Influence of ketoanalogs supplementation on the progression in chronic kidney disease patients who had training on low-protein diet.
A low-protein diet (LPD) is a conservative treatment in patients with chronic kidney disease (CKD) to improve uremic symptoms and slow the progression of renal dysfunction. However, the deleterious effects of protein restriction on nutritional status have raised concern. We investigated whether ketoanalogs supplementation in CKD patients who had training on LPD retards the progression of CKD and maintains nutritional status. Data were collected retrospectively from 120 consecutive patients in the CKD stages III and IV. Firstly all patients were restricted to LPD alone for 6 months (LPD alone), and then ketoanalogs of essential amino acids (KA) were supplemented for 6 months. The adequate LPD had not achieved in both periods. The declining slopes of glomerular filtration rate (GFR) during the LPD + KA period were significantly lower than those during the LPD alone period. This improvement in GFR was apparent in both subjects with diabetics and non-diabetic patients. Mean serum total cholesterol levels decreased in LPD + KA compared with LPD alone period. However, serum albumin levels did not change. Responders showed a higher prevalence of diabetes and higher serum albumin levels during the LPD alone period. Multivariate analysis revealed that responsiveness to LPD + KA was independently related to diabetes (p = 0.006) and high serum albumin levels (p = 0.011) in the LPD alone period. KA supplementation on over LPD delayed the progression of CKD without deteriorating nutritional status, and initial serum albumin levels could be an independent factor.


10-year survival of a patient with metastatic prostate cancer: Case report and literature review.
Prostate cancer is the most common malignancy in men. The 5-year relative survival for all stages combined is 98.8%. Patients diagnosed with metastatic prostate cancer have median survival from 2 to 3 years. We describe a case of 64-year old man who clinically presented with inguinal lymphadenopathy. Because of elevated PSA levels biopsy of prostate was done and adenocarcinoma was diagnosed. Biopsy of inguinal lymph nodes confirmed the diagnosis of prostate cancer. Hormonal treatment was started and at the most recent follow-up, 10 years later, the patient is asymptomatic with no clinical signs of disseminated disease.


Evolution in a metapopulation with space-limited subpopulations.
A model for the dynamics of a metapopulation with space-limited subpopulations (Roughgarden & Iwasa, 1985) is extended to include genetic variation for life-history traits. The traits include those expressed by the sessile adults in the space-limited subpopulations and traits expressed by the dispersing larvae. Conditions for increase of a new allele at a single locus are derived using two formulations, one that omits, and one that includes, age-structure among the sessile adults. From both formulations a criterion indicating the general direction of evolutionary change is derived: a new allele enters the population if it increases the average productivity of larvae from the subpopulations relative to the larval mortality rate, where the average is computed by weighting the productivity from each subpopulation by the amount of unoccupied space in it. This criterion may offer a start towards a theory for the evolution of life histories appropriate to the population structure of sessile marine invertebrates with pelagic larvae. In particular, the basal area of a sessile adult in a population with space-limited recruitment is a selectively neutral character.


Differential expression of systemic inflammatory mediators in amputees with chronic residual limb pain.
Chronic postsurgical pain impacts most amputees, with more than half experiencing neuralgic residual limb pain. The transition from normal acute postamputation pain to chronic residual limb pain likely involves both peripheral and central inflammatory mechanisms. As part of the Veterans Integrated Pain Evaluation Research study, we investigated links between systemic inflammatory mediator levels and chronic residual limb pain. Subjects included 36 recent active duty military traumatic amputees with chronic residual limb pain and 40 without clinically significant pain. Blood samples were obtained and plasma concentrations of an array of inflammatory mediators were analyzed. Residual limb pain intensity and pain catastrophizing were assessed to examine associations with inflammatory mediators. Pro-inflammatory mediators including tumor necrosis factor (TNF)-α, TNF-β, interleukin (IL)-8, ICAM-1, Tie2, CRP, and SAA were elevated in patients with chronic residual limb pain. Across all patients, residual limb pain intensity was associated positively with levels of several proinflammatory mediators (IL-8, TNF-α, IL-12, TNF-β, PIGF, Tie2, SAA, and ICAM-1), and inversely with concentrations of the anti-inflammatory mediator IL-13, as well as IL-2 and Eotaxin-3. Pain catastrophizing correlated positively with IL-8, IL-12, TNF-β, PIGF, and ICAM-1, and inversely with IL-13. Significant associations between catastrophizing and residual limb pain intensity were partially mediated by TNF-α, TNF- β, SAA, and ICAM-1 levels. Results suggest that chronic postamputation residual limb pain is associated with excessive inflammatory response to injury or to inadequate resolution of the postinjury inflammatory state. Impact of pain catastrophizing on residual limb pain may be because of part to common underlying inflammatory mechanisms.


Specific inhibitor of MEK-mediated cross-talk between ERK and p38 MAPK during differentiation of human osteosarcoma cells.
Osteosarcoma is the most common primary malignant bone tumor, accounting for approximately 20% of all primary sarcomas in bone. Although treatment modalities have been improved over the past decades, it is still a tumor with a high mortality rate in children and young adults. Based on histological considerations, osteosarcoma arises from impaired differentiation of these immature cells into more mature types and that correction of this impairment may reduce malignancy and increase the efficiency of chemotherapy. The purpose of this study was to determine the effect of specific inhibitors of MAPK extracellular signaling-regulated kinase (ERK) kinase (MEK) and p38 on the differentiation of human osteosarcoma cell line SaOS-2 cells. We found that PD98059, a specific inhibitor of MEK, inhibited the serum-stimulated proliferation of SaOS-2 cells; whereas SB203580, a specific inhibitor of p38 MAPK, had little effect on it. SB203580 suppressed ALPase activity, gene expression of type I collagen, and expression of ALP and BMP-2 mRNAs; whereas PD98059 upregulated them dose dependently. In addition, immunoblot and immunostaining analysis revealed that phosphorylation of ERK was increased by treatment with SB203580; whereas PD98059 increased the phosphorylation of p38, which implies a seesaw-like balance between ERK and p38 phosphorylation. We suggest that osteosarcoma cell differentiation is regulated by the balance between the activities of the ERK and p38 pathways and that the MEK/ERK pathway negatively regulates osteosarcoma cell differentiation, whereas the p38 pathway does so positively. MEK inhibitor may thus be a good candidate for altering the expression of the osteosarcoma malignant phenotype.


Lack of IL-12 signaling in human allergen-specific Th2 cells.
IL-12 is a powerful skewer of CD4+ T cell responses toward the Th1 phenotype by inducing IFN-gamma production in naive Th cells. In the present study we addressed the question of whether IL-12 can reverse established Th2 responses into Th1/Th0 responses by inducing IFN-gamma production in memory Th2 cells. To this aim, allergen-specific CD4+ T cell clones (TCC) were generated from the peripheral blood of three atopic patients, and their cytokine profiles were analyzed. The majority of these TCC exhibited a strongly polarized Th2 cytokine profile, and the production of IFN-gamma could not be induced by exogenous IL-12. Only those TCC with low IFN-gamma levels in the absence of IL-12 responded to IL-12 by additional enhancement of IFN-gamma production. The IL-12 nonresponsiveness of the Th2 clones was further evident by the total lack of IL-12-induced phosphorylation of STAT4 (signal transducer and activator of transcription-4), a transcription factor that is typically involved in IL-12 signaling. Consequently, IL-12 also failed to induce the DNA-binding activity of STAT4-containing complexes in the nuclei of these Th2 clones. All TCC expressed equal levels of the low-affinity IL-12R beta1 subunit. Our results indicate that human allergen-specific Th cells with strongly polarized Th2 cytokine profiles do not respond to IL-12 and, therefore, cannot be induced to produce IFN-gamma. The apparent high frequency of IL-12-nonresponsive Th cells within the allergen-specific populations in atopic patients predicts a limited skewing potential of IL-12 in the case of established Th2 responses, but only affecting newly recruited naive Th cells.


Discordance between lactic acidemia and hemodynamics in patients with advanced heart failure.
Elevated lactic acid (LA) levels carry a poor prognosis in patients with shock. Data are lacking on the significance of LA levels in patients with acute decompensated heart failure (ADHF). This study assessed the relationship between LA levels, hemodynamics and clinical outcomes. This was a retrospective analysis of registry data of 100 advanced heart failure patients presenting for right heart catheterization (RHC) for concern of ADHF. LA levels (normal ≤2.1 mmol/L) were obtained prior to RHC; no significant changes in therapy were made between LA collection and RHC. Median age was 58 (47.3, 64.8) years; 57% were receiving inotropes prior to RHC. Median pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) were 28 (21, 35) mmHg and 2.0 (1.7, 2.5) L/min/m2 , respectively. Eighty patients had normal LA prior to RHC. There was no correlation between LA levels and PCWP (R = 0.09, p = .38); 63% of the normal LA group had a PCWP >24 mmHg. There was a moderate inverse correlation between LA and CI (R = - 0.40; p < .001); 58% of the normal LA group had a CI <2.2 L/min/m2 . Thirty-day survival free of death/hospice, inotrope dependence, progression to heart transplant/left-ventricular assist device implant was comparable between the normal and elevated LA groups (28% vs. 20%; p = .17). In patients presenting with ADHF, normal LA levels do not exclude the presence of depressed CI (a hemodynamic criteria for cardiogenic shock) and may not offer accurate risk stratification. Invasive hemodynamics should not be delayed based on normal LA levels alone.


A progress report on electronic health records in U.S. hospitals.
Given the substantial federal financial incentives soon to be available to providers who make "meaningful use" of electronic health records, tracking the progress of this health care technology conversion is a policy priority. Using a recent survey of U.S. hospitals, we found that the share of hospitals that had adopted either basic or comprehensive electronic records has risen modestly, from 8.7 percent in 2008 to 11.9 percent in 2009. Small, public, and rural hospitals were less likely to embrace electronic records than their larger, private, and urban counterparts. Only 2 percent of U.S. hospitals reported having electronic health records that would allow them to meet the federal government's "meaningful use" criteria. These findings underscore the fact that the transition to a digital health care system is likely to be a long one.


In situ EPR investigation of the addition of persistent benzyl radicals to acrylates on ZSM-5 zeolites. Direct spectroscopic detection of the initial steps in a supramolecular photopolymerization.
Photolysis of dibenzyl ketone derivatives adsorbed on ZSM-5 zeolites produces persistent benzyl radicals (initiator radicals), which add to methyl acrylates (monomers) to generate persistent adduct radicals. Both initiator and adduct radicals are readily observable by conventional steady-state EPR spectroscopy at room temperature and are persistent for time periods ranging from seconds to many days. The rate of the formation and the amount of the adduct persistent radical formed depends on the structure of the initiator radical (benzyl radical derivative) and the structure of the monomer (acrylate derivative). The lifetimes of the initiator and adduct radicals depend on the supramolecular structure of the radical@zeolite complex and the diffusion and reaction dynamics of the radicals in the complex. The most intense signal and highest addition rate to methyl acrylate were observed for the smallest initiator radical, the benzyl radical, because of its high mobility and relatively rapid diffusion within the internal zeolite surface. With increasing length of an alkyl chain (methyl, ethyl, and pentyl) on either the initiator (alpha position of the radical) or monomer (alkyl group of acrylate ester), the rate of radical addition to the monomer decreased, a result that is consistent with the decreased mobility and diffusion of the initiator radical or monomer. Deuterium isotope experiments and variation of the methyl acrylate concentration demonstrated that the initial adduct radical from methyl acrylate adds to another methyl acrylate to generate a secondary adduct radical, which, in turn, can continue to propagate to form a polymer that is cross-linked to the zeolite crystals. The results demonstrate that EPR can be a powerful tool for the direct in situ analysis of supramolecular photochemistry involving radicals rendered persistent by supramolecular steric effects. The latter eliminate the need for sophisticated flash photolysis equipment to investigate the structure and dynamics of reactive radicals and require only the use of simpler steady-state lamps.


Validation of plasma fibrinogen as a marker of carotid atherosclerosis in subjects free of clinical cardiovascular disease.
Fibrinogen has been found to be an independent risk factor for cardiovascular disease. The aim of this study was to validate the measurement of plasma fibrinogen as a marker of subclinical atherosclerosis in a series of asymptomatic subjects (n=519, median age 55.5 years, 80% men). All individuals had a complete clinical examination, lipid profile (cholesterol and its high and low density lipoprotein fractions and triglycerides), global vascular risk assessment (PROCAM), and B-mode ultrasonography of the carotid arteries to determine the intima-media thickness (IMT) and the presence of atheroma plaques. C-reactive protein (CRP), and von Willebrand factor (vWF) were also measured in all subjects as markers of inflammation/endothelial damage. In the univariate model, a positive relationship was found between plasma fibrinogen concentration and carotid IMT (p<0.001). Fibrinogen concentration also correlated positively with age (p<0.001), systolic blood pressure (p<0.001), smoking (p<0.05), diabetes (p<0.05), PROCAM (p<0.001), CRP and vWF (p<0.001). In the multivariate analysis, the association of fibrinogen with carotid IMT remained significant (p=0.008) after adjustment for all parameters analyzed. In a population sample of adults without clinically overt atherosclerotic disease, elevated fibrinogen levels was related to carotid IMT independently of a wide range of important confounding variables. Plasma fibrinogen may represent a systemic marker of carotid atherosclerosis.


MRI-based intelligence quotient (IQ) estimation with sparse learning.
In this paper, we propose a novel framework for IQ estimation using Magnetic Resonance Imaging (MRI) data. In particular, we devise a new feature selection method based on an extended dirty model for jointly considering both element-wise sparsity and group-wise sparsity. Meanwhile, due to the absence of large dataset with consistent scanning protocols for the IQ estimation, we integrate multiple datasets scanned from different sites with different scanning parameters and protocols. In this way, there is large variability in these different datasets. To address this issue, we design a two-step procedure for 1) first identifying the possible scanning site for each testing subject and 2) then estimating the testing subject's IQ by using a specific estimator designed for that scanning site. We perform two experiments to test the performance of our method by using the MRI data collected from 164 typically developing children between 6 and 15 years old. In the first experiment, we use a multi-kernel Support Vector Regression (SVR) for estimating IQ values, and obtain an average correlation coefficient of 0.718 and also an average root mean square error of 8.695 between the true IQs and the estimated ones. In the second experiment, we use a single-kernel SVR for IQ estimation, and achieve an average correlation coefficient of 0.684 and an average root mean square error of 9.166. All these results show the effectiveness of using imaging data for IQ prediction, which is rarely done in the field according to our knowledge.


Triacylglycerol in the human erythrocyte: quantification and fatty acyl turnover in normal subjects and chronic alcoholics.
1. Triacylglycerol in erythrocytes from normal human subjects was estimated to average 2.7 +/- 0.7 nmol/10(10) cells, equivalent to 0.07% of total lipids or 0.3% of neutral lipids. 2. The specific activity of triacylglycerol labelling attained by incubating intact erythrocytes with [3H]oleic acid was 10 nmol/mumol, a value 20-fold higher than that of the highest labelled phospholipid, sphingomyelin; as isolated by ultracentrifugation over a density gradient, the youngest erythrocytes exhibited a labelling rate 10-fold higher than that of older cells. 3. The triacylglycerol content was not modified in erythrocytes from chronic alcoholics, whereas the mean rate of triacylglycerol labelling was 31% (P less than 0.05) higher than that of control subjects, and did not normalize 4 weeks after alcohol withdrawal. 4. These results indicate that triacylglycerol, although a quantitatively minor component, is one of the most active metabolites in the lipid matrix of the human erythrocyte membrane and appears to be implicated in the membrane response to antagonistic agents.


Is There a Relationship between Fish Cannibalism and Latitude or Species Richness?
Cannibalism has been commonly observed in fish from northern and alpine regions and less frequently reported for subtropical and tropical fish in more diverse communities. Assuming all else being equal, cannibalism should be more common in communities with lower species richness because the probability of encountering conspecific versus heterospecific prey would be higher. A global dataset was compiled to determine if cannibalism occurrence is associated with species richness and latitude. Cannibalism occurrence, local species richness and latitude were recorded for 4,100 populations of 2,314 teleost fish species. Relationships between cannibalism, species richness and latitude were evaluated using generalized linear mixed models. Species richness was an important predictor of cannibalism, with occurrences more frequently reported for assemblages containing fewer species. Cannibalism was positively related with latitude for both marine and freshwater ecosystems in the Northern Hemisphere, but not in the Southern Hemisphere. The regression slope for the relationship was steeper for freshwater than marine fishes. In general, cannibalism is more frequent in communities with lower species richness, and the relationship between cannibalism and latitude is stronger in the Northern Hemisphere. In the Southern Hemisphere, weaker latitudinal gradients of fish species richness may account for the weak relationship between cannibalism and latitude. Cannibalism may be more common in freshwater than marine systems because freshwater habitats tend to be smaller and more closed to dispersal. Cannibalism should have greatest potential to influence fish population dynamics in freshwater systems at high northern latitudes.


Leukocyte ionized calcium and sodium content and blood pressure in humans.
The relationship between leukocyte ionized calcium concentration, sodium content, and blood pressure was studied in normotensive subjects with (n = 17) and without (n = 21) a family history of hypertension and in untreated patients with essential hypertension (n = 22). There was a highly significant correlation between intracellular ionized calcium and mean supine blood pressure (measured on the same occasion) in normal subjects with no family history of hypertension (r = +0.73, p less than 0.01). This relationship was lost in normal subjects with a family history of hypertension, and in hypertensive patients there was a nonsignificant negative correlation between intracellular ionized calcium and blood pressure (r = +0.08 and -0.31, respectively). Intracellular ionized calcium was similar in the normotensive groups (both, 126 +/- 7 nmol/L) and slightly but nonsignificantly elevated in hypertensive patients (143 +/- 10 nmol/L; p = 0.09). There was no correlation between intracellular ionized calcium and sodium content in any group (r less than 0.1). These results indicate that while leukocyte ionized calcium in normotensive subjects with no family history of hypertension may reflect smooth muscle contractility resulting in the positive correlation between leukocyte ionized calcium and blood pressure, this relationship is lost in hypertensive patients and subjects predisposed to hypertension. This may be due to an altered relationship between leukocyte and smooth muscle calcium handling in these subjects or to non-calcium-mediated influences on blood pressure.


Diagnostic Accuracy of Follow-Up FDG PET or PET/CT in Patients With Head and Neck Cancer After Definitive Treatment: A Systematic Review and Meta-Analysis.
The purpose of this study was to assess the diagnostic performance of FDG PET or PET/CT for detection of local, regional, and distant recurrences in the follow-up of patients with head and neck cancer who underwent definitive treatment. A systematic search was performed in MEDLINE and Cochrane Library (updated September 2014) to identify relevant published studies. Studies investigating the accuracy of FDG PET/CT that were performed at least 4 months after therapy were included. Two authors independently screened all retrieved articles, selected studies that met the inclusion criteria, and extracted the data. Histopathologic confirmation or clinical follow-up of at least 6 month (or both) was considered as the reference standard. Twenty-three studies constituting a total of 2247 FDG PET/CT examinations met our inclusion criteria. The pooled sensitivity and specificity of follow-up PET/CT for detection of recurrence were 0.92 (95% CI, 0.90-0.94), and 0.87 (95% CI, 0.82-0.91), respectively. The pooled sensitivity and specificity of scans performed 4-12 months after treatment were 0.95 (95% CI, 0.91-0.97) and 0.78 (95% CI, 0.70-0.84), respectively. Similar estimates for scans performed at or more than 12 months after treatment were 0.92 (95% CI, 0.85-0.96) and 0.91 (95% CI, 0.78-0.96), respectively. The overall accuracy of FDG PET/CT in detecting recurrence is higher in patients without suspicion of recurrence before the scan compared with the patients with suspected recurrence. The high diagnostic performance of FDG PET/CT in detecting recurrence in curatively treated patients with head and neck cancer supports its use in clinical practice for patient follow-up. Further studies are needed to evaluate the prognostic utility of PET/CT in the follow-up of head and neck cancer.


Acute and chronic effects of cigarette smoking on arterial stiffness.
Pulse wave velocity (PWV) is an indicator of arterial stiffness, especially in the aorta, and a marker for vascular damage. Smoking is reported to increase arterial stiffness. We examined the acute and chronic effects of smoking on arterial stiffness by measuring brachial--ankle PWV (baPWV) using an oscillometric method (VP 1000, Colin Co., Komaki, Japan). All healthy male subjects (chronic smokers, n=40, 30.3 years old vs non-smokers, n=40, 28.3 years old) smoked two cigarettes (nicotine 1.5 mg) within 10 min and measured blood pressure (BP), heart rate and baPWV at baseline, 5, 15, 30, 45 and 60 min and compared with controls (n=20, 29.3 years old). Systolic BP was higher in chronic smokers than non-smokers or controls. Smoking increased the systolic and diastolic BP and heart rate significantly at 5 min in both chronic smokers and non-smokers as compared with baseline levels or controls (respectively, p<0.001) and returned to baseline level at 15 min. Pulse pressure did not increase significantly. baPWV increased significantly in both chronic smokers and non-smokers at 5 min (12.1--17.3 m/s vs 11.1--12.7 m/sec, respectively) and remained higher for 30 min compared with controls (p<0.001). Smoking increased baPWV to a greater extent in chronic smokers than in non-smokers (p<0.01). Acutely, cigarette smoking increased BP, heart rate and baPWV in chronic smokers and non-smokers. These effects were more prominent in chronic smokers than in non-smokers. These findings suggest that cigarette smoking have deleterious effects on cardiovascular system by stiffening arteries.


Carrier-mediated uptake of the endogenous cannabinoid anandamide in RBL-2H3 cells.
Anandamide (N-arachidonylethanolamide) is an endogenous cannabinoid that mimics the pharmacologic effects of Delta(9)-tetrahydrocannabinol, the major bioactive substance in marijuana. Anandamide appears to be synthesized, released, and inactivated by mechanisms similar to those for other neurotransmitters. Of interest to the present studies are reports that anandamide undergoes carrier-mediated uptake into neuronal or glial cells after release, followed by rapid intracellular degradation by the intracellular fatty acid amidohydrolase. In addition to effects in the brain, anandamide has multiple effects in the periphery, particularly on cells of the immune system that express both a peripheral cannabinoid receptor and amidohydrolase enzyme. We have performed a detailed characterization of anandamide uptake in the cognate mast cell line RBL-2H3 to test the hypothesis that the uptake system in peripheral cells is also carrier-mediated and functionally similar to that observed in the central nervous system. RBL-2H3 cells exhibited robust, saturable transport of [(3)H]anandamide that was both time- and temperature-sensitive. This transport activity was not dependent on extracellular ion gradients for uptake and was inhibited selectively by other fatty acid-derived molecules, anandamide congeners, and the psychoactive cannabinoids such as Delta(9)-tetrahydrocannabinol. We conclude that anandamide transport in the RBL-2H3 cells is carrier-mediated, and uptake in peripheral cells is functionally and pharmacologically identical with that observed in neurons and astrocytes.


Risk of upper gastrointestinal complications in a cohort of users of nimesulide and other nonsteroidal anti-inflammatory drugs in Friuli Venezia Giulia, Italy.
Information on the risk of upper gastrointestinal complications (UGIC) in users of nimesulide, the most used nonsteroidal anti-inflammatory drug (NSAID) in Italy, is scarce. In the context of the European regulatory review on nimesulide, we estimated and compared the risk associated with nimesulide and other individual NSAIDs with the risk in nonusers. We used 2001-2008 data from regional health databases in Friuli Venezia Giulia (FVG), Italy, to conduct a cohort and nested case-control study of users of NSAIDs. Cases were identified by specific and nonspecific hospital discharge diagnoses in primary and secondary position and validated through hospital records. Ten controls per case were selected using density-based sampling from the cohort. Conditional logistic regression was used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). The cohort included 588,827 NSAIDs users and 3031 UGIC cases. Nonspecific codes contributed to 23% of cases and secondary codes to 5%. Among current users, IR per 1000 person-years decreased from 4.45 cases in 2001 to 2.21 cases in 2008. The RR (95%CI) for current use of NSAIDs was 3.28 (2.86, 3.76). RR was <2 for rofecoxib, celecoxib, and nimesulide; 2 to <5 for naproxen, ibuprofen, diclofenac, etoricoxib, and meloxicam; and ≥ 5 for ketoprofen, piroxicam, and ketorolac. IRs of UGIC in FVG decreased about 50% between 2001 and 2008. Nimesulide was in the low-medium range of RR. A complete ascertainment of UGIC cases in databases may require validation of nonspecific codes, secondary codes, and additional codes such as peritonitis and acute posthemorrhagic anemia.


Effect of buthionine sulfoximine on toxicity of verapamil and doxorubicin to multidrug resistant cells and to mice.
Resistance of tumor cells to chemotherapeutic drugs may be due to several mechanisms within a single cell line. Resistance to doxorubicin in the human multidrug resistant breast cancer cell line, MCF-7 AdrR, has been attributed to increased glutathione (GSH) S-transferase and GSH peroxidase activity, as well as to increased expression of the mdr1 gene product, P-glycoprotein. We studied the potentiation of doxorubicin activity in these cells by buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, and by verapamil and trans-flupenthixol, agents which interact with P-glycoprotein. Treatment with BSO enhanced the effect of doxorubicin by 1.5-fold, while verapamil or transflupenthixol caused a greater reversal of drug resistance. The combination of BSO with trans-flupenthixol produced no further potentiation of doxorubicin activity. However, the combination of BSO with verapamil and doxorubicin caused up to a 10-fold increment in antiproliferative effect. To explore the mechanism by which BSO interacted with this drug combination, we determined whether or not BSO might potentiate the effects of verapamil. These studies demonstrated that the effects of BSO were predominantly due to an increase in verapamil toxicity rather than to doxorubicin toxicity. In addition, when mice received concentrations of BSO in their drinking water sufficient to deplete GSH and were treated with verapamil, the calcium channel blocker was lethal to 9 of 12 mice receiving BSO compared to 1 of 10 control animals receiving verapamil alone. These studies demonstrate that BSO does not markedly increase the pharmacological effect of doxorubicin against MCF-7 AdrR cells and suggest that alterations in GSH and related enzymes are not a major factor in drug resistance in this cell line. Furthermore, BSO can increase the toxicity of verapamil, a finding which may have important implications for clinical trials.


Infection of colonized cat fleas, Ctenocephalides felis (Bouché), with a rickettsia-like microorganism.
We report the ultrastructure of a rickettsia-like microorganism in a colonized population of the cat flea Ctenocephalides felis (Bouché). The microorganism occurs principally in the cytoplasm of midgut cells, but similar microorganisms were detected in the tracheal matrix, muscle, hypodermis, ovaries, and the epithelial sheath of the testes. The microorganism has a well-defined cell membrane consistent with rickettsia and measures 0.25-0.45 microns in diameter with lengths up to 1.5 microns. It was observed repeatedly in fleas of 1 laboratory colony, including newly emerged non-bloodfed specimens, but not in specimens from several other sources.


Slanted, asymmetric microfluidic lattices as size-selective sieves for continuous particle/cell sorting.
Hydrodynamic microfluidic platforms have been proven to be useful and versatile for precisely sorting particles/cells based on their physicochemical properties. In this study, we demonstrate that a simple lattice-shaped microfluidic pattern can work as a virtual sieve for size-dependent continuous particle sorting. The lattice is composed of two types of microchannels ("main channels" and "separation channels"). These channels cross each other in a perpendicular fashion, and are slanted against the macroscopic flow direction. The difference in the densities of these channels generates an asymmetric flow distribution at each intersection. Smaller particles flow along the streamline, whereas larger particles are filtered and gradually separated from the stream, resulting in continuous particle sorting. We successfully sorted microparticles based on size with high accuracy, and clearly showed that geometric parameters, including the channel density and the slant angle, critically affect the sorting behaviors of particles. Leukocyte sorting and monocyte purification directly from diluted blood samples have been demonstrated as biomedical applications. The presented system for particle/cell sorting would become a simple but versatile unit operation in microfluidic apparatus for chemical/biological experiments and manipulations.


Biomechanical correlation at the knee joint between static lunge and single-leg drop landing - a comparative study among three different toe directions.
Toe direction is a critical factor affecting knee biomechanics during various movements including closed kinetic chain (CKC) exercise and landing tasks. Physiotherapists always concentrate on the control of toe direction during CKC exercise as a first step for athletes, as it is believed that correction of toe direction during CKC exercise is important to maintain the appropriate toe position even in high demanding activities such as landing tasks. The purpose of the present study was to investigate knee biomechanics during CKC exercise as well as landing tasks with three different toe directions, and clarify whether biomechanical parameters during CKC exercise would be related to those during landing tasks. A total of 23 male recreational level athletes (mean age = 20.0 ± 1.1 yrs) participated. Tegner activity score were 7 for all male subjects. First, the subjects performed weight-bearing static lunge tests (SL) under three different toe directions, including 0 degrees (Toe-neutral: TN), 20 degrees (Toe-In: TI), and - 20 degrees (Toe-out: TO). Thereafter, SLDL was done under three different toe directions. Three-dimensional knee kinematics and kinetics at 60 degrees of knee flexion were calculated. As a statistical analysis, Pearson's correlation coefficient was used to evaluate the relationship between SL and SLDL. The statistical significance level wasset at P=0.05. Knee abduction angle showed significant correlation between SL and SLDL in all three different directions (TI: r=0.631, p<0.001, TN: r=0.678, p<0.001, TO: r=0.572, p<0.001). In terms of knee internal rotation, strong correlation was also found (TI: r=0.846, p<0.001, TN: r=0.791, p<0.001, TO: r=0.749, p<0.001). In addition, external knee abduction moment presented significant correlation in all three different directions (TI: r=0.574, p<0.001, TN: r=0.499, p<0.01, TO: r=0.469, p<0.01). From the present study, significant correlation between SL and SLDL was found in knee abduction angle, knee internal rotation, and external knee abduction moment under all three different directions including TI, TN, and TO. Physiotherapist should take care of toe direction and reform the movements especially for athletes who present malalignment of the knee joint during SL with TI or TO to prevent ACL injury in landing tasks.


Quantum dots in photocatalytic applications: efficiently enhancing visible light photocatalytic activity by integrating CdO quantum dots as sensitizers.
The amalgamation of a wide optical band gap photocatalyst with visible-light-active CdO quantum dots (QDs) as sensitizers is one of the most efficient ways to improve photocatalytic performance under visible light irradiation. The photocatalytic performance of cadmium benzoate ((Cd(C7H5O2)2)3(CH3CN)1) is comprehensively investigated. The estimated optical band gap of cadmium benzoate is 2.64 eV and the EPc and EPv are about -0.09 V (vs. NHE) and +2.55 V (vs. NHE), respectively, which implies that cadmium benzoate possesses a high negative reduction potential of excited electrons due to its higher conduction band position, and hence, the locations of the conduction band minimum and the valence band maximum meet the redox capacity. Thus, this composite photocatalyst exhibits superior activity in visible-light-driven photocatalytic H2 evolution. We found that introducing the QDs enhance the photocatalytic performance towards the visible light region. The electronic band structure shows high k-dispersion bands around the Fermi level, which implies low effective masses, and hence, the high mobility carriers favor the enhancement of the charge transfer process. The mobility of the photogenerated carriers significantly influences the photocatalytic efficiency and the higher photogenerated carriers' mobility enhances the photocatalytic performance. Moreover, the result shows a great effective mass difference between electrons (e-) and holes (h+), which can facilitate the e- and h+ migration and separation, and finally improve the photocatalytic performance. The large mobility difference is useful for the separation of e- and h+, the reduction of the e- and h+ recombination rate, and the improvement of the photocatalytic activity. Thus, cadmium benzoate exhibits rapid generation of e--h+ pairs with photoexcitation and a high negative reduction potential of excited electrons due to its higher CB position. Based on these results one can conclude that cadmium benzoate satisfied all requirements to be an efficient photocatalyst. This will greatly improve the search efficiency and greatly help experimentalists in saving resources in the exploration of new photocatalysts with good photocatalytic performance.


A decision aid for diagnosis of liver lesions on MRI.
Abdominal magnetic resonance imaging (MRI) plays an important role in the evaluation of liver abnormalities. The interpretation of MR images requires expert training in a rapidly changing field. DAFODILL (Decision Aid for Diagnosing Liver Lesions) is a decision-support tool designed to aid radiologists in the diagnosis of hepatic lesions seen on MRI. DAFODILL uses a knowledge base of MRI findings and a belief-network inference engine to generate probabilistic differential diagnoses of the most commonly encountered hepatic lesions. DAFODILL performs limited image processing to identify clinically relevant features, which are presented to the user for confirmation before they are used by the network. Preliminary evaluation of an initial version of the system suggests that DAFODILL may be a useful tool for radiology residents and nonexpert radiologists in interpreting MR images of the liver.


Reduction of hematopoietic stem cells and adaptive increase in cell cycle rate in rickets.
The close but complex physiological interactions between osteogenesis and hematopoiesis during differentiation, development, and function are unclear. As vitamin D has a major role in bone metabolism and function, we have investigated the effects of vitamin D deficiency on bone marrow cellular kinetics. Using rats in vitamin D-deficient status in utero as well as in postfetal life, we have investigated changes in hematopoiesis. Total cellularity, colony-forming unit (CFU) content, and the cycled rate were determined from the axial compartment of the femoral marrow. A marked reduction in the CFU content and a corresponding increase in the cycle fraction began at 30 days of age and stabilized by 45 days of age at 4.2 +/- 0.4 CFUs per 1 X 10(5) nucleated cells in the vitamin D-deficient animals as compared with 9.4 +/- 1.6 in the control group. During the same period of time the CFU generation time decreased from 61 +/- 5 h in the normal animals to 24 +/- 6 h in the vitamin D-deficient animals. Administration of either 1,25-dihydroxyvitamin D [1,25-(OH)2D3] or 24,25-(OH)2D3 at 45 days of age on a daily basis for 7-14 days failed to correct the defect although the serum calcium and phosphate were corrected. The data indicate that factors influencing the development of bones may affect bone marrow cells as well. Vitamin D metabolites may be needed for normal development and function of marrow-colony-forming cells in utero.


Common and mutation specific phenotypes of KRAS and BRAF mutations in colorectal cancer cells revealed by integrative -omics analysis.
Genes in the Ras pathway have somatic mutations in at least 60 % of colorectal cancers. Despite activating the same pathway, the BRAF V600E mutation and the prevalent mutations in codon 12 and 13 of KRAS have all been linked to different clinical outcomes, but the molecular mechanisms behind these differences largely remain to be clarified. To characterize the similarities and differences between common activating KRAS mutations and between KRAS and BRAF mutations, we used genome editing to engineer KRAS G12C/D/V and G13D mutations in colorectal cancer cells that had their mutant BRAF V600E allele removed and subjected them to transcriptome sequencing, global proteomics and metabolomics analyses. By intersecting differentially expressed genes, proteins and metabolites, we uncovered (i) two-fold more regulated genes and proteins when comparing KRAS to BRAF mutant cells to those lacking Ras pathway mutation, (ii) five differentially expressed proteins in KRAS mutants compared to cells lacking Ras pathway mutation (IFI16, S100A10, CD44, GLRX and AHNAK2) and 6 (CRABP2, FLNA, NXN, LCP1, S100A10 and S100A2) compared to BRAF mutant cells, (iii) 19 proteins expressed differentially in a KRAS mutation specific manner versus BRAF V600E cells, (iv) regulation of the Integrin Linked Kinase pathway by KRAS but not BRAF mutation, (v) regulation of amino acid metabolism, particularly of the tyrosine, histidine, arginine and proline pathways, the urea cycle and purine metabolism by Ras pathway mutations, (vi) increased free carnitine in KRAS and BRAF mutant RKO cells. This comprehensive integrative -omics analysis confirms known and adds novel genes, proteins and metabolic pathways regulated by mutant KRAS and BRAF signaling in colorectal cancer. The results from the new model systems presented here can inform future development of diagnostic and therapeutic approaches targeting tumors with KRAS and BRAF mutations.


Structural features resulting in convulsive activity of carbapenem compounds: effect of C-2 side chain.
The neurotoxicity of meropenem was much lower than that of both imipenem and panipenem after intraventricular administration to mice. To clarify the major structural features responsible for the induction of convulsions by carbapenem antibiotics, the structure-activity relationship on convulsant activity was investigated in N-acetyl-2-pyrroline and cyclopentene derivatives which correspond to the 5-membered ring containing the C-2 side chain of carbapenem antibiotics. Among these derivatives, compounds with strong basicity in the side chain showed convulsant activity similar to that of the parent carbapenem compounds. In addition to the strength of the basicity of the amino group, the distance from the carboxyl to the amino group and steric crowding around the amino group also appeared to play an important role in the induction of convulsions. The results of gamma aminobutyric acid (GABAA) receptor binding assays indicated that the induction of convulsions was caused predominantly by the inhibition of GABAA-mediated inhibitory transmission. However, the in vivo convulsant activity of some of these compounds did not correlate with their in vitro inhibitory effect on GABAA receptor binding.


Infection of human immunodeficiency virus 1 transgenic mice with Toxoplasma gondii stimulates proviral transcription in macrophages in vivo.
Human immunodeficiency virus (HIV) 1 transgenic mice expressing low or undetectable levels of viral mRNA in lymphoid tissue were infected with the intracellular protozoan Toxoplasma gondii. Exposure to this parasite resulted in an increase in HIV-1 transcript in lymph nodes, spleens, and lungs during the acute phase of infection and in the central nervous system during the chronic stage of disease. In vivo and ex vivo experiments identified macrophages as a major source of the induced HIV-1 transcripts. In contrast, T. gondii infection failed to stimulate HIV-1 transcription in tissues of two HIV-1 transgenic mouse strains harboring a HIV-1 proviral DNA in which the nuclear factor (NF) kappa B binding motifs from the viral long terminal repeats had been replaced with a duplicated Moloney murine leukemia virus core enhancer. A role for NF-kappaB in the activation of the HIV-1 by T. gondii was also suggested by the simultaneous induction of NF-kappaB binding activity and tumor necrosis factor alpha synthesis in transgenic mouse macrophages stimulated by exposure to parasite extracts. These results demonstrate the potential of an opportunistic pathogen to induce HIV-1 transcription in vivo and suggest a mechanism for the in vivo dissemination of HIV-1 by macrophages.


Meleney's synergistic gangrene: a case study.
Meleney's synergistic gangrene is caused by S aureus and streptococcus organisms. One of the identifying symptoms is the presence of extremely painful lesions, which usually form in the second week after surgery or minor trauma. The ulcers that form at the center of the lesion are usually covered by a black eschar and encircled by a gangrenous margin. With knowledge of the pathophysiology and characteristics of this process, nurses can aid in the recognition of this unexpected complication. Nursing interventions can be planned around the needs of these patients. The key to recovery is early identification of the infection and prompt treatment.


Celiac disease: pathogenesis of a model immunogenetic disease.
Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. Although celiac disease is predicted by screening studies to affect approximately 1% of the population of the United States and is seen both in children and in adults, 10%-15% or fewer of these individuals have been diagnosed and treated. This article focuses on the role of adaptive and innate immune mechanisms in the pathogenesis of celiac disease and how current concepts of immunopathogenesis might provide alternative approaches for treating celiac disease.


The source of the truth bias: Heuristic processing?
People believe others are telling the truth more often than they actually are; this is called the truth bias. Surprisingly, when a speaker is judged at multiple points across their statement the truth bias declines. Previous claims argue this is evidence of a shift from (biased) heuristic processing to (reasoned) analytical processing. In four experiments we contrast the heuristic-analytic model (HAM) with alternative accounts. In Experiment 1, the decrease in truth responding was not the result of speakers appearing more deceptive, but was instead attributable to the rater's processing style. Yet contrary to HAMs, across three experiments we found the decline in bias was not related to the amount of processing time available (Experiments 1-3) or the communication channel (Experiment 2). In Experiment 4 we found support for a new account: that the bias reflects whether raters perceive the statement to be internally consistent.


Schisanhenol attenuated ox-LDL-induced apoptosis and reactive oxygen species generation in bovine aorta endothelial cells in vitro.
The aim of this paper was to investigate the protective effect of schisanhenol (Sal) isolated from Schisandra rubriflora Rhed, on human ox-LDL-induced bovine aorta endothelial cells (BAECs) apoptosis and intracellular reactive oxygen species (ROS) production in vitro. The BAECs were cultured with ox-LDL (200 microg/ml) in the presence and absence of Sal (10 and 50 micromol L(- 1)) for 24 h. The cytotoxicity of ox-LDL was evaluated by LDH leakage, cell viability and morphological change. Cell apoptosis was estimated by DNA ladder, chromatin condensation, and flow cytometry assay. The intracellular ROS production was detected by using DCF, a ROS probe, with laser confocal microscopy and flow cytometry. Sal was shown to reduce LDH leakage and increase cell viability. Sal also attenuated ox-LDL-induced BAECs apoptosis as indicated in typical internucleosomal DNA degradation (DNA ladder), condensed chromatin, and the sub-G1 peak appearance in flow cytometry assay. Furthermore, Sal was shown to inhibit ROS generation in BAECs with stimulation of ox-LDL. The results indicated that the anti-apoptosis effect of Sal on BACSs might be related to its inhibition of ROS generation.


The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma.
Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of SHH expression appear to correlate with cancer progression. However, the role of SHH in the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is still unclear. No studies have compared the expression of SHH in different subtypes of OSCC and focused on the relationship between the tumor parenchyma and stroma. In this study, we analyzed SHH and expression of its receptor, Patched-1 (PTCH), in the TME of different subtypes of OSCC. Fifteen endophytic-type cases (ED type) and 15 exophytic-type cases (EX type) of OSCC were used. H&E staining, immunohistochemistry (IHC), double IHC, and double-fluorescent IHC were performed on these samples. ED-type parenchyma more strongly expressed both SHH and PTCH than EX-type parenchyma. In OSCC stroma, CD31-positive cancer blood vessels, CD68- and CD11b-positive macrophages, and α-smooth muscle actin-positive cancer-associated fibroblasts partially expressed PTCH. On the other hand, in EX-type stroma, almost no double-positive cells were observed. These results suggest that autocrine effects of SHH induce cancer invasion, and paracrine effects of SHH govern parenchyma-stromal interactions of OSCC. The role of the SHH pathway is to promote growth and invasion.


Effects of variations in access to care for children with atopic dermatitis.
An estimated 50% of children in the US are Medicaid-insured. Some of these patients have poor health literacy and limited access to medications and specialty care. These factors affect treatment utilization for pediatric patients with atopic dermatitis (AD), the most common inflammatory skin disease in children. This study assesses and compares treatment patterns and healthcare resource utilization (HCRU) between large cohorts of Medicaid and commercially insured children with AD. Pediatric patients with AD were identified from 2 large US healthcare claims databases (2011-2016). Included patients had continuous health plan eligibility for ≥6 months before and ≥12 months after the first AD diagnosis (index date). Patients with an autoimmune disease diagnosis within 6 months of the index date were excluded. Treatment patterns and all-cause and AD-related HCRU during the observation period were compared between commercially and Medicaid-insured children. A minority of children were evaluated by a dermatology or allergy/immunology specialist. Several significant differences were observed between commercially and Medicaid-insured children with AD. Disparities detected for Medicaid-insured children included: comparatively fewer received specialist care, emergency department and urgent care center utilization was higher, a greater proportion had asthma and non-atopic morbidities, high- potency topical corticosteroids and calcineurin inhibitors were less often prescribed, and prescriptions for antihistamines were more than three times higher, despite similar rates of comorbid asthma and allergies among antihistamine users. Treatment patterns also varied substantially across physician specialties. Results suggest barriers in accessing specialty care for all children with AD and significant differences in management between commercially and Medicaid-insured children. These disparities in treatment and access to specialty care may contribute to poor AD control, especially in Medicaid-insured patients.


Cost-effectiveness of endovascular thrombectomy in patients with acute ischemic stroke.
To evaluate the cost-effectiveness of adding endovascular thrombectomy to standard care in patients with acute ischemic stroke. The cost-effectiveness analysis of endovascular thrombectomy in patients with acute ischemic stroke was based on a decision-analytic Markov model. Primary outcomes from ESCAPE, Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA), Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours (REVASCAT), and Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) along with data from published studies and registries were used in this analysis. We used a health care payer perspective and a lifelong time horizon to estimate costs and effects. The model showed that adding thrombectomy with stent retrievers to guideline-based care (including IV thrombolysis) resulted in a gain of 0.40 life-years and 0.99 quality-adjusted life-years along with a cost savings of approximately $221 per patient. The sensitivity analysis showed that the results were not sensitive to changes in uncertain parameters or assumptions. Adding endovascular treatment to standard care resulted in substantial clinical benefits at low costs. The results were consistent throughout irrespective of whether data from ESCAPE, EXTEND-IA, MR CLEAN, REVASCAT, or SWIFT PRIME were used in this model.


Evolutionary Events Associated with an Outbreak of Meningococcal Disease in Men Who Have Sex with Men.
Meningococci spread via respiratory droplets, whereas the closely related gonococci are transmitted sexually. Several outbreaks of invasive meningococcal disease have been reported in Europe and the United States among men who have sex with men (MSM). We recently identified an outbreak of serogroup C meningococcal disease among MSM in Germany and France. In this study, genomic and proteomic techniques were used to analyze the outbreak isolates. In addition, genetically identical urethritis isolates were recovered from France and Germany and included in the analysis. Genome sequencing revealed that the isolates from the outbreak among MSM and from urethritis cases belonged to a clade within clonal complex 11. Proteome analysis showed they expressed nitrite reductase, enabling anaerobic growth as previously described for gonococci. Invasive isolates from MSM, but not urethritis isolates, further expressed functional human factor H binding protein associated with enhanced survival in a newly developed transgenic mouse model expressing human factor H, a complement regulatory protein. In conclusion, our data suggest that urethritis and outbreak isolates followed a joint adaptation route including adaption to the urogenital tract.


Learning improves growth rate in grasshoppers.
To quantify the adaptive significance of insect learning, we documented the behavior and growth rate of grasshoppers (Schistocerca americana) in an environment containing two artificial food types, one providing a balanced diet of protein and carbohydrate, which maximizes growth, and the other being carbohydrate-deficient, which is unsuitable for growth. Grasshoppers in the Learning treatment experienced a predictable environment, where the spatial location, taste, and color of each food source remained constant throughout the experiment. In contrast, grasshoppers of the Random treatment developed in a temporally varying environment, where the spatial location, taste, and color of the balanced and deficient food types randomly alternated twice each day. Our results show that the grasshoppers that could employ associative learning for diet choice experienced higher growth rates than individuals of the Random treatment, demonstrating the adaptive significance of learning in a small short-lived insect.


Notch in the niche.
Notch signaling is essential for hematopoietic stem cell (HSC) formation during embryogenesis, and hitherto it was also thought to be required for HSC maintenance. However, in this issue of Cell Stem Cell, Maillard et al. (2008) demonstrate rather conclusively that inactivation of the Notch pathway in HSCs does not interfere with their self-renewal.


A study on rural-urban differences in neonatal mortality rate in China, 1996-2006.
This study examined the differences in neonatal mortality rates between urban and rural areas in China. Data were taken from a database collected by the Chinese surveillance network for mortality of children under 5 years of age. The risk ratio of neonatal mortality for rural versus urban areas was between 2.2 and 2.7 for 1996-2006 and it declined to 2.0 in 2005-6. Pneumonia, birth asphyxia and preterm birth or low birth weight were the major contributors to the urban-rural differences in neonatal mortality, together with a relatively high proportion of home delivery and a relatively lower proportion of hospital treatment in rural areas. The urban-rural differences reflect the gap between the developed and the underdeveloped regions in China at that period. The neonatal mortality rate in China's rural areas could decrease further if continuous efforts are successful to increase the rates of hospital delivery in rural areas.


Evaluation of a medication monitor-based treatment strategy for drug-sensitive tuberculosis patients in China: study protocol for a cluster randomised controlled trial.
Treatment for drug-sensitive tuberculosis (TB) is taken for at least 6 months and problems with adherence are common. Therefore, there is substantial interest in the possible use of eHealth interventions to support patients to take their treatment. Electronic medication monitors have been shown to improve adherence to TB medication, but the impact on clinical outcomes is unknown. We aim to evaluate the impact of a medication monitor-based treatment strategy for drug-sensitive TB patients on a composite poor outcome measured over 18 months from start of TB treatment. We will conduct an open, pragmatic, cluster randomised superiority trial, with 24 counties/districts in three provinces in China, randomised 1:1 to implement the intervention or standard of care. Adults (aged ≥ 18 years) with a new episode of GeneXpert-positive and rifampicin-sensitive pulmonary TB, who plan to be in the study area for the next 18 months, and will receive daily fixed-dose combination tablets for 6 months of treatment are eligible. The intervention is centred around a medication monitor that holds a 1-month supply of medication and has three key functions: as an audio and visual reminder for patients to take their daily medication; reminds patients of upcoming monthly visit; and records date and time whenever the box is opened. At the monthly follow-up visit, the doctor downloads these data to generate a graphical display of the last month's adherence record for discussion with the patient and potentially to switch the patient to more intensive management. The primary outcome is a composite poor outcome measured over 18 months from start of TB treatment, defined as either of poor outcome at the end of treatment (death, treatment failure, or loss to follow-up) or subsequent recurrence (culture positive for TB at 12 or 18 months or re-starting TB treatment in the follow-up period). An economic evaluation will also be conducted as part of this study. This trial will assess whether a medication monitor-based treatment strategy can improve clinical outcomes for TB patients. Several trials of other eHealth interventions for TB treatment are ongoing and are summarised in this paper. This trial will provide an important part of the emerging evidence base for the potential of eHealth to improve TB treatment outcomes. This trial was registered with Current Controlled Trials (identifier: ISRCTN35812455 ). Registered on May 19, 2016.


Coronary heart disease in the Pima Indians. Electrocardiographic findings and postmortem evidence of myocardial infarction in a population with a high prevalence of diabetes mellitus.
The frequency of electrocardiographic evidence of coronary heart disease (CHD) and the rate of autopsy-proved myocardial infarction were determined in the Pima, a tribe of American Indians with a high prevalence of diabetes mellitus. The electrocardiograms of 701 Pimas, aged 40 years and over (85 per cent of the adult reservation population, 45 per cent of whom had diabetes) were read according to the Minnesota Code, and 120 postmortem examinations were reviewed for evidence of myocardial infarction. The frequency of CHD as evidenced by major Q-wave changes in the Pima (1.6/100) was about one-half that found in Tecumseh, Michigan (p less than 0.10). The relatively low rate of myocardial infarction at autopsy (15 per cent of males and 8 per cent of females aged 40 years and over) was consistent with the low prevalence of Q-wave changes. The subjects with diabetes had a higher rate of CHD than nondiabetics, both electrocardiographically and at postmortem examination, although the differences were not statistically significant. The low prevalence of CHD in the living Pima and the low rate of infarction at autopsy indicate that this tribe has a low frequency of CHD despite the extraordinarily high prevalence of diabetes mellitus.


Edward Harrison and the treatment of spinal deformities in the nineteenth century.
At the beginning of the nineteenth century, doctors and lay practitioners became interested in the treatment of spinal deformity, but it took two centuries for the specialty to become established. The provision of care was fragmented, and treatment was in the hands of physicians, surgeons, mechanics, masseurs and bonesetters. In 1837, Dr Edward Harrison founded the first infirmary for spinal diseases in London with only six beds. Harrison was a forceful character who had trained in Scotland. He held no voluntary hospital appointment and faced great opposition from the London Royal Colleges and the orthodox establishment, including Sir Charles Bell and John Shaw. This paper describes Harrison's treatment of patients afflicted by spinal deformity and analyses the medical environment of the time as well as Harrison's legacy.


Living cardiac tissue slices: an organotypic pseudo two-dimensional model for cardiac biophysics research.
Living cardiac tissue slices, a pseudo two-dimensional (2D) preparation, have received less attention than isolated single cells, cell cultures, or Langendorff-perfused hearts in cardiac biophysics research. This is, in part, due to difficulties associated with sectioning cardiac tissue to obtain live slices. With moderate complexity, native cell-types, and well-preserved cell-cell electrical and mechanical interconnections, cardiac tissue slices have several advantages for studying cardiac electrophysiology. The trans-membrane potential (Vm) has, thus far, mainly been explored using multi-electrode arrays. Here, we combine tissue slices with optical mapping to monitor Vm and intracellular Ca(2+) concentration ([Ca(2+)]i). This combination opens up the possibility of studying the effects of experimental interventions upon action potential (AP) and calcium transient (CaT) dynamics in 2D, and with relatively high spatio-temporal resolution. As an intervention, we conducted proof-of-principle application of stretch. Mechanical stimulation of cardiac preparations is well-established for membrane patches, single cells and whole heart preparations. For cardiac tissue slices, it is possible to apply stretch perpendicular or parallel to the dominant orientation of cells, while keeping the preparation in a constant focal plane for fluorescent imaging of in-slice functional dynamics. Slice-to-slice comparison furthermore allows one to assess transmural differences in ventricular tissue responses to mechanical challenges. We developed and tested application of axial stretch to cardiac tissue slices, using a manually-controlled stretching device, and recorded Vm and [Ca(2+)]i by optical mapping before, during, and after application of stretch. Living cardiac tissue slices, exposed to axial stretch, show an initial shortening in both AP and CaT duration upon stretch application, followed in most cases by a gradual prolongation of AP and CaT duration during stretch maintained for up to 50 min. After release of sustained stretch, AP duration (APD) and CaT duration reverted to shorter values. Living cardiac tissue slices are a promising experimental model for the study of cardiac mechano-electric interactions. The methodology described here can be refined to achieve more accurate control over stretch amplitude and timing (e.g. using a computer-controlled motorised stage, or by synchronising electrical and mechanical events) and through monitoring of regional tissue deformation (e.g. by adding motion tracking).


Impact of the Bologna process in Bachelor nursing programmes: The Swedish case.
The higher education reform in Europe known as the "Bologna Process" implies further harmonisation and integration of nursing programmes into the higher education system. This study explores this process in Sweden, where the development of nursing education into an undergraduate programme started in 1977. The aim of this study was to analyse characteristics of the major subject and its relationship to other subject areas, such as medical sciences and social sciences, in Bachelor level nursing programmes in Sweden following initial implementation of the Bologna process. A constructivist approach and descriptive content analysis were employed to analyse the 2008 nursing curricula and syllabi of 27 undergraduate programmes at 26 Swedish universities and university colleges. The results revealed variation in terms and concepts used for the major subject as well as its scientific foundation, demarcation between the major subject and other subjects included in the study programmes and its relationship to the profession. These variations are linked to the variety of research orientations under debate in the Scandinavian countries: Nursing Science and Caring Science; representing different knowledge domains, focus, challenges and visions for the discipline. Potential implications of basing curricula on a major subject other than Nursing Science in a Bachelor level nursing programme are highlighted.


The Desmoteplase in Acute Ischemic Stroke (DIAS) clinical trial program.
Desmoteplase is a novel, highly fibrin-specific thrombolytic agent in phase III of clinical development. In comparison to alteplase, it has high fibrin selectivity, is associated with minimal or no neurotoxicity, and has no apparent negative effect on the blood-brain barrier. The safety and efficacy of desmoteplase is being studied in the Desmoteplase in Acute Ischemic Stroke clinical trial program. Three studies (Dose Escalation Study of Desmoteplase in Acute Ischemic Stroke, Desmoteplase in Acute Ischemic Stroke, and Desmoteplase in Acute Ischemic Stroke-2) have been completed, two large randomized, double-blind, placebo-controlled, phase III trials are ongoing at >200 sites worldwide (Desmoteplase in Acute Ischemic Stroke-3 and Desmoteplase in Acute Ischemic Stroke-4, n = 800; DIAS-3 and DIAS-4), and a randomized, double-blind, placebo-controlled, dose-escalation phase II trial is ongoing in Japan (Desmoteplase in Acute Ischemic Stroke-Japan, n = 48; DIAS-J). The objective of DIAS-3 and DIAS-4 is to evaluate the safety and efficacy of a single IV bolus injection of 90 μg/kg desmoteplase given three- to nine-hours after onset of ischemic stroke (National Institutes of Health Stroke Scale 4-24, age 18-85 years). The objective of DIAS-J is to evaluate the safety and tolerability of desmoteplase 70 and 90 μg/kg three- to nine-hours after ischemic stroke onset in Japanese patients. Patients are included with occlusion or high-grade stenosis (thrombolysis in myocardial infarction 0-1) in proximal cerebral arteries on magnetic resonance or computed tomography angiography but excluded with extended ischemic edema on computed tomography or diffusion-weighted imaging. Desmoteplase is the only thrombolytic agent in late-stage development for acute ischemic stroke that is now tested in patients with proven stroke pathology. The results of the Desmoteplase in Acute Ischemic Stroke clinical trial program will show whether patients with major artery occlusions but not extended ischemic brain damage can be safely and effectively treated up to nine-hours after onset.


Plasma lipoprotein levels as predictors of cardiovascular death in women.
The association of lipoprotein levels with cardiovascular disease (CVD) is less well understood in women than in men. To better characterize any relationships, associations between CVD death and total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and triglyceride levels in women were explored using data from female participants in the Lipid Research Clinics' Follow-up Study. Using a sample of 1405 women aged 50 to 69 years from the Lipid Research Clinics' Follow-up Study, age-adjusted CVD death rates and summary relative risk (RR) estimates by categories of lipid and lipoprotein levels were calculated. Multivariate analysis was performed to provide RR estimates adjusted for other CVD risk factors. Average follow-up was 14 years. High-density lipoprotein and triglyceride levels were strong predictors of CVD death in age-adjusted and multivariate analyses. Low-density lipoprotein and total cholesterol levels were poorer predictors of CVD mortality. After adjustment for other CVD risk factors, HDL levels less than 1.30 mmol/L (50 mg/dL) were strongly associated with cardiovascular mortality (RR = 1.74; 95% confidence interval [CI], 1.10 to 2.75). Triglyceride levels were associated with increased CVD mortality at levels of 2.25 to 4.49 mmol/L (200 to 399 mg/dL) (RR = 1.65; 95% CI, 0.99 to 2.77) and 4.50 mmol/L (400 mg/dL) or greater (RR = 3.44; 95% CI, 1.65 to 7.20). At total cholesterol levels of 5.20 mmol/L (200 mg/dL) or greater and at all levels of LDL and triglycerides, women with HDL levels of less than 1.30 mmol/L (< 50 mg/dL) had CVD death rates that were higher than those of women with HDL levels of 1.30 mmol/L (50 mg/dL) or greater. High-density lipoprotein and triglyceride levels are independent lipid predictors of CVD death in women. Cholesterol screening guidelines should be re-evaluated to reflect the importance of HDL and triglyceride levels in determining CVD risk in women.


Transcutaneous bilirubinometry: effect of postnatal age.
The purpose of this study was to determine whether the postnatal age might affect the accuracy and reliability of transcutaneous bilirubin measurements. A total of 576 transcutaneous bilirubin measurements were performed on 336 Japanese full-term breast-fed newborn infants during the first 12 days of life. We divided them into three groups according to postnatal age and studied the effect of postnatal age on the accuracy and reliability of TcB measurements. Our study revealed that the most reliable site for transcutaneous bilirubin measurements changed from the forehead to the sternum with advancing postnatal age (i.e. forehead for 0-3 days, chest for 4-5 days, sternum for 6 days and later).


Promising Therapy Candidates for Liver Fibrosis.
Liver fibrosis is a wound-healing process in response to repeated and chronic injury to hepatocytes and/or cholangiocytes. Ongoing hepatocyte apoptosis or necrosis lead to increase in ROS production and decrease in antioxidant activity, which recruits inflammatory cells from the blood and activate hepatic stellate cells (HSCs) changing to myofibroblasts. Injury to cholangiocytes also recruits inflammatory cells to the liver and activates portal fibroblasts in the portal area, which release molecules to activate and amplify cholangiocytes. No matter what origin of myofibroblasts, either HSCs or portal fibroblasts, they share similar characteristics, including being positive for α-smooth muscle actin and producing extracellular matrix. Based on the extensive pathogenesis knowledge of liver fibrosis, therapeutic strategies have been designed to target each step of this process, including hepatocyte apoptosis, cholangiocyte proliferation, inflammation, and activation of myofibroblasts to deposit extracellular matrix, yet the current therapies are still in early-phase clinical development. There is an urgent need to translate the molecular mechanism of liver fibrosis to effective and potent reagents or therapies in human.


Pursuit and prediction in the tracking of moving food by a teleost fish (Acanthaluteres spilomelanurus).
1. The path, eye and body movements of a teleost fish (the leatherjacket Acanthaluteres spilomelanurus) approaching and taking food were measured by cinematography. 2. Fixation of the food by movement of the eyes is an invariable feature of the approach. The eyes then remain aligned with the target while the body moves forward and round to bring the mouth to the food. 3. When pursuing pieces of food moving vertically at constant velocity through the water these fish normally trace out the pathway that can be calculated by assuming the fish aims constantly at the food. Predictive pathways that imply anticipation of the point of intersection with the food are not regularly seen. 4. Deviations from pursuit occur sporadically, usually in the direction of a predictive path, particularly when the fish approach falling food from below. 5. The geometry of the situation suggests that predictive paths may sometimes be generated if the alignment of eye and body during the pursuit of moving food can be delayed. In approaches from below this may be because forward movement of the fish would tend to stabilize the image of the falling food in the retina. 6. We suggest that a simple linked control system using both eye and body movements to fixate retinal images will on occasions generate predictive pathways without any need for the central nervous system to calculate them in advance.


A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.
Deletions in the 2p16.3 region that includes the neurexin (NRXN1) gene are associated with intellectual disability and various psychiatric disorders, in particular, autism and schizophrenia. We present three unrelated patients, two adults and one child, in whom we identified an intragenic 2p16.3 deletion within the NRXN1 gene using an oligonucleotide comparative genomic hybridization array. The three patients presented dual diagnosis that consisted of mild intellectual disability and autism and bipolar disorder. Also, they all shared a dysmorphic phenotype characterized by a long face, deep set eyes, and prominent premaxilla. Genetic analysis of family members showed two inherited deletions. A comprehensive neuropsychological examination of the 2p16.3 deletion carriers revealed the same phenotype, characterized by anxiety disorder, borderline intelligence, and dysexecutive syndrome. The cognitive pattern of dysexecutive syndrome with poor working memory and reduced attention switching, mental flexibility, and verbal fluency was the same than those of the adult probands. We suggest that in addition to intellectual disability and psychiatric disease, NRXN1 deletion is a risk factor for a characteristic cognitive and dysmorphic profile. The new cognitive phenotype found in the 2p16.3 deletion carriers suggests that 2p16.3 deletions might have a wide variable expressivity instead of incomplete penetrance.


Short-term effects of severe dietary carbohydrate-restriction advice in Type 2 diabetes--a randomized controlled trial.
This study sought to examine the effects of a 3-month programme of dietary advice to restrict carbohydrate intake compared with reduced-portion, low-fat advice in obese subjects with poorly controlled Type 2 diabetes. One hundred and two patients with Type 2 diabetes were recruited across three centres and randomly allocated to receive group education and individual dietary advice. Weight, glycaemic control, lipids and blood pressure were assessed at baseline and 3 months. Dietary quality was assessed at the end of study. Weight loss was greater in the low-carbohydrate (LC) group (-3.55 +/- 0.63, mean +/- sem) vs. -0.92 +/- 0.40 kg, P = 0.001) and cholesterol : high-density lipoprotein (HDL) ratio improved (-0.48 +/- 0.11 vs. -0.10 +/- 0.10, P = 0.01). However, relative saturated fat intake was greater (13.9 +/- 0.71 vs. 11.0 +/- 0.47% of dietary intake, P < 0.001), although absolute intakes were moderate. Carbohydrate restriction was an effective method of achieving short-term weight loss compared with standard advice, but this was at the expense of an increase in relative saturated fat intake.


Reproducibility of a scoring system for computed tomography scanning in cystic fibrosis.
Computerized tomography (CT) scanning shows promise as an outcome surrogate for cystic fibrosis (CF) lung disease progression. The scoring system used to convert the CT image to numeric data is an essential determinant of the performance of CT scanning. Three radiologists independently scored 16 high-resolution CT scans performed on children in the Wisconsin CF Neonatal Screening Project. The test scans were selected to provide a broad range of disease severity. The scoring system provided subscores for the presence and severity of 5 findings of CF lung disease. The sum of the subscores provided a total score. The CT scans were then read again by each of the radiologists at least 11 months later. Using Mixed Effects Linear Model Analysis, the sources of error (scan-to-scan variation, interrater variance, and intrarater variance) were calculated. For the total score, the scan-to-scan variation was 14.48, interrater variance was 0.28, and intrarater variance was 0.45, with an overall reproducibility of 95%. The square root of scan-to-scan variance, a measure of sensitivity, was 3.81. Evaluation of the subscores showed higher reproducibility for bronchiectasis and hyperinflation (95% and 88%, respectively). The bronchiectasis score was more sensitive than the air-trapping score (1.46 vs. 0.89). This system was developed to provide a reproducible method that could be used to evaluate the lobar location, severity, and extent of a broad spectrum of CT features of CF lung disease, especially in children. This study demonstrates that the overall score is both sensitive to variation in the severity of lung disease and reproducible.


Signaling by fibroblast growth factors: the inside story.
Polypeptide growth factors bind to the extracellular domains of cell surface receptors, triggering activation of receptor-intrinsic or receptor-associated protein kinases. Although this central thesis is widely accepted, one family of proteins, the fibroblast growth factors (FGFs), have for more than a decade attracted a research "counterculture" looking for direct FGF actions inside cells. Goldfarb discusses how the search for alternative signaling pathways is moving mainstream with the help of two recent publications reporting specific intracellular targets for FGF and FGF-like proteins.


BiCoN: network-constrained biclustering of patients and omics data.
Unsupervised learning approaches are frequently used to stratify patients into clinically relevant subgroups and to identify biomarkers such as disease-associated genes. However, clustering and biclustering techniques are oblivious to the functional relationship of genes and are thus not ideally suited to pinpoint molecular mechanisms along with patient subgroups. We developed the network-constrained biclustering approach Biclustering Constrained by Networks (BiCoN) which (i) restricts biclusters to functionally related genes connected in molecular interaction networks and (ii) maximizes the difference in gene expression between two subgroups of patients. This allows BiCoN to simultaneously pinpoint molecular mechanisms responsible for the patient grouping. Network-constrained clustering of genes makes BiCoN more robust to noise and batch effects than typical clustering and biclustering methods. BiCoN can faithfully reproduce known disease subtypes as well as novel, clinically relevant patient subgroups, as we could demonstrate using breast and lung cancer datasets. In summary, BiCoN is a novel systems medicine tool that combines several heuristic optimization strategies for robust disease mechanism extraction. BiCoN is well-documented and freely available as a python package or a web interface. PyPI package: https://pypi.org/project/bicon. https://exbio.wzw.tum.de/bicon. Supplementary data are available at Bioinformatics online.


Induced Stem Cells as a Novel Multiple Sclerosis Therapy.
Stem cell replacement is providing hope for many degenerative diseases that lack effective therapeutic methods including multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. Transplantation of neural stem cells or mesenchymal stem cells is a potential therapy for MS thanks to their capacity for cell repopulation as well as for their immunomodulatory and neurotrophic properties. Induced pluripotent stem cell (iPSC), an emerging cell source in regenerative medicine, is also being tested for the treatment of MS. Remarkable improvement in mobility and robust remyelination have been observed after transplantation of iPSC-derived neural cells into demyelinated models. Direct reprogramming of somatic cells into induced neural cells, such as induced neural stem cells (iNSCs) and induced oligodendrocyte progenitor cells (iOPCs), without passing through the pluripotency stage, is an alternative for transplantation that has been proved effective in the congenital hypomyelination model. iPSC technology is rapidly progressing as efforts are being made to increase the efficiency of iPSC therapy and reduce its potential side effects. In this review, we discuss the recent advances in application of stem cells, with particular focus on induced stem/progenitor cells (iPSCs, iNSC, iOPCs), which are promising in the treatment of MS.


Blunt hepatic injury: minimal intervention is the policy of treatment.
Many publications recommend nonoperative treatment for stable blunt hepatic injury patients. Unstable hemodynamic status is the only indication for surgery. When operation is indicated, controversies exist regarding which operative procedure will be more beneficial to the patients. The purposes of this study are to compare the results of operative and nonoperative management of patients with blunt hepatic injuries and to identify the optimal surgical approach when surgery is indicated. Different prospective protocols of treating adult blunt hepatic injuries were conducted. From 1992 to 1993 (group I), urgent surgery would be performed in the presence of hemoperitoneum. The policy shifted to aggressive nonoperative approach between 1996 and 1997 (group II). The patients from each period were divided into three subgroups. Group A included the patients who received nonoperative treatment in either period. Group B consisted of the patients who received surgery in the first period and nonoperative management in the second period. Group C included the patients who were operated on in either group. Comparisons were made between matched groups. Groups IA and IIA patients had minor injuries and could be successfully treated nonoperatively. The results of groups IB and IIB were similar concerning hospital stay, morbidity, and mortality. Transfusion requirements of group IIB patients were significantly higher (2.2 vs. 1.1 units,p = 0.01) than those of group IB. However, 25 (58%) celiotomies of group IB patients were nontherapeutic. When surgery was indicated, group IC patients had significantly higher liver-related mortality (14 of 49 vs. 3 of 55, p = 0.002). Anatomic resection was performed more frequently in that period. Nonoperative treatment significantly decreased the rate of nontherapeutic laparotomy but carried the risks of higher transfusion requirements and delaying operation. When surgery was indicated, the policy of minimal intervention positively affected the patients' outcomes. The goal of surgery should be hemorrhage control rather than resection of the injured liver tissues.


Tradition and transition: parasitic zoonoses of people and animals in Alaska, northern Canada, and Greenland.
Zoonotic parasites are important causes of endemic and emerging human disease in northern North America and Greenland (the North), where prevalence of some parasites is higher than in the general North American population. The North today is in transition, facing increased resource extraction, globalisation of trade and travel, and rapid and accelerating environmental change. This comprehensive review addresses the diversity, distribution, ecology, epidemiology, and significance of nine zoonotic parasites in animal and human populations in the North. Based on a qualitative risk assessment with criteria heavily weighted for human health, these zoonotic parasites are ranked, in the order of decreasing importance, as follows: Echinococcus multilocularis, Toxoplasma gondii, Trichinella and Giardia, Echinococcus granulosus/canadensis and Cryptosporidium, Toxocara, anisakid nematodes, and diphyllobothriid cestodes. Recent and future trends in the importance of these parasites for human health in the North are explored. For example, the incidence of human exposure to endemic helminth zoonoses (e.g. Diphyllobothrium, Trichinella, and Echinococcus) appears to be declining, while water-borne protozoans such as Giardia, Cryptosporidium, and Toxoplasma may be emerging causes of human disease in a warming North. Parasites that undergo temperature-dependent development in the environment (such as Toxoplasma, ascarid and anisakid nematodes, and diphyllobothriid cestodes) will likely undergo accelerated development in endemic areas and temperate-adapted strains/species will move north, resulting in faunal shifts. Food-borne pathogens (e.g. Trichinella, Toxoplasma, anisakid nematodes, and diphyllobothriid cestodes) may be increasingly important as animal products are exported from the North and tourists, workers, and domestic animals enter the North. Finally, key needs are identified to better assess and mitigate risks associated with zoonotic parasites, including enhanced surveillance in animals and people, detection methods, and delivery and evaluation of veterinary and public health services.


Characterization of ESBL disseminating plasmids.
Bacteria producing extended-spectrum β-lactamases (ESBLs) constitute a globally increasing problem that contributes to treatment complications and elevated death rates. The extremely successful dissemination by ESBL-producing Enterobacteriaceae during the latest decades is a result of the combination of mobilization, evolution and horizontal spread of β-lactamase genes on plasmids. In parallel, spread of these plasmids to particularly well-adapted bacterial clones (outbreak clones) has expanded. In this review we describe ESBL-producing bacteria and the genetic mechanisms for dissemination of ESBL resistance. We describe available methodology for studying plasmids and the importance of including plasmids in epidemiological typing as natural parts of the organisms. Plasmids play a fundamental role in how resistance arises and disseminates.


What can a meta-analysis tell us about traditional birth attendant training and pregnancy outcomes?
to summarise the available published and unpublished studies on traditional birth attendant (TBA) training effectiveness. a meta-analysis. sixty studies (n=60) spanning 1971-1999 from 24 countries and three regions. the effect size index, Cohen's h for each outcome; the variance-weighted mean effect size and 95% confidence interval for sub-group of outcomes; homogeneity tests on the distribution of the weighted mean effect sizes; and sensitivity analysis to detect the presence of publication bias. TBA training was associated with significant increases in attributes such as TBA 'knowledge' (90%), 'attitude' (74%), 'behaviour' (63%) and 'advice' (90%) over the untrained TBA baseline. Results for 'behaviour' and 'advice' in specific content areas related to peri-neonatal health outcome, however, reveal sources of variability and underscore the conflicting evidence on TBA training. TBA training was also associated with small but significant decreases in peri-neonatal mortality (8%) and birth asphyxia mortality (11%). Incomplete reporting limited the assessment of neonatal mortality due to tetanus and acute respiratory infection, maternal mortality, as well as assessment of the relationship between intervention characteristics and outcomes. The quality of studies included in the meta-analysis lack sufficient rigour to address the question of causality. Thus, while the data suggest that TBA training is effective in terms of the outcomes measured, we are unable to demonstrate that it is a cost-effective intervention. skilled attendance at birth is a distant reality in many developing countries and effective community-based strategies are needed to help reduce high levels of mortality. Given the magnitude of peri-neonatal mortality, the associations observed between TBA training peri-neonatal and birth asphyxia mortality, and TBA attributes in content relevant to peri-neonatal survival, we suggest that these strategies may usefully include TBA training in appropriate settings. If TBAs are to be trained, however, it is imperative that their training be adequately evaluated in order to develop the strong evidence base that is lacking to-date and that is necessary for sound policy and programming.


Synergistic Anticancer Effects of Formononetin and Temozolomide on Glioma C6 Cells.
Temozolomide (TMZ) is currently the first-line drug used for clinical postoperative or non-surgical chemotherapy for glioma, but acquired and intrinsic resistance to TMZ limits its application. The anti-proliferative effect of formononetin on human glioma cells had been confirmed. To improve therapeutic effects of TMZ, we studied the effect of formononetin in combination with TMZ on C6 glioma cells. The anti-proliferative effect of C6 cells was tested by 3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay. The synergy was evaluated by Chou-Talalay method. Morphological changes were observed by hematoxylin-eosin (HE) staining. The effect of formononetin in combination with TMZ on apoptosis of C6 cells was investigated by flow cytometry. The effect of formononetin in combination with TMZ on migration of cells was investigated by wound healing assay and transwell assay. The expression of proteins related to apoptosis and migration were detected by Western blot. These results showed that formononetin or TMZ alone could inhibit the growth of C6 cells in dose-dependent manner and formononetin in combination with TMZ had synergy effect on C6 cells. Further changes in cell morphology could be observed in drug combination by HE staining. Drug combination enhanced the expression of Bax, Cleaved Caspase-3, Cleaved Caspase-9, decreased the expression of Bcl-2, and promoted tumor cells apoptosis. In addition, the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) were down-regulated via drug combination which resulted into inhibiting migration of C6 cell. In conclusion, formononetin in combination with TMZ can play a synergistic role in anti-C6 cells, the mechanisms of synergy depended on multiple pathways.


Bronchoscopic lung volume reduction.
Emphysema is a debilitating lung disease continuing to be a major source of morbidity and mortality in the developed countries. Medical treatment is the mainstay of therapy and consists of smoking cessation, pulmonary rehabilitation, administration of bronchodilators and, when indicated, steroids and supplemental oxygen. Various surgical procedures have been promoted in the past to relieve dyspnoea and improve quality of life in patients with advanced emphysema; whilst early results were often encouraging, a sustained objective functional improvement was rarely achieved and most of those procedures were progressively abandoned. Despite controversies, LVRS has been shown to be beneficial to selected patients with end-stage emphysema when medical therapy has failed. There is no doubt that LVRS allows a significative functional improvement in a selected group of patients; however, it still carries a substantial morbidity, even if mortality is low at the centers with the larger experience. Patients with a most advanced functional deterioration show a higher surgical mortality and less impressive functional results, suggesting that LVRS should be considered more carefully in these situations. Bronchoscopic alternatives to the surgical approach have been recently proposed and some of them may play an important role in the future; in particular, the airway bypass and bronchoscopic lung volume reduction with one-way valves are certainly one step beyond on their way to clinical application. We hereby report the initial experimental and clinical experience with these new treatment options.


Up-regulation of the ATP-binding cassette transporter A1 inhibits hepatitis C virus infection.
Hepatitis C virus (HCV) establishes infection using host lipid metabolism pathways that are thus considered potential targets for indirect anti-HCV strategies. HCV enters the cell via clathrin-dependent endocytosis, interacting with several receptors, and virus-cell fusion, which depends on acidic pH and the integrity of cholesterol-rich domains of the hepatocyte membrane. The ATP-binding Cassette Transporter A1 (ABCA1) mediates cholesterol efflux from hepatocytes to extracellular Apolipoprotein A1 and moves cholesterol within cell membranes. Furthermore, it generates high-density lipoprotein (HDL) particles. HDL protects against arteriosclerosis and cardiovascular disease. We show that the up-regulation of ABCA1 gene expression and its cholesterol efflux function in Huh7.5 hepatoma cells, using the liver X receptor (LXR) agonist GW3965, impairs HCV infection and decreases levels of virus produced. ABCA1-stimulation inhibited HCV cell entry, acting on virus-host cell fusion, but had no impact on virus attachment, replication, or assembly/secretion. It did not affect infectivity or properties of virus particles produced. Silencing of the ABCA1 gene and reduction of the specific cholesterol efflux function counteracted the inhibitory effect of the GW3965 on HCV infection, providing evidence for a key role of ABCA1 in this process. Impaired virus-cell entry correlated with the reorganisation of cholesterol-rich membrane microdomains (lipid rafts). The inhibitory effect could be reversed by an exogenous cholesterol supply, indicating that restriction of HCV infection was induced by changes of cholesterol content/distribution in membrane regions essential for virus-cell fusion. Stimulation of ABCA1 expression by GW3965 inhibited HCV infection of both human primary hepatocytes and isolated human liver slices. This study reveals that pharmacological stimulation of the ABCA1-dependent cholesterol efflux pathway disrupts membrane cholesterol homeostasis, leading to the inhibition of virus-cell fusion and thus HCV cell entry. Therefore besides other beneficial roles, ABCA1 might represent a potential target for HCV therapy.


Effects of exposure to alcohol in mother's milk on infant sleep.
To test the hypothesis that exposure to alcohol in breast milk affects infants' sleep and activity levels in the short term. Thirteen lactating women and their infants were tested on 2 days, separated by an interval of 1 week. On each testing day, the mother expressed 100 mL of milk, while a small, computerized movement detector called an actigraph was placed on the infant's left leg to monitor sleep and activity patterning. After the actigraph had been in place for approximately 15 minutes, the infants ingested their mother's breast milk flavored with alcohol (32 mg) on one testing day and breast milk alone on the other. The infants' behaviors were monitored for the next 3.5 hours. The infants spent significantly less time sleeping during the 3.5 hours after consuming the alcohol-flavored milk (78.2 minutes compared with 56.8 minutes after feeding alcohol in breast milk). This reduction was apparently attributable to a shortening in the longest sleeping bout (34.5 compared with 56.7 minutes for sleeping after breast milk alone) and the amount of time spent in active sleep (25.8 minutes compared with 44.2 minutes after breast milk alone); the decrease in active sleep was observed in all but 2 of the 13 infants tested. Although the mechanisms underlying the reduction in sleep remain to be elucidated, this study shows that short-term exposure to small amounts of alcohol in breast milk produces distinctive changes in the infant's sleep-wake patterning.