of the A (1.92 eV) and B (2.02 eV) exciton peaks in the dielectric function reduce significantly upon annealing, accompanied by spectral weight transfer in a broad energy range. Interestingly, the original spectral weights are recovered upon controlled oxygen exposure. This tunability of the excitonic effects is likely due to passivation and reemergence of the gap states in the band structure during oxygen adsorption and desorption, respectively, as indicated by ab initio density functional theory calculation results. This Letter unravels and emphasizes the important role of adsorbed oxygen in the optical spectra and many-body interactions of MoS_{2}.


Anterior cingulate cortex activity as a candidate biomarker for treatment selection in social anxiety disorder.
We aimed to identify biomarkers to guide the decision to add selective serotonin reuptake inhibitors (SSRI) to psychological treatment for social anxiety disorder (SAD). Forty-eight patients with SAD underwent functional magnetic resonance imaging and collection of clinical and demographic variables before treatment with cognitive-behavioural therapy, combined on a double-blind basis with either escitalopram or placebo for 9 weeks. Pre-treatment neural reactivity to aversive faces in the dorsal anterior cingulate cortex (ACC), but not clinical/demographic variables, moderated clinical outcomes. Cross-validated individual-level predictions accurately identified 81% of responders/non-responders. Dorsal ACC reactivity is thus a potential biomarker for SAD treatment selection. None.


Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome.
Richter syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate, 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade ≥3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted. This trial was registered at www.clinicaltrials.gov as #NCT03054896.


Electromagnetic Separation of Isotopes at Oak Ridge: An informal account of history, techniques, and accomplishments.
In 1960 I attended a European conference on isotope separation, after which I visited the Niels Bohr Institute in Copenhagen. A staff member there ventured the opinion that the separation of isotopes will be first on the list of important contributions to the peaceful uses of the atom when the Atomic Energy Commission's memoirs are written in the year 2000. In 1968 the AEC Division of Research contracted with the National Research Council of the National Academy of Sciences to conduct a review of the AEC program for the separation of stable isotopes by electromagnetic and thermal diffusion methods. This ad hoc panel comprised seven scientists from the fields of chemistry, classical physics, geochemistry, geophysics, medicine, and physics. In their final report on national uses and needs for separated stable isotopes (9), they referred to the store of separated isotopes as a "real national asset that attains increasing value as science and technology develop" and recommended "continuation of the program as a national resource of great value to the United States." Later, in a discussion of this report with A. M. Weinberg, J. Koch, himself a pioneer in electromagnetic isotope separation and member of the Danish Atomic Energy Program, said he would correct the statement that the Oak Ridge electromagnetic facility is a "national asset" to read "international asset." From my narrow viewpoint after an extended and complete engrossment with this program for so many years, it is gratifying to learn that such men as those mentioned above share my belief that the work has indeed been worthwhile.


[Neuropharmacological aspects of the regulation of body functions under acoustic stress].
Experiments on white rats were made to study the actions of aminazine, haloperidol, nitrazepam, barbamyl and other substances on the acid-base equilibrium, the blood content of lactic acid, sugar, urea, ATP and nonesterified fatty acids under acoustic stress. All the substances under study were discovered to normalize, to one/or another degree, the glycolytic and energy-forming processes in the body, which were markedly altered as a result of exposure to acoustic stress.


Double blanket effect caused by two layers of black carbon aerosols escalates warming in the Brahmaputra River Valley.
First ever 3-day aircraft observations of vertical profiles of Black Carbon (BC) were obtained during the Cloud Aerosol Interaction and Precipitation Enhancement Experiment (CAIPEEX) conducted on 30(th) August, 4(th) and 6(th) September 2009 over Guwahati (26° 11'N, 91° 44'E), the largest metropolitan city in the Brahmaputra River Valley (BRV) region. The results revealed that apart from the surface/near surface loading of BC due to anthropogenic processes causing a heating of 2 K/day, the large-scale Walker and Hadley atmospheric circulations associated with the Indian summer monsoon help in the formation of a second layer of black carbon in the upper atmosphere, which generates an upper atmospheric heating of ~2 K/day. Lofting of BC aerosols by these large-scale circulating atmospheric cells to the upper atmosphere (4-6 Km) could also be the reason for extreme climate change scenarios that are being witnessed in the BRV region.


Decentralization and health resource allocation: a case study at the district level in Indonesia.
Health resource allocation has been an issue of political debate in many health systems. However, the debate has tended to concentrate on vertical allocation from the national to regional level. Allocation within regions or institutions has been largely ignored. This study was conducted to contribute analysis to this gap. The objective was to investigate health resource allocation within District Health Offices (DHOs) and to compare the trends and patterns of several budget categories before and after decentralization. The study was conducted in three districts in the Province of Nanggroe Aceh Darussalam. Six fiscal year budgets, two before decentralization and four after, were studied. Data was collected from the Local Government Planning Office and DHOs. Results indicated that in the first year of implementing a decentralization policy, the local government budget rose sharply, particularly in the wealthiest district. In contrast, in relatively poor districts the budget was only boosted slightly. Increasing total local government budgets had a positive impact on increasing the health budget. The absolute amount of health budgets increased significantly, but by percentage did not change very much. Budgets for several projects and budget items increased significantly, but others, such as health promotion, monitoring and evaluation, and public-goods-related activities, decreased. This study concluded that decentralization in Indonesia had made a positive impact on district government fiscal capacity and had affected DHO budgets positively. However, an imbalanced budget allocation between projects and budget items was obvious, and this needs serious attention from policy makers. Otherwise, decentralization will not significantly improve the health system in Indonesia.


Traction sutures in a tracheostomy using a ligature passer.
1. A history of tracheostomy is reported, indicating the relatively recent use of traction sutures. 2. The indications for a tracheostomy are listed. 3. The complications of a tracheostomy are mentioned briefly with emphasis on tube displacement and how this provides the rationale for the use of traction sutures. 4. The technique of placement of the traction sutures with the use of a new instrument, the ligature passer, is described. 4. An illustrative case is reported to demonstrate the significance of traction sutures.


Two neurologic facets of CTLA4-related haploinsufficiency.
To describe the clinical and radiologic neurologic characteristics of patients with cytotoxic T-lymphocyte antigen-4 (CTLA4) haploinsufficiency. Three patients from 2 families had neurologic manifestations in the context of CTLA4 haploinsufficiency. Their clinical and MRI findings are presented. A 16-year-old boy with a previous diagnosis of combined immunodeficiency presented with severe recurrent episodes of headaches, motor deficit, and seizures associated with waxing and waning gadolinium-enhancing FLAIR cortical/juxtacortical hyperintensities. His sister, who also had combined immunodeficiency, had a brain MRI when she was aged 13 years due to recent headaches and transient right hemianopsia. It revealed a gadolinium-enhancing left occipital white matter hyperintensity. Another 49-year-old woman had progressive visual loss and cerebellar ataxia in the context of recurrent pulmonary infections. All 3 patients were found to have inherited CTLA4 haploinsufficiency. Patient 1's general condition and neurologic manifestations were completely controlled with abatacept (CTLA4-Ig). These cases suggest that in addition to the variable clinical penetrance and wide spectrum of CTLA4 haploinsufficiency, its neurologic spectrum is broad, ranging from recurrent tumefactive lesions to progressive deficits including cerebellar ataxia and optic atrophy with leukoencephalopathy. These phenotypes must be recognized, and should lead to a complete immunologic workup, because potentially effective targeted immunotherapy exists.


NBS1 is regulated by two kind of mechanisms: ATM-dependent complex formation with MRE11 and RAD50, and cell cycle-dependent degradation of protein.
Nijmegen breakage syndrome (NBS), a condition similar to Ataxia-Telangiectasia (A-T), is a radiation-hypersensitive genetic disorder showing chromosomal instability, radio-resistant DNA synthesis, immunodeficiency, and predisposition to malignances. The product of the responsible gene, NBS1, forms a complex with MRE11 and RAD50 (MRN complex). The MRN complex is necessary for the DNA damage-induced activation of ATM. However, the regulation of MRN complex formation is still unclear. Here, we investigated the regulatory mechanisms of MRN complex formation. We used an immunoprecipitation assay to determine whether levels of the MRN complex were increased by radiation-induced DNA damage and found that the levels of these proteins and their mRNAs did not increase. ATM-dependent phosphorylation of NBS1 contributed to the DNA damage-induced MRN complex formation. However, pre-treatment of cells with an ATM-specific inhibitor did not affect homologous recombination (HR) and non-homologous end-joining (NHEJ) repair. G0 phase cells, decreasing NBS1 and HR activity but not NHEJ, gained HR-related chromatin association of RAD51 by overexpression of NBS1, suggesting that the amount of NBS1 may be important for repressing accidental activation of HR. These evidences suggest that NBS1 is regulated by two kind of mechanisms: complex formation dependent on ATM, and protein degradation mediated by an unknown MG132-resistant pathway. Such regulation of NBS1 may contribute to cellular responses to double-strand breaks.


Chemical and Physical Culture Conditions Significantly Influence the Cell Mass and Docosahexaenoic Acid Content of Aurantiochytrium limacinum Strain PKU#SW8.
Thraustochytrids are well-known unicellular heterotrophic marine protists because of their promising ability to accumulate docosahexaenoic acid (DHA). However, the implications of their unique genomic and metabolic features on DHA production remain poorly understood. Here, the effects of chemical and physical culture conditions on the cell mass and DHA production were investigated for a unique thraustochytrid strain, PKU#SW8, isolated from the seawater of Pearl River Estuary. All the tested fermentation parameters showed a significant influence on the cell mass and concentration and yield of DHA. The addition of monosaccharides (fructose, mannose, glucose, or galactose) or glycerol to the culture medium yielded much higher cell mass and DHA concentrations than that of disaccharides and starch. Similarly, organic nitrogen sources (peptone, yeast extract, tryptone, and sodium glutamate) proved to be beneficial in achieving a higher cell mass and DHA concentration. PKU#SW8 was found to grow and accumulate a considerable amount of DHA over wide ranges of KH2PO4 (0.125-1.0 g/L), salinity (0-140% seawater), pH (3-9), temperature (16-36 °C), and agitation (140-230 rpm). With the optimal culture conditions (glycerol, 20 g/L; peptone, 2.5 g/L; 80% seawater; pH 4.0; 28 °C; and 200 rpm) determined based on the shake-flask experiments, the cell mass and concentration and yield of DHA were improved up to 7.5 ± 0.05 g/L, 2.14 ± 0.03 g/L, and 282.9 ± 3.0 mg/g, respectively, on a 5-L scale fermentation. This study provides valuable information about the fermentation conditions of the PKU#SW8 strain and its unique physiological features, which could be beneficial for strain development and large-scale DHA production.


Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish.
Bone mineralization is an essential step during the embryonic development of vertebrates, and bone serves vital functions in human physiology. To systematically identify unique gene functions essential for osteogenesis, we performed a forward genetic screen in zebrafish and isolated a mutant, no bone (nob), that does not form any mineralized bone. Positional cloning of nob identified the causative gene to encode ectonucleoside triphosphate/diphosphohydrolase 5 (entpd5); analysis of its expression pattern demonstrates that entpd5 is specifically expressed in osteoblasts. An additional mutant, dragonfish (dgf), exhibits ectopic mineralization in the craniofacial and axial skeleton and encodes a loss-of-function allele of ectonucleotide pyrophosphatase phosphodiesterase 1 (enpp1). Intriguingly, generation of double-mutant nob/dgf embryos restored skeletal mineralization in nob mutants, indicating that mechanistically, Entpd5 and Enpp1 act as reciprocal regulators of phosphate/pyrophosphate homeostasis in vivo. Consistent with this, entpd5 mutant embryos can be rescued by high levels of inorganic phosphate, and phosphate-regulating factors, such as fgf23 and npt2a, are significantly affected in entpd5 mutant embryos. Our study demonstrates that Entpd5 represents a previously unappreciated essential player in phosphate homeostasis and skeletal mineralization.


Developmental changes in myocardial contractile reserve in the lamb.
We have assessed serial changes in myocardial contractility and reserve in the normal lamb over the first month of life using an in vivo adaptation of the endsystolic pressure-volume relationship. Via a left thoracotomy, we insert a catheter tip pressure transducer into the left ventricle, affix an echo transducer onto the left ventricular epicardium, place an electromagnetic flow transducer around the pulmonary artery, and insert catheters for monitoring and infusions. We measure contractility by generating left ventricular wall stress-volume index (the cube of dimension) curves, at the same time increasing afterload by infusing phenylephrine. The slope of the endsystolic wall stress-volume index relationship is our index of contractility. Weekly studies were performed at rest and during isoproterenol infusion in 12 animals, and after propranolol administration in four. The data showed a progressive decrease in resting contractility but no change in maximal contractility during isoproterenol infusion over the 4 wk. Taking each week separately, the average increase in contractility during isoproterenol infusion was small at 1 wk (13%), moderate at 2 and 3 wk (24 and 26%, respectively), and large at 4 wk (79%). beta-Adrenergic blockade with propranolol caused a significant decrease in contractility in three of four animals studied at 1 wk, in only one of four animals at 2 wk, and in none of four animals at 3 or 4 wk. Thus, the newborn lamb shows a limited reserve in contractility that increases progressively with age; the limited reserve appears secondary to a high resting beta-adrenergic state.


The role of bevacizumab in the treatment of glioblastoma.
Bevacizumab has been used in patients with GBM as a salvage therapy since its approval in the United States for recurrent GBM in 2009. In order to review the therapeutic effect of bevacizumab in the primary and recurrent clinical setting we have performed a systematic analysis of data from the published literature. Weighted median progression free survival and overall survival were calculated and compared to standard therapy or other experimental therapies. A qualitative analysis of the limited studies on health related quality of life and effects on steroid requirements was also undertaken. We found that the available literature supports the use of bevacizumab for prolonging PFS and OS in the recurrent setting either alone or in combination with a cytotoxic agent (P < 0.05), but does not support its use in the primary setting (P > 0.05). The survival advantage of bevacizumab compared to experimental therapy at recurrence is limited to 4 months. There is no additional benefit reported to date in health-related quality of life with the use of bevacizumab, although it may reduce steroid requirements. On average there is one side-effect event per patient and 74% of these events are grade 3 toxicity or higher. Further studies investigating the role of bevacizumab in combination with cytotoxic agents at recurrence are awaited.


Muscle Na,K-pump dysfunction may expose the heart to dangerous K levels during exercise.
During exercise, potassium leaks out of muscle cells and interstitial potassium concentration may rise to 15 mmol/l. Potassium is then in part transported back to the cells by the Na,K-pump. The leak of potassium from working human muscles can be calculated to 15 mumol/g/min. Human muscles contain 300 pmol/g wet weight Na,K-pumps and have a maximum capacity for potassium uptake of 5 mumol/g/min. At rest only a small percentage is used, but during maximum stimulation the entire capacity can probably be used. During exercise, total potassium leakage from the human muscle pool is 400 mmol/min and maximum active reuptake capacity is 100 mmol/min. ECV contains only 50 mmol potassium. During heavy exercise the capacity for active potassium uptake in muscle pool may be exceeded and interstitial potassium equilibrates with plasma potassium, which then may rise to 10 mmol/l. Training can decrease the rise in plasma potassium during exercise by 0.2-0.5 mmol/l. Variation in muscle Na,K-pump concentration may be associated with changed plasma potassium homeostasis during exercise, which if disadvantageous may be dangerous to the heart.


Sodium and potassium ion transport accelerations in erythrocytes of DOC, DOC-salt, two-kidney, one clip, and spontaneously hypertensive rats. Role of hypokalemia and cell volume.
Sodium (Na+) and potassium (K+) transport by the furosemide-sensitive Na+-K+ transport system, the Na+-K+ pump, and the cation leak(s) were studied in erythrocytes from DOC-water, DOC-salt, two-kidney, one clip (Sprague-Dawley), and spontaneously hypertensive rats (Wistar-Kyoto). Rubidium (Rb+) was used as a tracer for K+. After 4 weeks of DOC-salt hypertension, inward K+ (Rb+) transport by the furosemide-sensitive system was increased threefold, and the inward Na+ leak and the red cell Na+ content were elevated by about 50%. The rise in cell Na+ accelerated K+ inward and Na+ outward transport by the Na+-K4 pump, DOC-water hypertension caused similar but less pronounced changes. In two-kidney, one clip hypertension, the Na+ leak and the Na+-K+ pump rates were slightly elevated, and furosemide-sensitive Rb+ uptake tended to be increased. In spontaneously hypertensive rats, furosemide-sensitive Rb+ uptake was accelerated by 50%. The marked hypokalemia in DOC-water and DOC-salt hypertension was associated with a slight loss of red cell K+ and an increase in mean cellular hemoglobin content (MCHC), indicative of cell shrinkage. Hypokalemia induced by dietary K+ deficiency caused alterations in red cell cation transport, content, and cell volume which were qualitatively similar but more pronounced than those seen in DOC-salt hypertension. Osmotic shrinkage in vitro induced a severalfold acceleration of furosemide-sensitive Rb+ uptake, similar to that observed in rat erythrocytes shrunken in vivo in K+-deficient states. It is concluded that the acceleration of furosemide-sensitive K+ (Rb+) transport in erythrocytes of mineralocorticoid hypertensive rats is largely caused by the hypokalemia and consecutive red cell K+ loss and shrinkage, respectively. Mean cellular hemoglobin content (MCHC) is thus a parameter that must be considered in studies on Na+ and K+ transport across the membrane of rat erythrocytes.


Chemical Profiling and Biological Screening of Some River Nile Derived-Microorganisms.
Chemical and biological studies of the River Nile derived-microorganisms are limited. Hence, this work was carried out to screen the River Nile habitat. Identification of the isolated organisms, chemical profiling of their ethyl acetate extracts as well as screening of their antimicrobial, antileishmanial, antitrypanosomal, and antimalarial activities were investigated. Identification of the microbial isolates were carried out using bacterial 16S rRNA and fungal 18S rRNA gene sequencing. Chemical profiling of the EtOAc extracts using LC-HRESIMS spectroscopy was carried out. The in vitro antimicrobial screening using the modified version of the CLSI method, antileishmanial and antitrypanosomal activities were screened using Leishmania donovani promastigote assay, L. donovani axenic amastigote assay, Trypanosoma brucei trypamastigotes assay and THP1 toxicity assay. The in vitro antimalarial activities against D6 (chloroquine sensitive) and W2 (chloroquine-resistant) strains of Plasmodium falciparum were evaluated. Seven isolated microorganisms were identified as Streptomyces indiaensis, Bacillus safensis, B. anthracis, Bacillus sp., and Aspergillus awamori. Chemical investigation of different extracts showed several bioactive compounds, identified as; nigragillin, 5-caboxybenzofuran and dyramide B from A. awamori and actinopolysporin B from S. indiaensis. On the other hand many nitrogenous compounds with high molecular weights showed no hits that may correspond to new long chain and/or cyclic peptides. The EtOAc extract of B. safensis fermentation broth showed the highest activity against P. falciparum D6 and P. falciparum W2 (IC50 = 25.94 and 27.28 μg/mL, respectively), while two isolates S. indiaensis and Bacillus sp. RN-011 extracts showed the highest antitrypanosomal activity (IC50 = 0.8 and 0.96 μg/mL). The River Nile could be a new source for production of promising bioactive leading compound where antimicrobial and antiparasitic activities may be correlated.


Early childhood general anaesthesia exposure and neurocognitive development.
A great deal of concern has recently arisen regarding the safety of anaesthesia in infants and children. There is mounting and convincing preclinical evidence in rodents and non-human primates that anaesthetics in common clinical use are neurotoxic to the developing brain in vitro and cause long-term neurobehavioural abnormalities in vivo. An estimated 6 million children (including 1.5 million infants) undergo surgery and anaesthesia each year in the USA alone, so the clinical relevance of anaesthetic neurotoxicity is an urgent matter of public health. Clinical studies that have been conducted on the long-term neurodevelopmental effects of anaesthetic agents in infants and children are retrospective analyses of existing data. Two large-scale clinical studies are currently underway to further address this issue. The PANDA study is a large-scale, multisite, ambi-directional sibling-matched cohort study in the USA. The aim of this study is to examine the neurodevelopmental effects of exposure to general anaesthesia during inguinal hernia surgery before 36 months of age. Another large-scale study is the GAS study, which will compare the neurodevelopmental outcome between two anaesthetic techniques, general sevoflurane anaesthesia and regional anaesthesia, in infants undergoing inguinal hernia repair. These study results should contribute significant information related to anaesthetic neurotoxicity in children.


Regulation of M2-type pyruvate kinase mediated by the high-affinity IgE receptors is required for mast cell degranulation.
M2-type pyruvate kinase (M2PK) was found to interact directly with the 'ITAM' region of the gamma chain of the high-affinity IgE receptor (FcvarepsilonRI). Our hypothesis was that mast cell degranulation might require the FcvarepsilonRI-mediated inhibition of M2PK activity. In rat basophilic leukaemia (RBL-2H3) cells, the effects of directly inhibiting M2PK or preventing the FcvarepsilonRI-mediated inhibition of M2PK (disinhibition) on degranulation was measured by hexosaminidase release. Effects of blocking the FcvarepsilonRI-mediated inhibition of M2PK was also assessed in vivo in a mouse model of allergen-induced airway hyper-responsiveness. Activation of FcvarepsilonRI in RBL-2H3 cells caused the rapid phosphorylation of tyrosine residues in M2PK, associated with a decrease in M2PK enzymatic activity. There was an inverse correlation between M2PK activity and mast cell degranulation. FcvarepsilonRI-mediated inhibition of M2PK involved Src kinase, phosphatidylinositol 3-kinase, PKC and calcium. Direct inhibition of M2PK potentiated FcvarepsilonRI-mediated degranulation and prevention of the FcvarepsilonRI-mediated inhibition of M2PK attenuated mast cell degranulation. Transfection of RBL-2H3 cells with M1PK which prevents FcvarepsilonRI-induced inhibition of M2PK, markedly reduced their degranulation and exogenous M1PK (i.p.) inhibited ovalbumin-induced airway hyper-responsiveness in vivo. We have identified a new control point and a novel biochemical pathway in the process of mast cell degranulation. Our study suggests that the FcvarepsilonRI-mediated inhibition of M2PK is a crucial step in responses to allergens. Moreover, the manipulation of glycolytic processes and intermediates could provide novel strategies for the treatment of allergic diseases.


An investigation of factors that influence help-seeking for hearing impairment in older adults.
To examine the influence of audiological and non-audiological factors on help-seeking for hearing impairment (HI) in older adults. A retrospective research design was employed. Participants completed 14 measures, after which two multivariate, multinomial logistic regression models were fitted to the data to determine which factors were associated with consultation for HI and hearing aid uptake. Three-hundred-and-seven individuals who were 60 years or older and who presented with a unilateral or bilateral HI participated in the study. Non-hearing aid owners were assigned to a non-consulter group (n=55) or a consulter group (n=92); hearing aid owners were assigned to an unsuccessful hearing aid owner group (n=75) or a successful hearing aid owner group (n=85). A similar combination of factors was associated with the decisions to consult a health professional about HI and/or to adopt hearing aids. The most important factors related to attitudinal beliefs (e.g. perceived benefits of hearing aids) and external cues to action (e.g. support from significant others). Greater HI also influenced consultation and adoption of hearing aids. Findings highlight the importance of non-audiological factors in hearing rehabilitation to improve consultation for HI and hearing aid adoption.


Dipolar Bent and Linear Acetylenes Substituted by Cationic Quinolinium and Anionic Benzoates. Formation of Mesomeric Betaines.
3-Ethynylquinoline was subjected to a Sonogashira-Hagihara reaction with methyl 2-, 3-, and 4-bromobenzoates, respectively, and then N-methylated to give 3-[((methoxycarbonyl)phenyl)ethynyl]-1-methylquinolinium salts (two X-ray analyses). On saponification of the 3- and 4-substituted benzoates, the mesomeric betaines 3- and 4-[(1-methylquinolinium-3-yl)ethynyl]benzoates were formed. By contrast, the 2-benzoate derivative gave either the corresponding (1-oxo-1H-isochromen-3-yl)quinolinium derivative or the mesomeric betaine 2-(1-methylquinolinium-3-yl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide depending on the reaction conditions. A DFT calculation predicts a transoid conformation of the acetylene bond in the intermediate 2-[(1-methylquinolinium-3-yl)ethynyl]benzoate which is due to a strong hydrogen bond between the carboxylate group and 2H of the quinolinium ring, in addition to a 1,5-interaction between the carboxylate group and the CC triple bond. The bond angles of the transoid CC triple bond were calculated to be 211.6° and -175.1° in vacuo. The corresponding linear triple bond is 50.4 kJ/mol less stable in vacuo according to the calculation, and the N-heterocyclic carbene quinoline-2-ylidene is not formed as a tautomer.


Os trigonum syndrome in ancient Anatolian settlements.
An os trigonum is a small, round bone situated just behind the ankle joint. Clinical research shows that the os trigonum is present in about 5-15 % of normal feet. It occurs when one part of the bone does not fuse with the rest of the talus during growth. The present study is made on the skeletons, which were found in the Karagündiiz, Dilkaya and Van Kalesi-Eski Van Sehri settlements, Van province, Anatolia, dated in the Middle Ages. In this study 228 skeletons were examined, 120 males and 108 females. 376 tall were studied: 227 from Karagiindtiz, 93 from Dilkaya, and 56 from Van Kalesi-Eski Van Sehri. The percentage of the os trigonum syndrome was recorded as 6.6 %.


A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number.
In addition to KIT and PDGFRA mutations, sequential accumulation of other genetic events is involved in the development and progression of gastrointestinal stromal tumors (GISTs). Until recently, the significance of these other alterations has not been thoroughly investigated. We report the first study that integrates gene expression profiling and high-resolution genomic copy number analyses in GIST. Fresh tissue specimens from 25 patients with GIST were collected, and gene expression profiling and high-resolution genomic copy number analyses were performed, using Affymetrix U133Plus and SNP array 6.0. We found that all 21 mutant GIST patients showed both macroscopic cytogenetic alterations and cryptic microdeletions or amplifications, whereas 75% (three of four) of wild-type patients with GIST did not show genomic imbalances. The most frequently observed chromosomal alterations in patients with mutant GIST included 14q complete or partial deletion (17 of 25), 1p deletion (14 of 25) and 22q deletion (10 of 25). Genetic targets of the chromosomal aberrations were selected by integrated analysis of copy number and gene expression data. We detected the involvement of known oncogenes and tumor suppressors including KRAS in chr 12p amplification and KIF1B, PPM1A, NF2 in chr 1p, 14q and 22p deletions, respectively. The genomic segment most frequently altered in mutated samples was the 14q23.1 region, which contains potentially novel tumor suppressors, including DAAM1, RTN1 and DACT1. siRNA-mediated RTN1 downregulation showed evidence for the potential role in GIST pathogenesis. The combination of gene expression profiling and high-resolution genomic copy number analysis offers a detailed molecular portrait of GISTs, providing an essential comprehensive knowledge necessary to guide the discovery of novel target genes involved in tumor development and progression.


Association between depression and COPD: results from the NHANES 2013-2018 and a bidirectional Mendelian randomization analysis.
Observational studies showed a bidirectional association between depression and chronic obstructive pulmonary disease (COPD). However, it is unclear whether the observed association is causal. Thus we estimated the relationship using observational studies combined with bidirectional Mendelian randomization [MR]. The study included 9977 participants from the 2013-2018 National Health and Nutrition Examination Survey and used weighted logistic regression analysis to assess the association between depression and COPD, followed by a bidirectional Mendelian randomization analysis to verify their causality. Adjusted-weighted logistic regression in observational studies showed a significant association between COPD and mild depression (OR (95% CI): 1.81 (1.30, 2.52), P = 0.002) and COPD and depression (OR (95% CI): 1.93 (1.49, 2.50), P < 0.001). MR suggested depression may play a causal role in COPD risk (OR (95% CI): 1.45 (1.32, 1.60), P < 0.001), but more evidence for reverse causation is lacking (reverse MR OR (95% CI): 1.03 (0.99, 1.07), P = 0.151). In conclusion, our study found depression may play a potential causal role in the morbidity of COPD suggesting depression might be the etiology of COPD. This finding needs to be validated in further prospective cohort studies with large sample sizes and adequate follow-up time.


Medicaid reimbursement of hearing services for infants and young children.
As newborn hearing-screening programs have expanded, more and more infants and young children need hearing services. Medicaid is one of the primary sources of funding for such services and, by law, must establish payment rates that are sufficient to enlist enough providers to provide services. In this study we compared 2005 Medicaid reimbursement rates for hearing services for infants and young children in 15 states with the payment rates for the same services by Medicare and commercially available health insurance. On average, Medicaid rates for the same services were only 67 as high as Medicare and only 38 as high as commercial fees. Furthermore, most Medicaid rates declined from 2000 to 2005, and many states did not have billing codes for a significant number of the hearing services needed by infants and young children. These factors likely contribute to infants and young children with hearing loss not being able to get the hearing services they need to benefit from early identification of hearing loss. These data also raise questions about the extent to which states are meeting the federal requirement that Medicaid payments be sufficient to enlist enough providers so that care and services are adequately available to the general population in the geographic area.


How preliminary data affect people's stated willingness to enter a hypothetical randomized controlled trial.
To explore how preliminary trial data affect the general public's stated willingness to enter a randomized clinical trial. We asked 165 prospective jurors to imagine that their physicians wanted them to enroll in a clinical trial. We then presented them with scenarios portraying preliminary trial results--for example, 9 out of 10 patients get better with drug A and 5 out of 10 get better with drug B--and asked after each scenario, whether they would choose to be part of the trial. We designed the scenarios to test how stated willingness to enter the trial would be influenced by: 1) the difference in effectiveness of the 2 treatments based on the patients enrolled thus far; and 2) by the chance that the difference in effectiveness was random (i.e., the P value). The subjects' willingness to enter the trial at various decision points was analyzed using logistic regression. Fewer subjects were willing to enter the trial as preliminary data indicated either an increasing difference in the effectiveness of the two treatments or an increasing statistical significance of that difference. For example 75% of subjects were willing to enter the research trial before any preliminary data were presented, but this number fell to 49% when subjects were presented with preliminary data showing that 9 out of 10 patients improved with one treatment and 5 out of 10 with the other. Multivariable logistic regression revealed that higher P values (odds ratio = 4.29; P < 0.001; 95% CI: 2.22-8.28) and smaller differences in effectiveness (odds ratio = 0.02; P < 0.001; 95% CI: 0.00-0.07) implicit in preliminary data presented to subjects made subjects less likely to agree to enter clinical trials. After adjustment for other relevant variables, male gender was associated with increased willingness to enter the trial. A subjects' willingness to enter the hypothetical trial was influenced by preliminary data. Fewer subjects were willing to enter the trial as the differences in benefit between 2 treatment groups increased. However, the majority of subjects were willing to enter the hypothetical trial even when preliminary evidence strongly favored one treatment over another. Given the importance of informed consent in entering patients in clinical trials, these results should be confirmed in actual trial settings.


Bismuth nanowires: electrochemical fabrication, structural features, and transport properties.
Electrochemical aspects of Bi electrocrystallization from a bath containing bismuth nitrate in a mixture of ethylene glycol and water are addressed. Bismuth nanowires with diameters of 50-120 nm and a length of up to a few dozen microns were prepared by electrodeposition into the pores of anodic aluminium oxide templates. Crystal structure and morphology of electrodeposited materials were characterized using electron microscopy, selected area electron diffraction, and X-ray diffraction analysis. Factors affecting the formation of single or polycrystalline nanowires and their crystallographic orientation are discussed. The prospects of electrodeposited Bi nanostructures for microelectronics are illustrated by the quantitative resistivity measurements of highly texturized Bi nanowires with a diameter of ca. 100 nm and a length varying from 160 to 990 nm in a temperature range from 300 to 1.2 K.


Heterogeneity of vascular smooth muscle alpha-adrenoceptors in canine blood vessels.
1. For the past decade, using radioligand binding, contractility and immunohistochemical techniques, we have been characterizing vascular smooth muscle (VSM) adrenoceptors in four functionally different canine blood vessels, namely the dog aorta (DAO), dog mesenteric artery (DMA), dog mesenteric vein (DMV) and dog saphenous vein (DSV). 2. This communication briefly reviews our findings (with a special emphasis on alpha-adrenoceptor subtypes), which showed that none of the four canine vessels showed the same complement of alpha-adrenoceptor subtypes. 3. All four vessels elicited alpha 1-adrenoceptor contractile responses (antagonized by prazosin), but alpha 2-adrenoceptor responses (sensitive to rauwolscine), were found only in DMV and DSV. 4. Pharmacological characterization using alpha 1-adrenoceptor subtype-selective antagonists showed that DAO contains mainly alpha 1B-adrenoceptors (some alpha 1D-adrenoceptors) and DMA has primarily alpha 1A/1L-adrenoceptors, alpha 1-Adrenoceptors in DMV are primarily of the alpha 1D subtype, but either a new or unusual alpha 1-adrenoceptor subtype was revealed in the DSV.


Does tranexamic acid reduce blood loss during head and neck cancer surgery?
Transfusion of blood and blood products poses several hazards. Antifibrinolytic agents are used to reduce perioperative blood loss. We decided to assess the effect of tranexamic acid (TA) on blood loss and the need for transfusion in head and neck cancer surgery. After Institutional Review Board approval, 240 patients undergoing supramajor head and neck cancer surgeries were prospectively randomised to either TA (10 mg/kg) group or placebo (P) group. After induction, the drug was infused by the anaesthesiologist, who was blinded to allocation, over 20 min. The dose was repeated every 3 h. Perioperative (up to 24 h) blood loss, need for transfusion and fluid therapy was recorded. Thromboelastography (TEG) was performed at fixed intervals in the first 100 patients. Patients were watched for post-operative complications. Two hundred and nineteen records were evaluable. We found no difference in intraoperative blood loss (TA - 750 [600-1000] ml vs. P - 780 [150-2600] ml, P = 0.22). Post-operative blood loss was significantly more in the placebo group at 24 h (P - 200 [120-250] ml vs. TA - 250 [50-1050] ml, P = 0.009), but this did not result in higher number of patients needing transfusions (TA - 22/108 and P - 27/111 patients, P = 0.51). TEG revealed faster clot formation and minimal fibrinolysis. Two patients died of causes unrelated to study drug. Incidence of wound complications and deep venous thrombosis was similar. In head and neck cancer surgery, TA did not reduce intraoperative blood loss or need for transfusions. Perioperative TEG variables were similar. This may be attributed to pre-existing hypercoagulable state and minimal fibrinolysis in cancer patients.


Influence of cerebral blood flow on the ventilatory response to hypoxia in humans.
The purpose of this study was to quantify the possible reduction in ventilation that could be attributed to changes in cerebral blood flow (CBF) with hypoxia to determine whether it could be of sufficient magnitude to underlie hypoxic ventilatory decline (HVD). Six subjects underwent 20 min of isocapnic hypoxia (end-tidal PO2, 50 mmHg). An index of CBF was obtained using transcranial Doppler ultrasound of the middle cerebral artery. The CBF sensitivities to hypoxia and hypercapnia were obtained from the percentage changes in CBF between the last 3 min of the hypoxic or hypercapnic exposure and the 3 min period prior to the exposure. The magnitude of HVD during hypoxia was estimated by fitting a simple model of the ventilatory response to the hypoxic stimulus. The predicted fall in expiratory ventilation (VE) due to a reduction in brain PCO2 generated by the increase in CBF with hypoxia in all subjects was less than the measured magnitude of HVD (33%). Thus, the results from this study suggest that, in awake humans, changes in CBF during acute isocapnic hypoxia are quantitatively insufficient to underlie HVD in humans.


Sertoli-leydig cell tumor of ovary- a diagnostic dilemma.
Sertoli Leydig Cell Tumours (SLCTs) are rare, unilateral, sex cord stromal tumours of ovary, which constitute less than 1% of all the ovarian neoplasms. These tumours can be functionally diverse and they may have heterologous elements. We aim to report a case of a 25-year- old woman who presented with suprapubic pain of 5 days duration, a unilateral adnexal mass, hypertestosteronism without virilization. Intraoperative frozen section of the unilateral salpingo-oophorectomy specimen was suggestive of granulosa cell tumour. Histopathological examination, supplemented with alpha-inhibin immunohistochemistry, was diagnostic of Meyer's type II SLCT. Clinical presentation, pathology and the diagnostic pitfalls in the present case have been presented with a brief review of literature.


Development of bladder control in children and adolescents with cerebral palsy.
The study aimed to investigate the development of bladder control in children with cerebral palsy (CP) and to determinate subgroups with deviant development of bladder control and a higher risk of not achieving urinary continence. Children and adolescents between the ages of 4 and 18 years with a diagnosis of CP, from six Dutch rehabilitation centres were included in the study (n=601). Parents of these participants were sent a questionnaire, of whom 76% responded. Prevalence of primary urinary incontinence was 23.5%. Survival curves were made to determine the development of achieving bladder control in CP. For participants who achieved urinary continence, the development was delayed in comparison with normally developing children and adolescents. The most important factors influencing the occurrence of urinary incontinence in CP were tetraplegia and low intellectual capacity. At age six, 54% of participants with spastic tetraplegia and 80% with spastic hemiplegia or diplegia gained urinary continence spontaneously. Of those who had low intellectual capacity, 38% were dry at this age.


Political experiments that matter: Ordering democracy from experimental sites.
Some recent work in STS has discussed various forms of 'political experiments'. But why and how do experiments matter, and for whom? Answering these questions requires that one leave the locality of the experimental site and account for the construction of wider spaces wherein experiments matter. Using examples related to the public debate on, critique and government of nanotechnology in France, the article identifies three of these spaces. The first one is characterized by the replication of technologies of participation, the second by the conduct of radical critique, and the third by the constitution of objects of government. Overall, the description of these spaces helps describe the current (and incomplete) transformation of French democracy, as the public administration attempts to include new elements, such as 'citizens as locals' or 'substances in a nanoparticulate state', in the French polity. Thus, the study of political experiments proposed here offers analytical entry points for an examination of democratic ordering.


Biotechnology Based Process for Production of a Disulfide-Bridged Peptide.
A disulfide-bridged peptide drug development candidate contained two oligopeptide chains with 11 and 12 natural amino acids joined by a disulfide bond at the N-terminal end. An efficient biotechnology based process for the production of the disulfide-bridged peptide was developed. Initially, the two individual oligopeptide chains were prepared separately by designing different fusion proteins and expressing them in recombinant E. coli. Enzymatic or chemical cleavage of the two fusion proteins provided the two individual oligopeptide chains which could be conjugated via disulfide bond by conventional chemical reaction to the disulfide-bridged peptide. A novel heterodimeric system to bring the two oligopeptide chains closer and induce disulfide bond formation was designed by taking advantage of the self-assembly of a leucine zipper system. The heterodimeric approach involved designing fusion proteins with the acidic and basic components of the leucine zipper, additional amino acids to optimize interaction between the individual chains, specific cleavage sites, specific tag to ensure separation, and two individual oligopeptide chains. Computer modeling was used to identify the nature and number of amino acid residue to be inserted between the leucine zipper and oligopeptides for optimum interaction. Cloning and expression in rec E. coli, fermentation, followed by cell disruption resulted in the formation of heterodimeric protein with the interchain disulfide bond. Separation of the desired heterodimeric protein, followed by specific cleavage at methionine by cyanogen bromide provided the disulfide-bridged peptide.


Light activation of fructose bisphosphatase in photosynthetically competent pea chloroplasts.
The fructose bisphosphatase (EC 18.104.22.168) activity of type A chloroplasts isolated from young (9-day-old) pea (Pisum sativum var. Progress no. 9) plants, assayed at physiological pH, substrate and Mg2+ concentrations, increased rapidly on illumination. The enzyme activity detected was more than sufficient to account for observed rates of Co2 fixation both during the induction period and during steady-state CO2 fixation, whether or not dihydroxyacetone phosphate had been added to the preparation. Omission of catalase from the suspension medium had no effect. On switching off the light, CO2 fixation by the chloroplasts ceased at once, yet fructose bisphosphatase activity decreased much more slowly. Changes in enzyme activity were much less marked if assays were conducted at 3 mM substrate and 10 mM-Mg2+. Chloroplasts from older (13--20-day-old) peas only fixed CO2 rapidly if catalase was present in the assay medium. The fructose bisphosphatase activity detected under physiological assay conditions was again more than sufficient to account for observed rates of Co2 fixation. In the presence of added dihydroxyacetone phosphate, however, the rate of Co2 fixation appeared to be determined by the rate of light activation of fructose bisphosphatase. In general, the rates of Co2 fixation and enzyme activation, and the final enzyme activity achieved, decreased markedly with increasing age of the plants. The role of light activation of fructose bisphosphatase as a means of controlling the rate of CO2 fixation in pea chloroplasts is discussed.


Additional primary malignancies in a Polish cohort of uveal melanoma patients: a review of 644 patients with long-term follow-up.
To investigate the frequency and location of additional primary malignancies in a Polish cohort of uveal melanoma (UM) patients registered in a single centre database. Retrospective data analysis of patients treated for uveal melanoma at the Department of Ophthalmology, Poznań University of Medical Sciences, Poland between 1991 and 2017. Data on the diagnosis of the additional malignancies were obtained during the follow-up visits in our Department and/or from the Greater Poland Cancer Registry. The exclusion criteria comprised no confirmed follow-up or incomplete clinical entry data. Among 644 UM patients registered in the database up to 2017, the additional malignancy was diagnosed in 126 (20%) patients: 71 men, 55 women at the median age of 67 years (range: 34-94). In 48 patients (38%), the additional malignancy occurred prior to the diagnosis of UM, in 73 (58%) patients - after it. The most common locations of second cancer were skin (20 cases / 15%), breast (17 cases / 13%) and lungs (15 cases / 12%). The median follow-up was 36 months (range: 3-242). 87 patients (69%) died by the study close, 32 (37%) of them due to metastatic disease from uveal melanoma, 41 (47%) due to another cancer. The frequency of additional primary malignancies was higher in our cohort than reported by most of other groups. If there is a certain predisposition to a specific type of additional primary carcinoma in UM patients, the analysis of larger database is required.


Single-dose and three-day regimens of ofloxacin versus trimethoprim-sulfamethoxazole for acute cystitis in women.
We compared the safety and efficacy of a single 400-mg dose of ofloxacin, ofloxacin (200 mg) once daily for 3 days, and trimethoprim-sulfamethoxazole (160:800 mg) twice daily for 7 days for the treatment of acute uncomplicated cystitis (urinary tract infection [UTI]) in women. At 5 weeks posttreatment, 35 (81%) of 43 patients treated with single-dose ofloxacin, 40 (89%) of 45 treated with 3 days of ofloxacin, and 41 (98%) of 42 treated with trimethoprim-sulfamethoxazole were cured (P = 0.03, single-dose ofloxacin group versus trimethoprim-sulfamethoxazole group). Retreatment for symptomatic recurrent UTI was given to 7 (16%) of 43 patients initially treated with single-dose ofloxacin, 3 (7%) of 45 patients treated with 3 days of ofloxacin, and 0 of 42 patients treated with trimethoprim-sulfamethoxazole (P = 0.01, single-dose ofloxacin group versus trimethoprim-sulfamethoxazole group). There was a trend in each of the three treatment groups toward an association between persistent or recurrent episodes of significant bacteriuria and a history of UTI in the past year and with diaphragm use. Ofloxacin was more effective than trimethoprim-sulfamethoxazole in eradicating Escherichia coli from rectal cultures during or soon after therapy, but there were no differences at later follow-up visits. Adverse effects were equally common among the three treatment groups. We conclude that single-dose ofloxacin was less effective than 7 days of trimethoprim-sulfamethoxazole for treatment of uncomplicated cystitis in women, while the 3-day ofloxacin regimen and the trimethoprim-sulfamethoxazole regimen were not significantly different in efficacy.


A review of shampoo surfactant technology: consumer benefits, raw materials and recent developments.
Surfactants form the core of all shampoo formulations, and contribute to a wide range of different benefits, including cleansing, foaming, rheology control, skin mildness and the deposition of benefit agents to the hair and scalp. The purpose of this review was to assist the design of effective, modern, shampoo surfactant technologies. The mechanisms through which surfactants help deliver their effects are presented, along with the appraisal techniques through which surfactant options can be tested and screened for product development. The steps that should be taken to select the most appropriate blend of surfactants are described, and useful information on the most widely used surfactants is provided. The review concludes with an examination of recent developments in 'greener' surfactants, 'sulphate-free' technologies and structured liquid phases for novel sensory properties and for suspending benefit agents.


Sparse Representation-Based Open Set Recognition.
We propose a generalized Sparse Representation-based Classification (SRC) algorithm for open set recognition where not all classes presented during testing are known during training. The SRC algorithm uses class reconstruction errors for classification. As most of the discriminative information for open set recognition is hidden in the tail part of the matched and sum of non-matched reconstruction error distributions, we model the tail of those two error distributions using the statistical Extreme Value Theory (EVT). Then we simplify the open set recognition problem into a set of hypothesis testing problems. The confidence scores corresponding to the tail distributions of a novel test sample are then fused to determine its identity. The effectiveness of the proposed method is demonstrated using four publicly available image and object classification datasets and it is shown that this method can perform significantly better than many competitive open set recognition algorithms.


Addressing Hospital Readmissions: Impact of Weekly Review.
The prevention of hospital readmissions has become an area for improvement for most health care organizations. Systematic reviews have been unable to identify a single intervention or bundle of interventions that reliably reduced risk of readmission in a generalizable manner. The aim of this quality improvement project was to examine the readmission rate to a family medicine residency program inpatient service following the implementation of a once per week session that reviewed patients who were readmitted during the prior week. The inpatient admissions and readmission to the family medicine inpatient service associated with a large academic health center were used for analysis. The impact of a regularly scheduled multidisciplinary team meeting that reviewed a list of patients was examined. Readmitted patients who were at high risk for readmission were specifically identified. Descriptive statistics were used to characterize and summarize the integral data obtained. The weekly readmission rate was presented using a control chart. The readmission rate for the patients hospitalized after the intervention was 18.4%, compared to the readmission rate prior to the intervention (23.0%). While not a statistically different rate, a significant signal was noted. Demographic differences were noted in the group of patients considered to be high risk for readmission. Regular rounds of an inpatient team that focuses on readmissions during the previous week reduced hospital readmissions. The impact of these sessions appears to be multifactorial.


Simulated gastrointestinal digestion of inclusion complexes based on ovalbumin nanoparticles and conjugated linoleic acid.
The objective of this work was to obtain and characterize conjugated linoleic acid (CLA) delivery systems based on ovalbumin nanoparticles (OVAn1 and OVAn2) and to study their behaviour under a standardised static in vitro digestion model. OVAn1 and OVAn2 were obtained by heat treatment (85 °C, 5 min, pH 11.35 and 7.5, respectively). OVAn1 and OVAn2 had hydrodynamic diameters of 24.63 ± 0.04 and 92.0 ± 0.2 nm, respectively, showing no significant differences in ζ potential values (p < 0.05) at pH 7.0. CLA nanocomplexes were examined in terms of size and ζ potential at pH 3.0 and 7.0, highlighting that binding of CLA caused an increase in size for OVA and both OVA nanoparticles. Morphological characterization was performed by confocal laser scanning microscopy (CSLM) finding that OVA and OVA nanoparticles had a circular shape. Also, the CLA encapsulation efficiency (EE) for OVA and OVA nanoparticles was studied, yielding EE values greater than 97% for all systems. Finally, systems were assayed for a standardized in vitro gastrointestinal digestion model considering gastric and intestinal steps. Macroscopic appearance, CSLM images and quantification of CLA retention by HPLC were evaluated after digestion. All the systems showed the formation of macroscopic aggregates both in gastric and intestinal phases, which generated a visible precipitate. In all systems, CSLM confirmed the presence of numerous undefined-form aggregates. Finally, high CLA retention (around 99%) was found for native protein and nanoparticles.


Importance of input perturbations and stochastic gene expression in the reverse engineering of genetic regulatory networks: insights from an identifiability analysis of an in silico network.
Gene expression profiles are an increasingly common data source that can yield insights into the functions of cells at a system-wide level. The present work considers the limitations in information content of gene expression data for reverse engineering regulatory networks. An in silico genetic regulatory network was constructed for this purpose. Using the in silico network, a formal identifiability analysis was performed that considered the accuracy with which the parameters in the network could be estimated using gene expression data and prior structural knowledge (which transcription factors regulate which genes) as a function of the input perturbation and stochastic gene expression. The analysis yielded experimentally relevant results. It was observed that, in addition to prior structural knowledge, prior knowledge of kinetic parameters, particularly mRNA degradation rate constants, was necessary for the network to be identifiable. Also, with the exception of cases where the noise due to stochastic gene expression was high, complex perturbations were more favorable for identifying the network than simple ones. Although the results may be specific to the network considered, the present study provides a framework for posing similar questions in other systems.


Positron emission tomography as predictor of rectal cancer response during or following neoadjuvant chemoradiation.
Positron emission tomography (PET) shows great promise as a tool to evaluate the effectiveness of rectal cancer neoadjuvant therapy as it has demonstrated high predictive value in several studies. Creating a standardized method of using PET has the potential to reduce ineffective treatments. However, relevant studies have been heterogenous in approach, making any unified standard difficult to establish. PET related parameters used to assess treatment response include magnitude and change of standard uptake value, total lesion glycolysis, and visual response. Finding the best evaluation interval and parameters to use for interpreting PET results in the neo-adjuvant treatment of rectal cancer needs additional study.


Early Abdominal Ectopic Pregnancy Masquerading as a Missed Miscarriage.
A 43-year-old lady, gravida 2 para 0, presented to our emergency department with complaints of vaginal bleeding and lower abdominal pain. Her urine pregnancy test was positive. She was unable to recall her last menstrual period. A trans-vaginal ultrasound revealed a pregnancy with a crown rump length of 47 mm corresponding to 11.4 weeks with no fetal heartbeat detected. She was diagnosed with a missed miscarriage and was sent for a second confirmatory scan. The repeat scan was concordant with the initial scan and she was counseled for an evacuation of uterus. Her serum beta human chorionic gonadotropin level was 45,195 IU/L and her hemoglobin level was 6.5 g/dL. She underwent an evacuation of uterus as planned, but the Hegar dilator was only able to be advanced to a cavity length of 6 cm with minimal products of conception obtained. A bedside ultrasound was performed and it showed that the Hegar dilator was in the uterine cavity but not in continuity with the gestational sac and fetus. The diagnosis of an ectopic pregnancy was made and the surgery was converted to a diagnostic laparoscopy. On entry into the abdominal cavity, there was frank hemoperitoneum with adhesions limiting access to the pelvis, therefore decision was made to convert to laparotomy. The findings at laparotomy revealed a large inflamed left tubo-ovarian complex with tubal rupture and expulsion of the entire fetus and placenta into the Pouch of Douglas (POD). The diagnosis of a secondary implantation of the ectopic pregnancy in the POD after tubal rupture was confirmed and we performed adhesiolysis and left salpingectomy. The patient recovered uneventfully and the final histology showed products of conception within the lumen of the left fallopian tube in keeping with ruptured tubal ectopic pregnancy.


The downstream core promoter element, DPE, is conserved from Drosophila to humans and is recognized by TAFII60 of Drosophila.
We analyzed the function of the downstream promoter element (DPE), a distinct 7-nucleotide core promoter element that is approximately 30 nucleotides downstream of the transcription start site of many TATA-box-deficient (TATA-less) promoters in Drosophila. There is a strict requirement for spacing between the Inr and DPE motifs, as an increase or decrease of 3 nucleotides in the distance between the Inr and DPE causes a seven- to eightfold reduction in transcription as well as a significant reduction in the binding of purified TFIID. These results suggest a specific and somewhat rigid interaction of TFIID with the Inr and DPE sequences. Photo-cross-linking analysis of purified TFIID with a TATA-less DPE-containing promoter revealed specific cross-linking of dTAFII60 and dTAFII40 to the DPE, with a higher efficiency of cross-linking to dTAFII60 than to dTAFII40. These data, combined with the previously well-characterized interactions between the two TAFs and their homology to histones H4 and H3, suggest that a dTAFII60-dTAFII40 heterotetramer binds to the DPE. Human and Drosophila transcription factors exhibit essentially the same requirements for DPE sequence and for Inr-DPE spacing. In addition, the TATA-less promoter of the human interferon regulatory factor-1 (IRF-1) gene contains a DPE that is important for transcriptional activity both in vitro and in cultured cells. Hence, these studies provide evidence for a direct role of TAFs in basal transcription of TATA-less DPE-containing genes and collectively indicate that the DPE is, in many respects, a downstream counterpart to the TATA box that is present in Drosophila to humans.


[Psychological distress in medical students - a comparison of the Universities of Munich and Witten/Herdecke].
This study compares the distress levels of medical students in two different academic settings. Data were collected from N= 76 medical students at the Witten/Herdecke University (UW/H) and N = 343 medical students at Ludwig Maximilians University Munich (LMU) with an online questionnaire battery of established questionnaire instruments for assessing distress as well as life and study satisfaction (SWE, ADS-K, PSQ, SF-12, STQL-S). Data analysis revealed significant differences between the students with regard to self efficacy expectation, depression, psychological distress, and satisfaction. Because no differences in coping strategies were found between the two groups of students, with the exception of relaxation techniques, the impact of contextual and structural factors on medical students' well-being is discussed.


LPA and its analogs-attractive tools for elucidation of LPA biology and drug development.
Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) is a simple phospholipid but displays an intriguing cell biology that is mediated via interactions with both G-protein-coupled seven transmembrane receptors (GPCRs) and nuclear hormone receptors. So far, seven GPCRs (LPA(1-5) and recently reported GPR87/LPA(6) and P2Y5/LPA(7)) and a nuclear hormone receptor, PPARgamma, have been identified. LPA is predominantly produced in blood and a plasma enzyme, autotaxin, is involved in its production. Recent gene manipulating studies of these proteins have shown that LPA is involved in both pathological and physiological states including brain development, neuropathy pain, implantation, protection against radiation-induced intestinal injury and blood vessel formation. In addition, lipids similar to LPA, such as sphingosine 1-phosphate (S1P) and 2-arachidonylglycerol (2-AG), share common cellular signaling pathways with LPA and are now considered as promising targets of human therapy including immunosuppressant and anti-obesity drugs. Thus, LPA is now one of the most attractive targets for prevention and treatment of various diseases. Receptor-selective antagonists and agonists as well as inhibitors of LPA producing enzymes are undoubtedly useful. Recognition of the ligand, LPA, by each receptor seems to be quite different, as LPA species with various fatty acids at either the sn-1 or sn-2 position of the hydroxy residue activate each receptor quite differently. In the last decade a series of LPA analogs in which the sn-1 or sn-2 hydroxy, acyl chain, glycerol and phosphate group are modified have been created and evaluated by several laboratories. Here we review recent advances in the development of LPA-receptor targeted compounds (agonists and antagonists) and anti-autotaxin inhibitors.


Clinical profiles of vitiligo in China: an analysis of 3742 patients.
Very few articles have aimed to illuminate the clinical profiles of vitiligo in China. We conducted this retrospective survey involving 4118 outpatients with vitiligo in order to identify the differences among various clinical types of vitiligo and their associated disorders. Completed questionnaires (3742) were validated and analysed. Of this large cohort, 1565 (41.8%) individuals presented vitiligo vulgaris, followed by focal, segmental, acrofacial, and universal, in that order. The mean age of vitiligo onset was 18.88 years. More than 60% of the patients were affected before 20 years of age. Patients with segmental vitiligo were affected earlier than those with other types of vitiligo (15.55 years; (P < 0.001). More than 74% of the patients presented with focal vitiligo at onset. After 3-5 years, 99% of active vitiligo was worse and shifted from one clinical type to another. However, there was no transformation between acrofacial vitiligo and segmental vitiligo. Compared with the general population, the patients with vitiligo were more likely to be affected by rheumatoid arthritis (P < 0.01), ichthyosis (P < 0.01), chronic urticaria (P < 0.01), or alopecia areata (P < 0.01).


Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research.
Reports on the modulatory role of the neuropeptide oxytocin on social cognition and behavior have steadily increased over the last two decades, stimulating considerable interest in its psychiatric application. Basic and clinical research in humans primarily employs intranasal application protocols. This approach assumes that intranasal administration increases oxytocin levels in the central nervous system via a direct nose-to-brain route, which in turn acts upon centrally-located oxytocin receptors to exert its behavioral effects. However, debates have emerged on whether intranasally administered oxytocin enters the brain via the nose-to-brain route and whether this route leads to functionally relevant increases in central oxytocin levels. In this review we outline recent advances from human and animal research that provide converging evidence for functionally relevant effects of the intranasal oxytocin administration route, suggesting that direct nose-to-brain delivery underlies the behavioral effects of oxytocin on social cognition and behavior. Moreover, advances in previously debated methodological issues, such as pre-registration, reproducibility, statistical power, interpretation of non-significant results, dosage, and sex differences are discussed and integrated with suggestions for the next steps in translating intranasal oxytocin into psychiatric applications.


Tradeoff Between Speed and Robustness in Primordium Initiation Mediated by Auxin-CUC1 Interaction.
Robustness is the reproducible development of a phenotype despite stochastic noise. It often involves tradeoffs with other performance metrics, but the mechanisms underlying such tradeoffs were largely unknown. An Arabidopsis flower robustly develops four sepals from four precisely positioned auxin maxima. The development related myb-like 1 ( drmy1) mutant generates stochastic noise in auxin signaling that disrupts both the robust position and number of sepal primordia. Here, we found that increased expression of CUP-SHAPED COTYLEDON1 ( CUC1 ), a boundary specification transcription factor, in the drmy1 mutant underlies this loss of robustness. CUC1 surrounds and amplifies stochastic auxin patches in drmy1 to form variably positioned auxin maxima and sepal primordia. Removing CUC1 from drmy1 provides time for the noise in auxin signaling to resolve into four precisely positioned auxin maxima, restoring robust sepal initiation. However, removing CUC1 decreases auxin maxima intensity and slows down sepal initiation. Thus, CUC1 increases morphogenesis speed but impairs robustness against auxin noise. Further, using a computational model, we found that the observed phenotype can be explained by the effect of CUC1 in repolarizing PIN FORMED1 (PIN1), a polar auxin transporter. Thus, our study illustrates a tradeoff between speed and robustness during development.


Early Activation of Metalloproteinases after Experimental Myocardial Infarction Occurs in Infarct and Non-infarct Zones.
The collagen matrix of the heart forms a network linking muscle fibers, muscle bundles, and intramyocardial blood vessels. Collagen turnover in the heart is normally a dynamic process that involves both collagen synthesis and degradation. Collagen breakdown generally involves its chemical digestion by matrix metalloproteinases (MMPs) which are activated in tissue repair, wound healing, and myocardial ischemia. We studied activation of MMPs by zymography in infarct (anterolateral wall) and non-infarct (septum) zones of rat hearts following coranary artery ligation, as well as in sham operated rats. Rats were sacrificed at 30 minutes, 1 hour, 2 hours, 4 hours, and 24 hours post infarction (six hearts for each time period). MMP activity was detected at different molecular weights, with bands at 54 kDa (MMP-1), 62 kDa (MMP-2), and 92 kDa (MMP-9) being the most prominent. MMP activities were indexed by densitometer optical reading. Activity was detected as early as 1 hour post infarct in the MI and remote zones at the 54 kDa (MMP-1) ( p < 0.01) and 62 kDa bands (MMP-2) ( p < 0.001), and at 2 hours post infarct in the infarct zone only at 92 kDa (MMP-9) ( p < 0.05). MMPs are activated early after infarction both in the infarct and importantly, non-infarct zones. This may contribute to collagen breakdown, infarct expansion, and left ventricular remodeling, known to occur early after infarction in experimental and clinical settings.


Tocilizumab in refractory aortitis: study on 16 patients and literature review.
Non-infectious aortitis is often refractory to standard immunosuppressive therapy. Since IL-6 has been implicated in the pathogenesis of aortitis, we assessed the efficacy of the anti-IL6 receptor monoconal antibody tocilizumab (TCZ) in a series of patients with refractory non-infectious aortitis. Review of 16 patients (14 women/2 men) with refractory aortitis diagnosed by imaging (CT angiography, MR angiography, and/or PET) that were treated with TCZ. The mean age±SD was 51.4±20.1 years. The underlying conditions were: Takayasu arteritis (TakA) (n=7 cases), giant cell arteritis (GCA) (n=7), relapsing polychondritis (RP) (n=1), and aortitis associated with retroperitoneal fibrosis (n=1). TCZ was the first biologic drug used in all patients with GCA and in the patient with aortitis associated with retroperitoneal fibrosis but in only 2 of 7 TakA patients. In the remaining cases anti-TNF inhibitors were prescribed before TCZ (standard dose was 8 mg/kg/iv/4 weeks). After a mean±SD follow-up of 11.8±6.6 months most patients experienced clinical improvement, showing reduction of erythrocyte sedimentation rate from 43±36 mm/1st h to 5±4 mm/1st h at last visit. At TCZ onset, 25% of patients had fever and 19% polymyalgia rheumatica. These manifestations disappeared after 3 months of TCZ therapy. A corticosteroid sparing effect was also achieved (from 27.3±17.6 mg/day of prednisone at TCZ onset to 4.2±3.8 mg/day at last visit). TCZ had to be discontinued in a patient because of severe neutropenia. TCZ appears to be effective and relatively safe in patients with inflammatory aortitis refractory to corticosteroids or to other biologic immunosuppressive drugs.


Information domain approach to the investigation of cardio-vascular, cardio-pulmonary, and vasculo-pulmonary causal couplings.
The physiological mechanisms related to cardio-vascular (CV), cardio-pulmonary (CP), and vasculo-pulmonary (VP) regulation may be probed through multivariate time series analysis tools. This study applied an information domain approach for the evaluation of non-linear causality to the beat-to-beat variability series of heart period (t), systolic arterial pressure (s), and respiration (r) measured during tilt testing and paced breathing (PB) protocols. The approach quantifies the causal coupling from the series i to the series j (C(ij)) as the amount of information flowing from i to j. A measure of directionality is also obtained as the difference between two reciprocal causal couplings (D(i,j) = C(ij) - C(ji)). Significant causal coupling and directionality were detected respectively when the median of C(ij) over subjects was positive (C(ij) > 0), and when D(i,j) was statistically different from zero (D(i,j) > 0 or D(i,j) < 0). The method was applied on t, s, and r series measured in 15 healthy subjects (22-32 years, 8 males) in the supine (su) and upright (up) positions, and in further 15 subjects (21-29 years, 7 males) during spontaneous (sp) and paced (pa) breathing. In the control condition (su, sp), a significant causal coupling was observed for C(rs), C(rt), C(st), and C(ts), and significant directionality was present only from r to t (D(r,t) > 0). During head-up tilt (up, sp), C(rs) was preserved, C(rt) decreased to zero median, and C(st) and C(ts) increased significantly; directionality vanished between r and t (D(r,t) = 0) and raised from s to t (D(s,t) > 0). During PB (su, pa), C(rs) increased significantly, C(rt) and C(ts) were preserved, and C(st) decreased to zero median; directionality was preserved from r to t (D(r,t) > 0), and raised from r to s (D(r,s) > 0). These results suggest that the approach may reflect modifications of CV, CP, and VP mechanisms consequent to altered physiological conditions, such as the baroreflex engagement and the dampening of respiratory sinus arrhythmia induced by tilt, or the respiratory driving on arterial pressure induced by PB. Thus, it could be suggested as a tool for the non-invasive monitoring of CV and cardiorespiratory control systems in normal and impaired conditions.


Microscale modelling of dielectrophoresis assembly processes.
This work presents a microscale approach for simulating the dielectrophoresis assembly of polarizable particles under an external electric field. The model is shown to capture interesting dynamical and topological features, such as the formation of chains of particles and their incipient aggregation into hierarchical structures. A quantitative characterization in terms of the number and size of these structures is also discussed. This computational model could represent a viable numerical tool to study the mechanical properties of particle-based hierarchical materials and suggest new strategies for enhancing their design and manufacture. This article is part of the theme issue 'Progress in mesoscale methods for fluid dynamics simulation'.


[Seroprevalence of T. cruzi infection in 6- and 12- year-old school children from three Uruguayan endemic departments].
The last national survey on seroprevalence of T. cruzi human infection in Uruguay, showed a 3.4% in adults from endemic areas. Since 1983, antivectorial actions of the control program have been carried out continually. In consequence, household infestation by Triatoma infestan, the main vector of T. cruzi in Uruguay, decreased in all endemic areas and was completely eliminated in some of them. The objectives of the present work are to evaluate the new seroepidemiological situation. A representative sampling of rural and urban population was undertaken, to include six and twelve year-old school children from three departments: Artigas, Rivera and Tacuarembo. The whole sample included 4,722 school children, evaluated by the indirect immunofluorescence (IFI) test for Chagaś disease. The seroprevalence of T. cruzi infection in the six year-old group was 0.3% in Artigas, 0.6% in Rivera and 1.0% in Tacuarembo. The seropositive children with seropositive mothers support the possible congenital transmission.


[The restoration of colon continuity after the Hartmann surgery].
The operation of Duhamel for restoration of intestinal continuity after its obstructive resection for cancer of colon in 42 patients was applied. Postoperative complications had occurred in 16.7% patients, insufficiency of anastomotic sutures wasn't noted. Two (4.75%) patients with an acute cardiovascular insufficiency died.


Measurement Properties of the Suicidal Behaviour Questionnaire-Revised in Autistic Adults.
We explored the appropriateness and measurement properties of a suicidality assessment tool (SBQ-R) developed for the general population, in autistic adults-a high risk group for suicide. 188 autistic adults and 183 general population adults completed the tool online, and a sub-sample (n = 15) were interviewed while completing the tool. Multi-group factorial invariance analysis of the online survey data found evidence for metric non-invariance of the SBQ-R, particularly for items three (communication of suicidal intent) and four (likelihood of suicide attempt in the future). Cognitive interviews revealed that autistic adults did not interpret these items as intended by the tool designers. Results suggest autistic adults interpret key questions regarding suicide risk differently to the general population. Future research must adapt tools to better capture suicidality in autistic adults.


Association between YAP expression in neoplastic and non-neoplastic breast tissue with arsenic urinary levels.
The Hippo pathway regulates cell proliferation and apoptosis and it has been noted that loss of critical components of this pathway can lead to uncontrolled cell growth. Yes-associated protein (YAP) is an important component of this Hippo pathway because YAP is the nuclear effector of the Hippo tumor suppressor pathway and it is crucial for the response to oxidative stress induced by cellular process and by different xenobiotics, including arsenic. It has been proposed that YAP dysregulation can contribute to a malignant cellular phenotype acting as both a tumor suppressor and an oncogene. The aim of the study was to assess and compare the expression of YAP in neoplastic and non-neoplastic breast tissue of women chronically exposed to arsenic through drinking water. YAP expression was assessed by immunohistochemistry in 120 breast biopsies from women with breast cancer and from women with other non-neoplastic breast pathologies. Arsenic concentration was quantified in urine. The results disclosed a significant lower percentage of cytoplasm YAP expression in cases and that YAP high-intensity staining in the cytoplasm but not in the nucleus decreases the risk for breast cancer. In conclusion, our overall data suggest that YAP may act as a tumor suppressor protein because their reduced expression in cases, which can induce an environment favorable for inhibition of apoptosis and promoting cellular proliferation by increasing genetic instability of cells, which might contribute to the pathogenesis of cancer. Copyright © 2017 John Wiley & Sons, Ltd.


Meal duration as a measure of orofacial nociceptive responses in rodents.
A lengthening in meal duration can be used to measure an increase in orofacial mechanical hyperalgesia having similarities to the guarding behavior of humans with orofacial pain. To measure meal duration unrestrained rats are continuously kept in sound attenuated, computerized feeding modules for days to weeks to record feeding behavior. These sound-attenuated chambers are equipped with chow pellet dispensers. The dispenser has a pellet trough with a photobeam placed at the bottom of the trough and when a rodent removes a pellet from the feeder trough this beam is no longer blocked, signaling the computer to drop another pellet. The computer records the date and time when the pellets were taken from the trough and from this data the experimenter can calculate the meal parameters. When calculating meal parameters a meal was defined based on previous work and was set at 10 min (in other words when the animal does not eat for 10 min that would be the end of the animal's meal) also the minimum meal size was set at 3 pellets. The meal duration, meal number, food intake, meal size and inter-meal interval can then be calculated by the software for any time period that the operator desires. Of the feeding parameters that can be calculated meal duration has been shown to be a continuous noninvasive biological marker of orofacial nociception in male rats and mice and female rats. Meal duration measurements are quantitative, require no training or animal manipulation, require cortical participation, and do not compete with other experimentally induced behaviors. These factors distinguish this assay from other operant or reflex methods for recording orofacial nociception.


Biosynthesis of algal pheromones. A model study with the composite Senecio isatideus.
Several cyclic and alicyclic C11 hydrocarbons have been shown to act as gamete releasing and/or attracting pheromones during sexual reproduction of brown algae (Phaeophyceae). The same compounds are also found in the essential oils of various plants, of which the occurrence of the cycloheptadiene-pheromone ectocarpene in Senecio isatideus (Compositae) is noteworthy. Administration of [3H]dodeca-3,6,9-trienoic acid to cuttings of this plant leads to incorporation of radioactivity into ectocarpene. Double-bond-deuterated nona-3,6-dienoic acid is converted to fucoserratene, the pheromone of several Fucales, which is certainly not present among the hydrocarbons of Senecio. This proves that the pool of medium-chain, multiply unsaturated fatty acids includes precursors of all types of highly unsaturated hydrocarbons. Appropriately labelled (deuterium markers) fatty acid homologues were synthesized and applied to Senecio plantlets to unravel the mechanistic aspects. The results strongly suggest radical initiation of the pheromone biosynthesis by abstraction of a single hydrogen from a 1,4-pentadienyl segment of the fatty acid followed by oxidation to the corresponding cation. This causes fragmentation of the reactive intermediate into an olefine and carbon dioxide by neighbouring-group participation of the flanking double bonds. A tentative biosynthetic scheme is deduced from the experimental results which also sets the stereochemistry of the algal pheromones into a uniform mechanistic concept.


Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo.
The brain capillary endothelium, which makes up the blood-brain barrier (BBB) in vivo, expresses high concentrations of transferrin receptor, and recent studies show that an antitransferrin receptor monoclonal antibody may function as a BBB drug transport vector. The present report examines the pharmacokinetics of clearance of radiolabeled antitransferrin receptor monoclonal antibody from the bloodstream in rats in vivo, and also assesses the extent to which brain selectively extracts the antibody from the blood compared to other peripheral organs such as liver, kidney, myocardium, or lung. [125I]Mouse immunoglobulin G2a control antibody was cleared monoexponentially with a half-time of 9.8 +/- 2.3 h. The clearance of the [3H]OX-26 antitransferrin receptor antibody from blood was biexponential with half-times of 2.2 +/- 0.8 min (61 +/- 10% of clearance) and 3.9 +/- 0.2 h (39 +/- 4% of clearance). The OX-26 antibody was rapidly taken up by liver during the first 60 min after injection, but this uptake reached rapid saturation, and hepatic OX-26 content actually declined subsequent to the first hour after injection. In contrast, brain continuously extracted the OX-26 antibody from the bloodstream, and the brain volume of distribution of OX-26 reached a value 18-fold greater than the volume of distribution of the mouse immunoglobulin G2a at 5 h after injection. There was no specific uptake of the OX-26 by myocardium or lung, and minor uptake by kidney was observed that also reached saturation within the first 60 min after injection.(ABSTRACT TRUNCATED AT 250 WORDS)


Investigation of heat induced reactions between lipid oxidation products and amino acids in lipid rich model systems and hazelnuts.
This study aimed to investigate the contribution of lipid oxidation to non-enzymatic browning reactions in lipid rich model and actual food systems. Hazelnut oil and model reaction mixtures consisting of different amino acids were heated under certain conditions to determine possible lipid oxidation and non-enzymatic browning reaction products. In model systems, the Schiff base of 2,4-decadienal, its decarboxylated form, and reaction products formed after hydrolytic cleavage of the Schiff base or decarboxylated form were identified by high resolution mass spectrometry. No furosine was detected in hazelnuts after roasting at 160 °C while the concentration of free amino acids significantly decreased. 2,4-Decadienal reacted effectively with all amino acids studied through a Maillard type carbonyl-amine condensation pathway. (2E,4E)-Deca-2,4-dien-1-amine was identified as a typical reaction product in model systems and roasted hazelnuts. In lipid-rich foods like hazelnuts, lipid-derived carbonyls might be responsible for potential modifications of free and protein bound amino acids during heating.


Peptides extracted from edible mushroom: Lentinus squarrosulus induces apoptosis in human lung cancer cells.
Lentinus squarrosulus Mont. (Polyporaceae) is an interesting source of diverse bioactive compounds. This is the first study of the anticancer activity and underlying mechanism of peptides extracted from Lentinus squarrosuls. Peptides were isolated from the aqueous extract of L. squarrosulus by employing solid ammonium sulphate precipitation. They were further purified by ion-exchange chromatography on diethylaminoethanol (DEAE)-cellulose and gel filtration chromatography on Sephadex G25. Anticancer activity was investigated in human lung cancer H460, H292 and H23 cells cultured with 0-40 μg/mL of peptide extracts for 24 h. Cell viability and mode of cell death were evaluated by MTT and nuclear staining assay, respectively. Western blotting was used to investigate the alteration of apoptosis-regulating proteins in lung cancer cells treated with peptide extracts (0-20 μg/mL) for 24 h. The cytotoxicity of partially-purified peptide extracts from L. squarrosulus was indicated with IC50 of ∼26.84 ± 2.84, 2.80 ± 2.14 and 18.84 ± 0.30 μg/mL in lung cancer H460, H292 and H23 cells, respectively. The extracts at 20 μg/mL induced apoptosis through the reduction of anti-apoptotic Bcl-2 protein (∼0.5-fold reduction) and up-regulation of BAX (∼4.5-fold induction), a pro-apoptotic protein. Furthermore, L. squarrosulus peptide extracts (20 μg/mL) also decreased the cellular level of death receptor inhibitor c-FLIP (∼0.6-fold reduction). This study provides the novel anticancer activity and mechanism of L. squarrosulus peptide extracts, which encourage further investigation and development of the extracts for anticancer use.


The cultural competence of health care professionals: conceptual analysis using the results from a national pilot study of training and assessment.
The cultural competence of health professionals affects the satisfaction with, and outcomes of, patient care. Patient-centered cultural training was implemented with 76 trainees. Four months later, they were assessed using standardized patient scenarios and their performance compared to a control group. A questionnaire was used to evaluate the training. Assessment scores were analyzed using t tests to compare groups. Interrater reliability was calculated for individual scenarios. The cultural training received positive evaluations with many trainees indicating their intention to change future practice. Those who received cultural training gained higher scores upon assessment than those who had not. This difference was significant for three scenarios with nonclinical evaluators. Interrater reliability ranged from .913 to .427. The significant difference in performance between the groups supports the validity and educational impact of this approach. However, variable reliability highlights the difficulties with developing robust assessments in this area that are feasible within resource constraints.


Use of DNA estimation for growth assessment in normal and hypoplastic fetal lungs.
Total DNA was estimated in the lungs of 80 fetuses and newborn infants varying in gestation from 14 weeks to term. In fetuses of appropriate weight for gestational age total lung DNA increased at a constant rate from about 35 mg at 17 weeks' gestation to 480 mg at term. The lungs of immature fetuses were heavier and contained more DNA relative to body weight than did those of mature infants. Small-for-dates infants had lower lung DNA levels for gestation than infants with weights appropriate for gestational age, but there was no difference when lung DNA was corrected for body weight. Lung hypoplasia defined in terms of lung/body weight ratio was associated with low lung DNA content for gestation, even when corrected for body weight. The total lung DNA at 34-40 weeks' gestation in infants with lung hypoplasia associated with fetal anuria or urinary outflow obstruction was equivalent to that seen in normal fetuses at 20-22 weeks' gestation. We conclude that the early second trimester is a critical period for human fetal lung growth.


Damage to Arousal-Promoting Brainstem Neurons with Traumatic Brain Injury.
Coma and chronic sleepiness are common after traumatic brain injury (TBI). Here, we explored whether injury to arousal-promoting brainstem neurons occurs in patients with fatal TBI. Postmortem examination of 8 TBI patients and 10 controls. Compared to controls, TBI patients had 17% fewer serotonergic neurons in the dorsal raphe nucleus (effect size: 1.25), but the number of serotonergic neurons did not differ in the median raphe nucleus. TBI patients also had 29% fewer noradrenergic neurons in the locus coeruleus (effect size: 0.96). The number of cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) was similar in TBI patients and controls. TBI injures arousal-promoting neurons of the mesopontine tegmentum, but this injury is less severe than previously observed in hypothalamic arousal-promoting neurons. Most likely, posttraumatic arousal disturbances are not primarily caused by damage to these brainstem neurons, but arise from an aggregate of injuries, including damage to hypothalamic arousal nuclei and disruption of other arousal-related circuitries.


Chromosomal mosaicism in human preimplantation embryos: a systematic review.
Although chromosomal mosaicism in human preimplantation embryos has been described for almost two decades, its exact prevalence is still unknown. The prevalence of mosaicism is important in the context of preimplantation genetic screening in which the chromosomal status of an embryo is determined by the analysis of a single cell from that embryo. Here we report a systematic review and meta-analysis of studies on the chromosomal constitution of human preimplantation embryos. In 36 studies, out of 2117 citations that met our search criteria, data were provided extensively enough to allow classification of each analysed embryo with prespecified criteria for its chromosomal makeup. The main outcome of this classification was the prevalence of chromosomal mosaicism in human preimplantation embryos. A total of 815 embryos could be classified. Of these, 177 (22%) were diploid, 599 (73%) were mosaic, of which 480 (59% of the total number of embryos) were diploid-aneuploid mosaic and 119 (14% of the total number of embryos) were aneuploid mosaic, and 39 (5%) contained other numerical chromosomal abnormalities. The distribution of the embryos over these categories was associated with the developmental stage of the embryos, the method used for analysis and the number of chromosomes analysed. Diploid-aneuploid mosaicism is by far the most common chromosomal constitution in spare human preimplantation embryos after IVF. This undermines the reliable determination of the ploidy status of a cleavage-stage embryo based on the analysis of a single cell. Future research should determine the origin and developmental potential of mosaic embryos.


Mesenchymal Stem Cell-Seeded High-Density Collagen Gel for Annular Repair: 6-Week Results From In Vivo Sheep Models.
Our group has previously demonstrated in vivo annulus fibrosus repair in animal models using an acellular, riboflavin crosslinked, high-density collagen (HDC) gel. To assess if seeding allogenic mesenchymal stem cells (MSCs) into this gel yields improved histological and radiographic benefits in an in vivo sheep model of annular injury. Fifteen lumbar intervertebral discs (IVDs) were randomized into 4 groups: intact, injury only, injury + acellular gel treatment, or injury + MSC-seeded gel treatment. Sheep were sacrificed at 6 wk. Disc height index (DHI), Pfirrmann grade, nucleus pulposus area, and T2 relaxation time (T2-RT) were calculated for each IVD and standardized to healthy controls from the same sheep. Quantitative histological assessment was also performed using the Han scoring system. All treated IVDs retained gel plugs on gross assessment and there were no adverse perioperative complications. The MSC-seeded gel treatment group demonstrated statistically significant improvement over other experimental groups in DHI (P = .002), Pfirrmann grade (P < .001), and T2-RT (P = .015). There was a trend for greater Han scores in the MSC-seeded gel-treated discs compared with injury only and acellular gel-treated IVDs (P = .246). MSC-seeded HDC gel can be delivered into injured IVDs and maintained safely in live sheep to 6 wk. Compared with no treatment and acellular HDC gel, our data show that MSC-seeded HDC gel improves outcomes in DHI, Pfirrmann grade, and T2-RT. Histological analysis shows improved annulus fibrosus and nucleus pulposus reconstitution and organization over other experimental groups as well.