Combinatorial protein display for the cell-based screening of biomaterials that direct neural stem cell differentiation.
Neural stem cell (NSC) has emerged as a potential source for cell replacement therapy following traumatic injuries and degenerative diseases of the central nervous system. However, clinical applications of NSC further require technological advances especially for controlling differentiation of NSC. This study aimed at developing biomaterials that serve to expand undifferentiated NSC or to induce cells with specific phenotypes. Our approach is to construct composite biomaterials that consist of extracellular matrix components and growth factors. In order to optimize matrix-growth factor combinations, we conducted the parallel and rapid screening of composite biomaterials through assays using cell-based arrays. The photo-assisted patterning of an alkanethiol self-assembled monolayer was employed to achieve site-addressable combinatorial immobilization of natural and synthetic matrices incorporated with growth factors including epidermal growth factor (EGF), ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and neurotrophin-3 (NT-3). NSC obtained from the rat embryonic striatum was cultured directly on the array to screen for cell adhesion, proliferation, and promotion of neuronal and glial specification. The results showed that the significant number of cells adhered to laminin-1, fibronectin, ProNectin, and poly(ethyleneimine). It was found that cells proliferated most extensively on a spot with immobilized EGF among the spots with different matrix-growth factor combinations. The results also showed that neuronal differentiation was promoted on the spots with immobilized NGF or NT-3, and astroglial differentiation with CNTF. Importantly, observed effects of growth factors were frequently altered depending on the type of co-immobilized matrices, suggesting synergic effects of adhesion and growth factor signals.


A Whole Methylome Study of Ethanol Exposure in Brain and Blood: An Exploration of the Utility of Peripheral Blood as Proxy Tissue for Brain in Alcohol Methylation Studies.
Recent reviews have highlighted the potential use of blood-based methylation biomarkers as diagnostic and prognostic tools of current and future alcohol use and addiction. Due to the substantial overlap that often exists between methylation patterns across different tissues, including blood and brain, blood-based methylation may track methylation changes in brain; however, little work has explored the overlap in alcohol-related methylation in these tissues. To study the effects of alcohol on the brain methylome and identify possible biomarkers of these changes in blood, we performed a methylome-wide association study in brain and blood from 40 male DBA/2J mice that received either an acute ethanol (EtOH) or saline intraperitoneal injection. To investigate all 22 million CpGs in the mouse genome, we enriched for the methylated genomic fraction using methyl-CpG binding domain (MBD) protein capture followed by next-generation sequencing (MBD-seq). We performed association tests in blood and brain separately followed by enrichment testing to determine whether there was overlapping alcohol-related methylation in the 2 tissues. The top result for brain was a CpG located in an intron of Ttc39b (p = 5.65 × 10-08 ), and for blood, the top result was located in Espnl (p = 5.11 × 10-08 ). Analyses implicated pathways involved in inflammation and neuronal differentiation, such as CXCR4, IL-7, and Wnt signaling. Enrichment tests indicated significant overlap among the top results in brain and blood. Pathway analyses of the overlapping genes converge on MAPKinase signaling (p = 5.6 × 10-05 ) which plays a central role in acute and chronic responses to alcohol and glutamate receptor pathways, which can regulate neuroplastic changes underlying addictive behavior. Overall, we have shown some methylation changes in brain and blood after acute EtOH administration and that the changes in blood partly mirror the changes in brain suggesting the potential for DNA methylation in blood to be biomarkers of alcohol use.


Meta-Analysis of Mindfulness-Based Program Soles of the Feet for Disruptive Behaviors.
Mindfulness-based programs are a promising intervention modality for reducing disruptive behavior, and Soles of the Feet (SOF) is one program that teaches internal awareness of personal events (e.g., unpleasant emotions) and a self-regulation strategy to decrease disruptive behaviors. This study conducted a meta-analysis of single-case research design (SCRD) studies that implemented SOF to decrease disruptive behaviors. Existing SOF studies were evaluated using high-quality SCRD standards, resulting in 15 studies included in the analysis (49 participants; mean age 23.12 years (SD = 15.87); highly heterogeneous backgrounds). Studies were analyzed to calculate effect sizes using Tau-U, an innovative non-parametric statistical approach for estimating effect sizes in SCRD studies. The aggregated weighted Tau-U effect size of SOF across all studies was -0.87. Moderator analyses indicated SOF's effectiveness was robust across participant characteristics and delivery formats. This meta-analysis suggests that SOF is a moderately effective evidence-based practice for reducing disruptive behavior.


Overview of MMP-13 as a Promising Target for the Treatment of Osteoarthritis.
Osteoarthritis (OA) is a common degenerative disease characterized by the destruction of articular cartilage and chronic inflammation of surrounding tissues. Matrix metalloproteinase-13 (MMP-13) is the primary MMP involved in cartilage degradation through its particular ability to cleave type II collagen. Hence, it is an attractive target for the treatment of OA. However, the detailed molecular mechanisms of OA initiation and progression remain elusive, and, currently, there are no interventions available to restore degraded cartilage. This review fully illustrates the involvement of MMP-13 in the initiation and progression of OA through the regulation of MMP-13 activity at the molecular and epigenetic levels, as well as the strategies that have been employed against MMP-13. The aim of this review is to identify MMP-13 as an attractive target for inhibitor development in the treatment of OA.


Lipid-anchored drugs for delivery into subcellular compartments.
Bioavailability is a quantitative measure of the capacity of a drug to reach systemic circulation. However, if a drug target is localized in a subcellular organelle, then the drug may not be able to reach it and the effect of the drug will not be attained. Although most drug targets are localized within intracellular compartments, specific targeting of drugs at the subcellular level is not well established. Membrane proteins, lipids, nutrients and some pathogens are internalized into the cell to be targeted to distinct subcellular compartments via membrane trafficking. Recent advances have identified novel methods of subcellular drug targeting, involving the use of conjugation to ligands of cell surface receptors or to lipid anchors. In this review, we focus on the importance of subcellular targeting of drugs, in particular, the mechanism of lipid-anchoring as a novel strategy and its potential application for the treatment of several diseases.


The Eukaryotic-Specific ISD11 Is a Complex-Orphan Protein with Ability to Bind the Prokaryotic IscS.
The eukaryotic protein Isd11 is a chaperone that binds and stabilizes the central component of the essential metabolic pathway responsible for formation of iron-sulfur clusters in mitochondria, the desulfurase Nfs1. Little is known about the exact role of Isd11. Here, we show that human Isd11 (ISD11) is a helical protein which exists in solution as an equilibrium between monomer, dimeric and tetrameric species when in the absence of human Nfs1 (NFS1). We also show that, surprisingly, recombinant ISD11 expressed in E. coli co-purifies with the bacterial orthologue of NFS1, IscS. Binding is weak but specific suggesting that, despite the absence of Isd11 sequences in bacteria, there is enough conservation between the two desulfurases to retain a similar mode of interaction. This knowledge may inform us on the conservation of the mode of binding of Isd11 to the desulfurase. We used evolutionary evidence to suggest Isd11 residues involved in the interaction.


Selective delivery of a therapeutic gene for treatment of head and neck squamous cell carcinoma using human neural stem cells.
Based on studies of the extensive tropism of neural stem cells (NSCs) toward malignant brain tumor, we hypothesized that NSCs could also target head and neck squamous cell carcinoma (HNSCC) and could be used as a cellular therapeutic delivery system. To apply this strategy to the treatment of HNSCC, we used a human NSC line expressing cytosine deaminase (HB1.F3-CD), an enzyme that converts 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU), an anticancer agent. HB1. F3-CD in combination with 5-FC were cocultured with the HNSCC (SNU-1041) to examine the cytotoxicity on target tumor cells in vitro. For in vivo studies, an HNSCC mouse model was created by subcutaneous implantation of human HNSCC cells into athymic nude mice. HB1.F3-CD cells were injected into mice using tumoral, peritumoral, or intravenous injections, followed by systemic 5-FC administration. In vitro, the HB1.F3-CD cells significantly inhibited the growth of an HNSCC cell line in the presence of the 5-FC. Independent of the method of injection, the HB1.F3-CD cells migrated to the HNSCC tumor, causing a significant reduction in tumor volume. In comparison to 5-FU administration, HB1.F3-CD cell injection followed by 5-FC administration reduced systemic toxicity, but achieved the same level of therapeutic efficacy. Transplantation of human NSCs that express the suicide enzyme cytosine deaminase combined with systemic administration of the prodrug 5-FC may be an effective regimen for the treatment of HNSCC.


Reliability and validity of the myositis disease activity assessment tool.
To test the interrater reliability and validity of the Myositis Disease Activity Assessment Tool, which consists of the Myositis Intention-to-Treat Activity Index and the Myositis Disease Activity Assessment Visual Analog Scales. Two phases of the study were conducted to assess the reliability and validity of the tool, which was modified following the first phase. In the first phase of the reliability study, 123 adult myositis patients were evaluated in 7 centers, and in the second phase 40 patients were evaluated in 2 centers. The validity study included 294 patients in 5 centers in the first phase and 65 patients in 3 centers in the second phase. The interrater reliability was assessed using intraclass correlation coefficients. The criterion validity was calculated using sensitivity, specificity, and positive predictive value (PPV) of a grade of A in any system. Spearman's rank correlation coefficient was used to measure the convergent validity of cross-sectional scores between the 2 instruments. There was a 2:1 ratio of female to male patients. There was no significant difference in mean age at diagnosis (46.3 versus 46.8 years) and mean disease duration (7.7 versus 10 years) between the 2 groups recruited for the different phases of the study. There was an improvement in interrater reliability in the second phase of the study. There was a significant improvement in the validity of the assessment tool following modification of the tool. The sensitivity, specificity, and PPV of a grade of A in any system improved from 86%, 92%, and 67% in the first phase to 96%, 94%, and 83%, respectively, in the second phase. Convergent validity between the 2 activity tools showed good correlation, ranging from 0.8 to 0.94, for the individual organ systems. This is the first major attempt to assess the reliability and validity of a disease activity index in myositis. Our findings indicate that, following within-study modification, the tool appears to be a reliable and valid instrument to assess myositis disease activity.


A silver lining? The connection between gasoline prices and obesity.
I find evidence of a negative association between gasoline prices and body weight using a fixed effects model with several robustness checks. I also show that increases in gas prices are associated with additional walking and a reduction in the frequency with which people eat at restaurants, explaining their effect on weight. My estimates imply that 8% of the rise in obesity between 1979 and 2004 can be attributed to the concurrent drop in real gas prices, and that a permanent $1 increase in gasoline prices would reduce overweight and obesity in the United States by 7% and 10%.


Barriers to access in pediatric living-donor liver transplantation.
Children receiving a LDLT have superior post-transplant outcomes, but this procedure is only used for 10% of transplant recipients. Better understanding about barriers toward LDLT and the sociodemographic characteristics that influence these underlying mechanisms would help to inform strategies to increase its use. We conducted an online, anonymous survey of parents/caregivers for children awaiting, or have received, a liver transplant regarding their knowledge and attitudes about LDLT. The survey was completed by 217 respondents. While 97% of respondents understood an individual could donate a portion of their liver, only 72% knew the steps in evaluation, and 69% understood the donor surgery was covered by the recipient's insurance. Individuals with public insurance were less likely than those with private insurance to know the steps for LDLT evaluation (44% vs 82%; P < 0.001). Respondents with public insurance were less likely to know someone that had been a living donor (44% vs 56%; P = 0.005) as were individuals without a college degree (64% vs 85%; P = 0.007). Nearly all respondents generally trusted their healthcare team. Among respondents, 82% believed they were well-informed about LDLT but individuals with public insurance were significantly less likely to feel well-informed (67% vs 87%; P = 0.03) and to understand how donor surgery might impact donor work/time off (44% vs 81%; P = 0.001). Substantial gaps exist in parental understanding about LDLT, including its evaluation, potential benefits, and complications. Greater emphasis on addressing these barriers, especially to individuals with fewer resources, will be helpful to expand the use of LDLT.


The older sickle cell patient.
The lifespan of sickle cell patients has increased substantially. We chose to compare the attributes of older sickle cell patients with younger ones within the confines of a single institutional study serving the local Bronx population. Laboratory and clinical assessments from 40 patients with sickle cell disease over 40 years of age were compared to 40 patients under 30 years of age. When the older group was compared to the younger group, hemoglobin, indirect bilirubin, and platelet counts were significantly lower. Creatinine clearances were lower and BUN levels were higher in the older group. Although the prevalence of radiographically measured cardiomegaly was significantly higher in the older group, systolic and diastolic blood pressures remained unchanged. The number of crises and number of admissions were higher in the younger group than in the older, but there was wide variation, and no significant differences could be detected; days spent in hospital over the previous 2 years did not differ. No statistically significant differences were observed for absolute reticulocyte count, MCV, % HbF, white cell count, liver function tests, or oxygen saturation. Comparing genders within age groups, younger males had higher hemoglobin levels and absolute reticulocyte counts than younger females, while only the older females had higher HbF levels than the corresponding males. Lower levels of hemoglobin associated with older age may reflect decreased hematopoietic potential that may in part be due to decreased renal function. Lower platelet counts in older sickle cell patients may be a consequence of this decreased hematopoietic potential but may also represent a secondary survival benefit effect in sickle cell anemia.


A new technique for the estimation of cardiac motion in echocardiography based on transverse oscillations: a preliminary evaluation in silico and a feasibility demonstration in vivo.
Quantification of regional myocardial motion and deformation from cardiac ultrasound is fostering considerable research efforts. Despite the tremendous improvements done in the field, all existing approaches still face a common limitation which is intrinsically connected with the formation of the ultrasound images. Specifically, the reduced lateral resolution and the absence of phase information in the lateral direction highly limit the accuracy in the computation of lateral displacements. In this context, this paper introduces a novel setup for the estimation of cardiac motion with ultrasound. The framework includes an unconventional beamforming technique and a dedicated motion estimation algorithm. The beamformer aims at introducing phase information in the lateral direction by producing transverse oscillations. The estimator directly exploits the phase information in the two directions by decomposing the image into two 2-D single-orthant analytic signals. An in silico evaluation of the proposed framework is presented on five ultra-realistic simulated echocardiographic sequences, where the proposed motion estimator is contrasted against other two phase-based solutions exploiting the presence of transverse oscillations and against block-matching on standard images. An implementation of the new beamforming strategy on a research ultrasound platform is also shown along with a preliminary in vivo evaluation on one healthy subject.


Why are long-acting beta-adrenoceptor agonists long-acting?
The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.


Expression of kidney-specific cadherin in chromophobe renal cell carcinoma and renal oncocytoma.
Kidney-specific cadherin (Ksp-cad) recently was proposed to differentiate chromophobe renal cell carcinoma (RCC) from oncocytoma based on a finding of Ksp-cad expression in 97% of chromophobe RCCs but only 3% of oncocytomas. However, another study showed no difference in Ksp-cad immunoreactivity between these 2 tumors. We attempted to evaluate Ksp-cad expression in renal tumors using expression microarrays and immunohistochemical analysis. Ksp-cad messenger RNA (mRNA) levels were examined in 158 renal tumors, including 15 chromophobe RCCs and 15 oncocytomas. Immunohistochemical analysis was performed on tissue microarrays containing 125 renal tumors, including 36 chromophobe RCCs and 41 oncocytomas. Ksp-cad mRNA compared with normal kidney tissue was 89% in chromophobe RCC and 64% in oncocytoma. Furthermore, 31 of 36 chromophobe RCCs and 31 of 41 oncocytomas showed Ksp-cad immunoreactivity. Ksp-cad was present in chromophobe RCCs and oncocytomas at mRNA and protein levels, providing strong evidence that Ksp-cad immunohistochemical analysis cannot be used in differentiating these tumors.


Treatment of hemorrhagic radiation proctitis with 4 percent formalin.
The purpose of this study was to review our results in patients undergoing treatment with 4 percent formalin for radiation-induced injury to the rectum. A retrospective review of office charts was performed, identifying all patients undergoing formalin treatment. Patient gender, initial malignancy, prior treatments, response to treatment with formalin, complications, and length of follow-up were reviewed. All patients had flexible endoscopy to assess for proximal sources of bleeding. The indication for treatment was a symptomatic patient with endoscopic evidence of radiation injury. A cotton pledget was used for direct application of 4 percent formalin to the affected area via a rigid proctoscope or anoscope. The treatment was repeated if blanching did not occur or if bleeding continued. Patients were followed up at three-week to four-week intervals and treatment was repeated based on the above indications. Treatments were continued until cessation of bleeding occurred or, when treatment failed, operative treatment was required. Thirty-six patients were identified. Three were lost to follow-up. Symptoms included bleeding in all but one patient, who presented with an ulcer. There were 33 (26 male) patients. Seventeen (51.5 percent) patients had prior treatment. The number of formalin treatments ranged from 1 to 13, with a mean of 3.4. The follow-up ranged from 1 to 60 months, with a mean of 18 months. Twenty-nine (88 percent) patients had improvement or cessation of symptoms. Four (12 percent) patients failed treatment. Two patients were noted to have full-thickness ulcers and both failed formalin treatment. No complications were noted related to formalin treatment. We conclude that formalin therapy is a safe and effective form of treatment that can be performed in the office with minimal discomfort and no complications. It can be performed multiple times until results are achieved. Formalin therapy may be useful as a first-line treatment for chronic radiation proctitis, however, a prospective controlled trial comparing modalities is required to prove this to be true.


Blindness and eye disease in Kenya: ocular status survey results from the Kenya Rural Blindness Prevention Project.
A series of eight regional eye surveys were conducted in Kenya as part of the Kenya Rural Blindness Prevention Project. Each survey consisted of clinical examinations of about 1800 individuals selected by a random cluster sampling technique in geographically distinct and culturally homogeneous rural areas; 13,803 examinations were completed in all. Together these surveys provide the basis for national estimates of the prevalence and aetiology of visual loss and ocular pathology. The results showed that 0.7% of rural Kenyans are blind in the better eye by WHO standards, and another 2.5% suffer significant visual impairment. Rates of visual loss tend to increase five-fold in each 20-year age cohort. Females have higher prevalence of visual loss than males over age 20, and certain geographical areas have markedly higher rates. The commonest cause of both blindness and visual impairment is cataract, accounting for 38% of all visual loss. Trachoma (a localised problem), glaucoma, macular degeneration, and severe refractive errors follow cataract as leading causes of blindness in the better eye. Trauma, corneal scars of various causes, phthisis, and staphyloma are important causes of monocular blindness. Nutritional eye disease does not appear to be a problem of any magnitude in rural Kenya.


Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells.
Activation of CD4(+) T cells is governed by interplay between stimulatory and inhibitory receptors; predominance of stimulatory signals favors autoimmune reactions. In patients with rheumatoid arthritis, expression of the critical costimulatory molecule, CD28, is frequently lost. Instead, CD4(+)CD28(null) T cells express killer immunoglobulin-like receptors (KIRs) with a preferential expression of the stimulatory receptor, CD158j. The frequency of CD4(+)CD28(null) T cells in rheumatoid arthritis (RA) correlates with the risk for more severe disease. Moreover, the KIR2DS2 gene, which encodes for CD158j, is a genetic risk factor for rheumatoid vasculitis. CD158j signals through the adaptor molecule, KARAP/DAP12, to positively regulate cytotoxic activity in NK cells. However, the majority of CD4(+)CD28(null) T cell clones lacked the expression of KARAP/DAP12. Despite the absence of KARAP/DAP12, CD158j was functional and augmented interferon-gamma production after T cell receptor stimulation. Cross-linking of CD158j resulted in selective phosphorylation of c-Jun NH(2)-terminal protein kinase (JNK) and its upstream kinase, MKK4 that led to the expression of ATF-2 and c-Jun, all in the absence of extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Mutation of the lysine residue within the transmembrane domain of CD158j abolished JNK activation, suggesting that an alternate adaptor molecule was being used. CD4(+)CD28(null) T cells expressed DAP10 and inhibition of phosphatidylinositol 3-kinase, which acts downstream of DAP10, inhibited JNK activation; however, no interaction of DAP10 with CD158j could be detected. Our data suggest that CD158j in T cells functions as a costimulatory molecule through the JNK pathway independent of KARAP/DAP12 and DAP10. Costimulation by CD158j may contribute to the autoreactivity of CD4(+)CD28(null) T cells in RA.


Crystal structure of the second PDZ domain of SAP97 in complex with a GluR-A C-terminal peptide.
Synaptic targeting of GluR-A subunit-containing glutamate receptors involves an interaction with synapse-associated protein 97 (SAP97). The C-terminus of GluR-A, which contains a class I PDZ ligand motif (-x-Ser/Thr-x-phi-COOH where phi is an aliphatic amino acid) associates preferentially with the second PDZ domain of SAP97 (SAP97(PDZ2)). To understand the structural basis of this interaction, we have determined the crystal structures of wild-type and a SAP97(PDZ2) variant in complex with an 18-mer C-terminal peptide (residues 890-907) of GluR-A and of two variant PDZ2 domains in unliganded state at 1.8-2.44 A resolutions. SAP97(PDZ2) folds to a compact globular domain comprising six beta-strands and two alpha-helices, a typical architecture for PDZ domains. In the structure of the peptide complex, only the last four C-terminal residues of the GluR-A are visible, and align as an antiparallel beta-strand in the binding groove of SAP97(PDZ2). The free carboxylate group and the aliphatic side chain of the C-terminal leucine (Leu907), and the hydroxyl group of Thr905 of the GluR-A peptide are engaged in essential class I PDZ interactions. Comparison between the free and complexed structures reveals conformational changes which take place upon peptide binding. The betaAlpha-betaBeta loop moves away from the C-terminal end of alphaB leading to a slight opening of the binding groove, which may better accommodate the peptide ligand. The two conformational states are stabilized by alternative hydrogen bond and coulombic interactions of Lys324 in betaAlpha-betaBeta loop with Asp396 or Thr394 in betaBeta. Results of in vitro binding and immunoprecipitation experiments using a PDZ motif-destroying L907A mutation as well as the insertion of an extra alanine residue between the C-terminal Leu907 and the stop codon are also consistent with a 'classical' type I PDZ interaction between SAP97 and GluR-A C-terminus.


T-cell-biased immune responses generated by a mucosally targeted adenovirus-σ1 vaccine.
As most pathogens enter through the mucosa, it is important to develop vaccines that induce mucosal immunity. To this end, we generated a novel adenovirus (Ad) vaccine that displays the σ1 protein from reovirus to target junctional adhesion molecule 1 and sialic acid. Replication-defective Ad5 vectors were modified by replacement of the Ad fiber protein with σ1 (T3Dσ1) protein of reovirus T3D in previous work. Ad5 and Ad5-σ1 were compared in mouse models for gene delivery and vaccination to monitor cytokine, antibody, and T-cell responses. The viruses were also tested for the ability to transduce and mature dendritic cells. Ad5-σ1 was 40-fold less efficient at gene delivery in vivo, yet it was capable of inducing equal or greater cellular immune responses and systemic interferon-γ levels than Ad5 after intranasal administration. Despite weaker gross transduction, intranasal administration of Ad5-σ1 produced more green fluorescent protein-positive (GFP+) major histocompatibility complex class II (MHC II) cells in the draining lymph nodes, less GFP+/MHC II+ cells in the lungs, and mediated modestly better maturation of dendritic cells in vitro. These data suggest that targeting gene-based vaccination via the σ1 protein may enhance the T-cell immune response, perhaps by skewing immune responses to encoded antigens.


Specific heat capacity of molten salt-based alumina nanofluid.
There is no consensus on the effect of nanoparticle (NP) addition on the specific heat capacity (SHC) of fluids. In addition, the predictions from the existing model have a large discrepancy from the measured SHCs in nanofluids. We show that the SHC of the molten salt-based alumina nanofluid decreases with reducing particle size and increasing particle concentration. The NP size-dependent SHC is resulted from an augmentation of the nanolayer effect as particle size reduces. A model considering the nanolayer effect which supports the experimental results was proposed.


Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.
The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with beta-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.


Multifactorial analysis of lung cancer dose-response relationships for workers at the Mayak nuclear enterprise.
Dose-response relationships for alpha-radiation-induced lung cancers (adenocarcinoma, squamous carcinoma and small cell carcinoma) were developed by multifactorial analysis using data for Mayak nuclear enterprise workers chronically exposed by inhalation to 239Pu. The three most important lung cancer risk factors (smoking, plutonium incorporation, and external gamma irradiation), out of six factors previously identified, were used. Relative risks (odds ratios) were determined for 500 nuclear enterprise workers (162 cancer cases, 338 control) for different dose levels using a case-control study design and logistic regression. A threshold at about 3.7 kBq or 0.80 Gy was discovered for incorporated plutonium, which is satisfactorily described by linear-quadratic and quadratic models. Excess relative risk was 0.020 kBq(-2) and 0.97 Gy(-2). This quadratic function was mainly due to adenocarcinoma. A trend for decreasing risk was noted for the lowest levels of plutonium incorporation, near permissible level. No clear-cut dose-response relationship for lung cancer induction by chronic external gamma irradiation was obtained. Lung cancer induction by cigarette smoking had a linear dependence: smoking of one pack of papiroses (a type of Russian cigarette) per day for 5 y increases the lung cancer risk twofold. The effect was most clearly manifested for squamous-cell carcinoma.


Impact of Pretransplant Bridging Locoregional Therapy for Patients With Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients From the US Multicenter HCC Transplant Consortium.
To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002-2013). Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P < 0.001; 4+ LRTs: HR 2.5, P < 0.001), and unfavorable waitlist alphafetoprotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P < 0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044). Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates.


Contribution of individual histidines to prion protein copper binding.
The prion protein is well-established as a copper binding protein. The N-terminus of the protein contains an octameric repeat region with each of the four repeats containing a histidine. The N-terminus has two additional histidines distal to the repeat region that has been commonly known as the fifth site. While binding of copper by the protein has been extensively studied, the contribution of each histidine to copper binding in the full-length protein has not. Here we used a battery of mutants of the recombinant mouse prion protein to assess copper binding with both isothermal titration calorimetry and cyclic voltammetry. The findings indicate that there is extensive cooperativity between different binding sites in the protein. The two highest-affinity binding events occur at the fifth site and at the octameric repeat region. However, the first binding is that to the octameric repeat region. Subsequent binding events after the two initial binding events have lower affinities within the octameric repeat region.


Role of liver biopsy in management of chronic hepatitis C: a systematic review.
This systematic review addresses 2 questions pertinent to the need for pretreatment liver biopsy in patients with chronic hepatitis C: how well do liver biopsy results predict treatment outcomes for chronic hepatitis C? How well do biochemical blood tests and serologic measures of fibrosis predict the biopsy findings in chronic hepatitis C? Medline and other electronic databases were searched from January 1985 to March 2002. Additional articles were sought in references of pertinent articles and recent journals and by querying experts. Articles were eligible for review if they reported original human data from a study that used virological, histological, pathologic, or clinical outcome measures. Paired reviewers assessed the quality of each eligible study and abstracted data. Studies suggested that advanced fibrosis or cirrhosis on initial liver biopsy is associated with a modestly decreased likelihood of a sustained virological response (SVR) to treatment. Also, studies relatively consistently showed that serum aminotransferases have modest value in predicting fibrosis on biopsy; that extracellular matrix tests hyaluronic acid and laminin may have value in predicting fibrosis, and that panels of tests may have the greatest value in predicting fibrosis or cirrhosis. Biochemical and serologic tests were best at predicting no or minimal fibrosis, or at predicting advanced fibrosis/cirrhosis, and were poor at predicting intermediate levels of fibrosis. Thus, evidence suggests that liver biopsy may have some usefulness in predicting efficacy of treatment in patients with chronic hepatitis C, and biochemical blood tests and serologic tests currently have only modest value in predicting fibrosis on liver biopsy.


Refractive and visual outcome of toric intraocular lens implantation following cataract surgery.
To evaluate the refractive and visual outcome of toric IOL implantation for correction of pre-existing corneal astigmatism following cataract surgery. In this retrospective study, 56 eyes of 30 patients who underwent implantation of toric IOL following regular phacoemulsification were divided into two groups based on the types of toric IOL implanted: group 1 patients received Acrysof toric (Alcon) and group 2 patients received AT-Torbi (Zeiss Meditech) IOLs. Pre-and post-operative corneal and refractive astigmatisms, and post-operative distance vision were investigated. Statistical analysis was carried out using the paired student t-test when necessary. Factors affecting the success of toric IOL implantation are discussed and recommendations are made to optimize the outcome. The mean age of all patients was 75.56 � 9.87 years. No statistical difference was observed between pre-and post-operative corneal astigmatism (p = 0.819). Postoperative refractive astigmatism was significantly less in both groups (Group 1: p = 0.0014; Group 2: p= less than0.00001). The best-corrected distance visual acuity was 6/12 or better in 95 % of group 1 and 100 % of group 2 patients. Toric IOL implantation is a viable and highly predictable method of correcting the corneal astigmatism. It allows correction without compromising the integrity of the cornea. Careful selection of the patient, accurate keratometry and precise alignment of the cylindrical axes are some of the factors to be considered for a superior outcome.


How antisolvent miscibility affects perovskite film wrinkling and photovoltaic properties.
Charge carriers' density, their lifetime, mobility, and the existence of trap states are strongly affected by the microscopic morphologies of perovskite films, and have a direct influence on the photovoltaic performance. Here, we report on micro-wrinkled perovskite layers to enhance photocarrier transport performances. By utilizing temperature-dependent miscibility of dimethyl sulfoxide with diethyl ether, the geometry of the microscopic wrinkles of the perovskite films are controlled. Wrinkling is pronounced as temperature of diethyl ether (TDE) decreases due to the compressive stress relaxation of the thin rigid film-capped viscoelastic layer. Time-correlated single-photon counting reveals longer carrier lifetime at the hill sites than at the valley sites. The wrinkled morphology formed at TDE = 5 °C shows higher power conversion efficiency (PCE) and better stability than the flat one formed at TDE = 30 °C. Interfacial and additive engineering improve further PCE to 23.02%. This study provides important insight into correlation between lattice strain and carrier properties in perovskite photovoltaics.


Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4.
We have recently shown that mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). Here, we report the exon-intron organization and partial sequence of the human HNF-1alpha gene. In addition, we have screened the ten exons and flanking introns of this gene for mutations in a group of 25 unrelated white subjects from Germany who presented with NIDDM before 35 years of age and had a first-degree relative with NIDDM. Mutations were identified in nine of these individuals, suggesting that mutations in the HNF-1alpha gene are a common cause of diabetes in German subjects with early-onset NIDDM and a family history of diabetes. Thus, screening for mutations in this gene may be indicated in subjects with early-onset NIDDM. Interestingly, three of the nine mutations occurred at the same site in exon 4 with insertion of a C in a polyC tract, centered around codon 290 (designated Pro291fsinsC), thereby resulting in a frameshift during translation and premature termination. Analyses of linked DNA polymorphisms in the HNF-1alpha gene indicated that the Pro291fsinsC mutation was present on a different haplotype in each subject, implying that the polyC tract represents a mutational hot spot. We have also identified the mutation in the HNF-1alpha gene in the Jutland pedigree, one of the original MODY pedigrees reported in the literature, as being a T-->G substitution in codon 241, resulting in the replacement of a conserved Cys by Gly (C241G). The information on the sequence of the HNF-1alpha gene and its promoter region will facilitate the search for mutations in other subjects and studies of the role of the gene in determining normal beta-cell functions.


Synthesis of 2H-Chromenes via Hydrazine-Catalyzed Ring-Closing Carbonyl-Olefin Metathesis.
The catalytic ring-closing carbonyl-olefin metathesis (RCCOM) of O-allyl salicylaldehydes to form 2H-chromenes is described. The method utilizes a [2.2.1]-bicyclic hydrazine catalyst and operates via a [3+2]/retro-[3+2] metathesis manifold. The nature of the allyl substitution pattern was found to be crucial, with sterically demanding groups such as adamantylidene or diethylidene offering optimal outcomes. A survey of substrate scope is shown along with a discussion of mechanism supported by DFT calculations. Steric pressure arising from syn-pentane minimization of the diethylidene moiety is proposed to facilitate cycloreversion.


A molecular approach to magnetic metallic nanostructures from metallopolymer precursors.
In recent years, metallopolymers have attracted much attention as precursors to generate magnetic metal/metal alloy nanoparticles (NPs) through pyrolysis or photolysis because they offer the advantages of ease of solution processability, atomic level mixing and stoichiometric control over composition. The as-generated NPs usually possess narrow size distributions with precise control of composition and density per unit area. Moreover, patterned NPs can be achieved on various substrates in this way owing to the good film-forming property of metallopolymers and such work is important for many applications based on metal nanostructures. By combining the merits of both the solution processability of metallopolymers and nanoimprint lithography (NIL), a new platform can be created for fabricating bit-patterned media (BPM) and the next-generation of nanoscale ultra-high-density magnetic data storage devices. Furthermore, most of these metallopolymers can be used directly as a negative-tone resist to generate magnetic metallic nanostructures by electron-beam lithography and UV photolithography. Self-assembly and subsequent pyrolysis of metalloblock copolymers can also afford well-patterned magnetic metal or metal alloy NPs in situ with periodicity down to dozens of nanometers. In this review, we highlight the use of metallopolymer precursors for the synthesis of magnetic metal/metal alloy NPs and their nanostructures and the related applications.


Microsurgical vasovasostomy after failed vasovasostomy.
We analyzed our experience with repeat microsurgical vasovasostomy after failed vasovasostomy and elucidate the possible predictors of surgical outcome. We evaluated 62 repeat vasectomy reversal cases with followup data available. Regardless of the intraoperative observation of sperm in the vasal fluid bilateral microsurgical 2-layer vasovasostomy was performed when surgically possible. Of these 62 patients 60 (97%) underwent bilateral (58) or unilateral (2) vasovasostomy and 2 (3%) underwent unilateral vasovasostomy with contralateral epididymovasostomy. Patency and pregnancy followup data were available on 62 and 42 patients, respectively. The overall patency and pregnancy rates achieved were 92% and 57%, respectively, and the natural birth rate was 52%. Increased age of the wife proved a negative prognostic factor for pregnancy (p = 0.018). The intraoperative detection of sperm and other factors, including obstructive interval, reconstruction type, anastomotic site, patient age and postoperative semen parameters, did not influence the surgical outcome. Regardless of the detection of sperm in the intravasal fluid during the operation repeat microsurgical vasovasostomy resulted in a better outcome than in other studies, in which adopted epididymovasostomy was done when sperm was absent from the vas fluid. Our study suggests that compromised anastomosis after previous surgery is the most common cause of failed vasovasostomy. We recommend that microsurgical vasovasostomy should be performed preferentially in failed vasovasostomy cases.


Specific IgM and IgG responses in primary and secondary dengue virus infections determined by enzyme-linked immunosorbent assay.
IgM- and IgG-capture ELISAs are widely used as diagnostic tests for confirmation of dengue virus infection. The positive rate of anti-dengue IgM and IgG detection was examined in primary and secondary dengue virus infections in the setting of a provincial hospital using IgM- and IgG-capture ELISAs. Disease day 1 was defined as the day of onset of symptoms. In total, 232 plasma samples were collected from 106 confirmed dengue cases consisting of 12 primary and 94 secondary infections. In primary infection, anti-dengue IgM was detected in 4 out of 5 samples collected on disease day 5 and in all the 21 samples collected on disease day 6 or later. Specific IgG was detected in 2 out of 5 samples collected on day 12, and in 5 out of 6 samples collected on disease days 13-15, but was not detected in samples collected on disease day 10 or earlier. In secondary infection, IgM was not detected in the samples on disease days 2 and 3, but detected in 20 out of 79 samples collected on days 4-6, in 44 out of 65 on disease days 7-11 and in 40 out of 51 samples on disease days 12-14. In contrast, specific IgG was detected in 21 out of 60 samples on disease days 4 and 5, in 13 out of 19 on disease day 6, in 62 out of 65 on disease days 7-11 and in all the samples collected on disease day 12 or later. The result indicate that seroconversion rates of IgM and IgG are different between primary and secondary infections, and suggest that detection of specific IgM and IgG is necessary for determining dengue virus infection and for differentiating primary and secondary dengue infections.


Chronic myeloid leukemia (CML): prognostic factors and survival analysis.
The prognostic value of different factors upon diagnosis of CML was analysed in 45 Philadelphia (Ph1)-positive patients. The median survival was 48 months. Univariate analysis showed 5 poor prognostic factors (male sex, under 45 years-old, bone marrow blasts greater than or equal to 10 percent, blood basophils greater than or equal to 6 percent and blood eosinophils greater than or equal to 6 percent) which provided for the development of a clinical staging system: Stage I with none or one factor and a two-year survival rate of 100 percent; Stage II with two or three factors and two-year survival of 72.2 percent; and Stage III with four or five factors and two-year survival of 0 percent (p = 0.00016). Multivariate survival analysis showed that combination of blood basophilia and bone marrow blasts had the strongest predictive relationship to survival time. We conclude that a combination of pretreatment factors identifies different risk subcategories in CML patients and is helpful in assessing the overall prognosis and the treatment approach.


Compartmentalised cAMP signalling in the primary cilium.
cAMP is a universal second messenger that relies on precise spatio-temporal regulation to control varied, and often opposing, cellular functions. This is achieved via selective activation of effectors embedded in multiprotein complexes, or signalosomes, that reside at distinct subcellular locations. cAMP is also one of many pathways known to operate within the primary cilium. Dysfunction of ciliary signaling leads to a class of diseases known as ciliopathies. In Autosomal Dominant Polycystic Kidney Disease (ADPKD), a ciliopathy characterized by the formation of fluid-filled kidney cysts, upregulation of cAMP signaling is known to drive cystogenesis. For decades it has been debated whether the primary cilium is an independent cAMP sub-compartment, or whether it shares a diffusible pool of cAMP with the cell body. Recent studies now suggest it is a specific pool of cAMP generated in the cilium that propels cyst formation in ADPKD, supporting the notion that this antenna-like organelle is a compartment within which cAMP signaling occurs independently from cAMP signaling in the bulk cytosol. Here we present examples of cAMP function in the cilium which suggest this mysterious organelle is home to more than one cAMP signalosome. We review evidence that ciliary membrane localization of G-Protein Coupled Receptors (GPCRs) determines their downstream function and discuss how optogenetic tools have contributed to establish that cAMP generated in the primary cilium can drive cystogenesis.


Neuroprotective Effects of Hesperidin on Cerebral Vasospasm After Experimental Subarachnoid Hemorrhage in Rats: Biochemical, Pathologic, and Histomorphometric Analysis.
We examined the protective effects of hesperidin on cerebral vasospasm by establishing an experimental rat model of subarachnoid hemorrhage and performing biochemical, pathologic, and histomorphometric analysis on these data. Forty albino Wistar rats were randomly divided into 5 groups of n = 8 in each: group (G)1, no experimental interventions; G2, subjected to subarachnoid hemorrhage; G3, subjected to subarachnoid hemorrhage and administered saline (100 mg/kg); G4, subjected to subarachnoid hemorrhage and treated with low-dose hesperidin (50 mg/kg); and G5, subjected to subarachnoid hemorrhage and treated with high-dose hesperidin (100 mg/kg). Subarachnoid hemorrhage was created by injecting 0.15 cc of autologous blood taken from the rat-tail artery and injected into the cisterna magna from the craniocervical junction. Drugs were administered intraperitoneally as twice daily doses for 48 hours. Rats were euthanized at the end of this period. No statistically significant decrease was observed in malondialdehyde levels, which is the end-product of lipid peroxidation, among the drug groups (G4 and G5). Thin sections prepared from the basilar artery were examined morphologically. Severe luminal narrowing and vessel-wall thickening were observed in the subarachnoid hemorrhage groups (G2, G3). In the hesperidin-administered groups (G4, G5), it was determined that vessel wall thickness measurements revealed thinner walls than in the subarachnoid hemorrhage groups (G2, G3) and the luminal diameters were significantly larger than in the subarachnoid hemorrhage groups (G2, G3). These findings suggest that hesperidin has no effect on malondialdehyde-associated lipid-peroxidation activity; however, it might be useful in subarachnoid hemorrhage therapy because of its beneficial effects on vessel wall thickness and luminal diameters.


R3DE: Radiation Risk Radiometer-Dosimeter on the International Space Station--optical radiation data recorded during 18 months of EXPOSE-E exposure to open space.
Radiation Risk Radiometer-Dosimeter E (R3DE) served as a device for measuring ionizing and non-ionizing radiation as well as cosmic radiation reaching biological samples located on the EXPOSE platform EXPOSE-E. The duration of the mission was almost 1.5 years (2008-2009). With four channels, R3DE detected the wavelength ranges of photosynthetically active radiation (PAR, 400-700 nm), UVA (315-400 nm), UVB (280-315 nm), and UVC (<280 nm). In addition, the temperature was recorded. Cosmic ionizing radiation was assessed with a 256-channel spectrometer dosimeter (see separate report in this issue). The light and UV sensors of the device were calibrated with spectral measurement data obtained by the Solar Radiation and Climate Experiment (SORCE) satellite as standard. The data were corrected with respect to the cosine error of the diodes. Measurement frequency was 0.1 Hz. Due to errors in data transmission or temporary termination of EXPOSE power, not all data could be acquired. Radiation was not constant during the mission. At regular intervals of about 2 months, low or almost no radiation was encountered. The radiation dose during the mission was 1823.98 MJ m(-2) for PAR, 269.03 MJ m(-2) for UVA, 45.73 MJ m(-2) for UVB, or 18.28 MJ m(-2) for UVC. Registered sunshine duration during the mission was about 152 days (about 27% of mission time).The surface of EXPOSE was most likely turned away from the Sun for considerably longer. R3DE played a crucial role on EXPOSE-EuTEF (EuTEF, European Technology Exposure Facility), because evaluation of the astrobiology experiments depended on reliability of the data collected by the device. Observed effects in the samples were weighted by radiation doses measured by R3DE.


Extreme pathway lengths and reaction participation in genome-scale metabolic networks.
Extreme pathways are a unique and minimal set of vectors that completely characterize the steady-state capabilities of genome-scale metabolic networks. A framework is provided to mathematically characterize extreme pathway length and to study how individual reactions participate in the extreme pathway structure of a network. The length of an extreme pathway is the number of reactions that comprise it. Reaction participation is the percentage of extreme pathways that utilize a given reaction. These properties were computed for the production of individual amino acids and protein production in Helicobacter pylori and individual amino acid production in Haemophilus influenzae. Reaction participation classifies the reactions into groups that are always, sometimes, or never utilized for the production of a target product. The utilized reactions can be further grouped into correlated subsets of reactions, some of which are non-obvious, and which may, in turn, suggest regulatory structure. The length of the extreme pathways did not correlate with product yield or chemical complexity. The distributions of extreme pathway lengths in H. pylori were also very different from those in H. influenzae, showing a distinct systemic difference between the two organisms, despite overall similar metabolic networks. Reaction participation and extreme pathway lengths thus serve to elucidate systemic biological features.


A sketch of language history in the Korean Peninsula.
Among 7100 languages spoken on Earth, the Koreanic language is the 13th largest, with about 77 million speakers in and around the Korean Peninsula. In comparison to other languages of similar size, however, surprisingly little is known about the evolution of the Koreanic language. This is mainly due to two reasons. The first reason is that the genealogical relationship of the Koreanic to other neighboring languages remains uncertain, and thus inference from the linguistic comparative method provides only provisional evidence. The second reason is that, as the ancestral Koreanic speakers lacked their own writing system until around 500 years ago, there are scant historical materials to peer into the past, except for those preserved in Sinitic characters that we have no straightforward way of interpreting. Here I attempt to overcome these disadvantages and shed some light on the linguistic history of the Korean Peninsula, by analyzing the internal variation of the Koreanic language with methods adopted from evolutionary biology. The preliminary results presented here suggest that the evolutionary history of the Koreanic language is characterized by a weak hierarchical structure, and intensive gene/culture flows within the Korean Peninsula seem to have promoted linguistic homogeneity among the Koreanic variants. Despite the gene/culture flows, however, there are still three detectable linguistic barriers in the Korean Peninsula that appear to have been shaped by geographical features such as mountains, elevated areas, and ocean. I discuss these findings in an inclusive manner to lay the groundwork for future studies.


Breastfeeding promotion: evidence and problems.
Although breastfeeding is associated with many health benefits in children and mothers, and World Health Organization (WHO) recommends exclusive breastfeeding until 6 months of age and continued breastfeeding until 2 years of age, overall breastfeeding rates remain low. Italian rates of exclusive breastfeeding do not differ from international data. The aim of this review is to evaluate evidence of breastfeeding promotion interventions and the remaining problems to achieve them. We found that breastfeeding support is a complex system of interventions, including individual, structural and environmental factors. Many systematic reviews report evidence that breastfeeding support offered to women increases duration and exclusivity of breastfeeding, both in full term healthy newborns and in preterm infants. Political and economic efforts should be made to ensure breastfeeding support to all women in the different settings, assuming it as a collective target.


A critical overview of the current myofascial pain literature - October 2015.
The number of publications about myofascial pain and trigger points (TrP) seems to increase every year. In the current overview we include 27 articles published in past months. The Basic Review section includes articles about the presence and characteristics of TrPs in various neck and shoulder muscles, the correlation between referred pain from active TrPs and knee osteoarthritis, and an anatomical study exploring whether the location of TrPs may be related to the nerve innervation of muscles. Zuil-Escobar and colleagues from Spain considered the intra-rater reliability of the identification of latent TrPs in several leg muscles and the possible correlation of TrP and the presence of a lower medial longitudinal arch. In the section on manual approaches, contributing author Rob Grieve and colleagues continue their studies of TrPs in the lower extremity muscles, while Méndez-Rebolledo and colleagues studied the impact of cross taping and compression. Dry needling (DN) continues to be a topic of interest. We included twelve papers addressing a wide range of topics, such as the effectiveness and safety of DN, and the impact of DN on proprioception, spasticity, and fibromyalgia. Two papers investigated the utilization of repetitive transcranial magnetic stimulation and laser on TrPs, The final section on other clinical studies and reviews includes 8 papers. The studies originated in thirteen different countries with Spain leading the charts with 7 contributions to the literature, followed by Brazil with four. As we have mentioned in previous editions of this literature overview, many studies suffer from very small sample sizes, which makes it difficult to reach definitive conclusions. Nevertheless, myofascial pain continues to be a topic of interest to researchers and clinicians around the globe.


The future of health behavior change research: what is needed to improve translation of research into health promotion practice?
It is well documented that the results of most behavioral and health promotion studies have not been translated into practice. In this article, reasons for this gap, focusing on study design characteristics as a central contributing barrier, are discussed. Four reviews of recent controlled studies in work sites, health care, school, and community settings are briefly discussed and summarized. Their implications for future research and for closing the gap between research and practice are then discussed. These reviews come to consistent conclusions regarding key internal and external validity factors that have and have not been reported. It is very clear that moderating variables and generalization issues have not been included or reported in the majority of investigations, and that as a consequence little is known about the representatives or the robustness of results from current studies. To significantly improve the current state of affairs, substantial changes will be required on the part of researchers, funding agencies, and review and editorial boards. In conclusion, recommendations for each of these entities are provided.


Resonant holography.
We present a method of enhancing the diffraction efficiency of a hologram by placing it inside a resonant optical cavity. The diffraction efficiency improves on account of the multiple passes that the incident light undergoes inside the optical cavity. The resonance condition in this case turns out to involve both mirror reflectivity and the optical path length inside the cavity. Experimental results for a resonantly enhanced angle-multiplexed holographic memory and an optical three-port element are shown.


Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target.
Broadly neutralizing antibodies (bNAbs), which develop over time in some HIV-1-infected individuals, define critical epitopes for HIV vaccine design. Using a systematic approach, we have examined neutralization breadth in the sera of about 1800 HIV-1-infected individuals, primarily infected with non-clade B viruses, and have selected donors for monoclonal antibody (mAb) generation. We then used a high-throughput neutralization screen of antibody-containing culture supernatants from about 30,000 activated memory B cells from a clade A-infected African donor to isolate two potent mAbs that target a broadly neutralizing epitope. This epitope is preferentially expressed on trimeric Envelope protein and spans conserved regions of variable loops of the gp120 subunit. The results provide a framework for the design of new vaccine candidates for the elicitation of bNAb responses.


Constraining the p-Mode-g-Mode Tidal Instability with GW170817.
We analyze the impact of a proposed tidal instability coupling p modes and g modes within neutron stars on GW170817. This nonresonant instability transfers energy from the orbit of the binary to internal modes of the stars, accelerating the gravitational-wave driven inspiral. We model the impact of this instability on the phasing of the gravitational wave signal using three parameters per star: an overall amplitude, a saturation frequency, and a spectral index. Incorporating these additional parameters, we compute the Bayes factor (lnB_{!pg}^{pg}) comparing our p-g model to a standard one. We find that the observed signal is consistent with waveform models that neglect p-g effects, with lnB_{!pg}^{pg}=0.03_{-0.58}^{+0.70} (maximum a posteriori and 90% credible region). By injecting simulated signals that do not include p-g effects and recovering them with the p-g model, we show that there is a ≃50% probability of obtaining similar lnB_{!pg}^{pg} even when p-g effects are absent. We find that the p-g amplitude for 1.4 M_{⊙} neutron stars is constrained to less than a few tenths of the theoretical maximum, with maxima a posteriori near one-tenth this maximum and p-g saturation frequency ∼70 Hz. This suggests that there are less than a few hundred excited modes, assuming they all saturate by wave breaking. For comparison, theoretical upper bounds suggest ≲10^{3} modes saturate by wave breaking. Thus, the measured constraints only rule out extreme values of the p-g parameters. They also imply that the instability dissipates ≲10^{51} erg over the entire inspiral, i.e., less than a few percent of the energy radiated as gravitational waves.


ASSOCIATION OF GERMFREE MICE WITH BACTERIA ISOLATED FROM NORMAL MICE.
Germfree mice were given food contaminated with pure cultures of various bacterial species isolated from ordinary healthy mice. The cultures were given singly, or in association, or consecutively at weekly intervals. Whatever the technique of administration, the lactobacilli and anaerobic streptococci immediately established themselves throughout the gastrointestinal tract, and became closely associated with the walls of the organs. In contrast, the organisms of the bacteroides group were found in large numbers only in the large intestine. Within a week after exposure, the populations of these three bacterial species reached levels similar to those found in ordinary mice. They remained at these characteristic levels throughout the period of observation (several months). Their presence resulted in a progressive decrease in the size of the cecum which eventually became normal in gross appearance. Coliform bacilli multiplied extensively and persisted at high levels in all parts of the gastrointestinal tract of germfree mice, even after these had become colonized with lactobacilli, anaerobic streptococci and bacteroides. However, the coliform population fell precipitously within a few days after the animals were fed the intestinal contents of healthy pathogen-free mice.


Reduced life span of anergic self-reactive B cells in a double-transgenic model.
The life span of anergic self-reactive B cells was determined by 5-bromo-2'-deoxyuridine (BrdU) loading of tolerant double-transgenic (Dbl-Tg) mice produced by mating hen egg lysozyme (HEL)-transgenic mice with the corresponding immunoglobulin-transgenic (Ig-Tg) mice, the B cells of which express anti-HEL IgM and IgD. B cells from Dbl-Tg mice, despite being exposed to soluble antigen throughout their development, are not deleted, but persist in an anergic state. As a prelude to studying the life span of these anergic B cells, BrdU was administered to nontransgenic mice; B cells from the bone marrow, spleen, and lymph nodes displayed distinct kinetic profiles based on reciprocal expression of the B220 isoform of CD45 and heat-stable antigen (HSA). Thus, immature B220lo/HSAhi B cells incorporated BrdU rapidly suggesting recent generation from dividing precursors, whereas uptake by B cells expressing the mature B220hi/HSAlo phenotype was significantly slower, consistent with a longer life span. Such gating allowed analysis to be directed at the stable mature B cell population in transgenic mice. Comparison of BrdU uptake in Ig- and Dbl-Tg mice indicated that B cells from Dbl-Tg mice were renewed at a much higher rate (50% renewal times of 0.64 vs. 3.4 wk for total B cells, and 1.2 vs. 5.0 wk for mature B200hi/HSAlo cells from Dbl- and Ig-transgenic mice, respectively). This difference was even more marked when analysis in Dbl-Tg mice was restricted to HEL-binding cells, which had a 50% renewal time of 3-4 d compared with 4-5 wk for non-HEL-binding B cells. While the proportion of B cells in cell cycle, and the rate of entry of newly generated B cells into the spleen of Ig- and Dbl-Tg mice, were similar, B cell numbers were reduced in Dbl-Tg mice. It was therefore concluded that anergic B cells have a markedly decreased life span in the periphery. According to studies in radiation chimeras produced by reconstituting HEL-transgenic recipients expressing different serum levels of antigen with Ig-Tg bone marrow, the reduced life span of anergic B cells was associated with the anergic state per se, the serum concentration of HEL being important only in attaining the critical threshold necessary for tolerance induction. B cells rendered tolerant by exposure to soluble self-antigen therefore survive for a relatively short period in an anergic state once they have reached peripheral lymphoid tissue and fail to enter the long-lived compartment.(ABSTRACT TRUNCATED AT 400 WORDS)


The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study).
The association between testosterone deficiency and insulin resistance in men with type 2 diabetes is well established. Current Endocrine Society and European Association of Urology guidelines recommend the measurement of testosterone levels in all men with type 2 diabetes and in men suffering from erectile dysfunction. It is recognised that a range of physical symptoms appear as the testosterone level falls but few studies have addressed the threshold at which symptoms improve with physiological replacement. We report the first double-blind placebo-controlled study conducted exclusively in a male type 2 diabetes population to assess the metabolic changes with testosterone replacement. The type 2 diabetes registers of seven general practices were screened to establish the prevalence of low testosterone and the associations with diabetes control. Of 550 eligible patients approached, 488 men (mean age 62.6) consented to take part in screening with a morning testosterone level, assessed between 8 and 11 am. This identified 211 patients for a double-blind placebo-controlled study of long acting testosterone undecanoate (TU) 1000 mg lasting 30 weeks followed by 52 weeks of open label use. The population was divided into a SEVERE group with either total testosterone (TT) of 8 nmol/l or less or free testosterone (FT) 180 pmol/l or less or a MILD group with TT 8.1-12 nmol/l or FT 181-250 pmol/l. Men in the SEVERE group increased mean through TT from 7.73 nmol/l at baseline to 9.93 at 30 weeks and the MILD group from 10.47 to 11.94. The SEVERE group showed marked improvement in sexual function, but no significant improvement in metabolic parameters. The MILD group showed no improvement in sexual function, but significant improvement in weight, body mass index, waist circumference and Hospital Anxiety and Depression Scale. Improvement was seen in all parameters during 52 weeks open label treatment where trough TT levels approached 15 nmol/l. Baseline prostate-specific antigen (PSA) was lower in the SEVERE group and increased with TU for 30 weeks and then stabilised. There was no increase in PSA with treatment in the MILD group. Testosterone undecanoate significantly improves sexual parameters and Ageing Male Symptom Score, but not metabolic factors at 30 weeks in men with SEVERE testosterone deficiency syndrome (TDS). In men with MILD TDS, significant improvements in metabolic but not sexual parameters were seen, suggesting that there are threshold levels for response to testosterone replacement therapy and that trials of therapy need to achieve sustained therapeutic levels to be effective. PSA showed minor rises, but only for 30 weeks in the SEVERE group.


Statins: beneficial or adverse for glucose metabolism.
Large-scale clinical trials have established that statin use for lowering blood cholesterol is beneficial in reducing atherosclerotic cardiovascular diseases in different populations. However, the general reputation of statins seems to be clouded by a potential adverse effect of a class of statins on glucose metabolism. This paper reviewed clinical data of statins regarding the effects on diabetes mellitus and glucose metabolism. At least five randomized controlled studies, primarily investigating the protective effect of statins on the risk of cardiovascular diseases, have addressed the effect of statins on glucose metabolism in Western countries. One study showed that pravastatin (40 mg/day) was protective against the development of diabetes mellitus. Two studies of atorvastatin (10 mg/day) and one study of simvastatin (40 mg/day) showed no measurable effect of these regimens on the risk of diabetes mellitus or the clinical course of diabetes mellitus. One study of atorvastatin (80 mg/day) versus pravastatin (40 mg/day) suggested a deterioration of glucose metabolism associated with a high dose of atorvastatin. In Japan, a few case reports have noted a potential adverse effect of atorvastatin on glycemic control in patients with diabetes mellitus; however, seven clinical trials have showed no such effect of atorvastatin although these studies were relatively small in size and short in follow-up. Only one of the two observational studies suggested a possible adverse effect of atorvastatin on glycemic control. Evidence is extremely limited regarding atorvastatin use and deterioration in glycemic control, and further studies are needed to draw a conclusion on this issue.


Prunella vulgaris L., an Edible and Medicinal Plant, Attenuates Scopolamine-Induced Memory Impairment in Rats.
Prunella vulgaris L. is as a major plant in the Chinese traditional functional beverage Guangdong herbal tea for the treatment of fevers, diarrhea, and sore mouth. In this study, ethyl acetate parts of aqueous extracts from P. vulgaris L. (EtOAc-APV) were found to demonstrate potent acetylcholinesterase (AChE) inhibition in vitro. Therefore, this study was designed to further investigate the effects of EtOAc-APV on scopolamine (SCOP)-induced aging rats. Male Wistar rats were randomly divided into four groups (n = 12) and given orally by gavage EtOAc-APV (100 mg/kg) for 3 weeks. SCOP (1 mg/kg, ip) was administered to rats 30 min before starting behavioral tests consecutively for 3 days. EtOAc-APV could attenuate SCOP-induced brain senescence in rats by improving behavioral performance and decreasing brain cell damage, which was associated with a notable reduction in AChE activity and MDA level, as well as an increase in SOD and GPx activities. Additionally, EtOAc-APV administration could reduce the expression of NF-κB and GFAP, which showed an anti-neuroinflammatory effect on the SCOP-treated rat. Overall, the current study highlights P. vulgaris L. as an antidementia dietary supplement.


Investigation of the chemical compositions in tobacco of different origins and maturities at harvest by GC-MS and HPLC-PDA-QTOF-MS.
Tobacco samples of a same cultivar grown in different plantations in China were evaluated for their chemical compositions at different maturities for the first time. This was accomplished by a comprehensive and reliable method using gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography-photodiode array-quadrupole time-of-flight mass spectrometry (HPLC-PDA-QTOF-MS) to analyze the fat-soluble and polar components in 12 batches of tobacco samples of three origins and four maturities. The GC-MS analyses showed that tobacco samples harvested at 40 days after transplantation exhibited more fat-soluble components, while those harvested at 100 days after transplantation exhibited the least fat-soluble components. Tentatively, identification of the main components as well as quantitative analyses of eight reference compounds, including five alkaloids, two polyphenols, and a coumarin, was performed by the developed HPLC-QTOF-PDA method. Results showed significant differences among origins and maturities in the contents of these compounds. The nicotine contents showed great variety among the 12 tobacco samples. The highest nicotine content were found in a sample from Zhengzhou harvested at 40 days after transplantation (ZZ-T with 25399.39 ± 308.95 μg/g), and the lowest nicotine level was detected in a sample from Zunyi harvested at 60 days after transplantation (ZY-X with 1654.49 ± 34.52 μg/g). The highest level of rutin was found in a Jiangchuan sample harvested at 60 days after transplantation (JC-X with 725.93 ± 40.70 μg/g), and the lowest rutin content was detected in a Zunyi tobacco sample harvested at 60 days after transplantation (ZY-X with 87.42 ± 2.78 μg/g). The developed method provided a convenient approach which might be applied for rapid maturity evaluation and tobacco flavor identification and also holds the potential for analysis of compounds present in other plants.


Waist circumference as compared with body-mass index in predicting mortality from specific causes.
Whether waist circumference provides clinically meaningful information not delivered by body-mass index regarding prediction of cause-specific death is uncertain. We prospectively examined waist circumference (WC) and body-mass index (BMI) in relation to cause-specific death in 225,712 U.S. women and men. Cox regression was used to estimate relative risks and 95% confidence intervals (CI). Statistical analyses were conducted using SAS version 9.1. During follow-up from 1996 through 2005, we documented 20,977 deaths. Increased WC consistently predicted risk of death due to any cause as well as major causes of death, including deaths from cancer, cardiovascular disease, and non-cancer/non-cardiovascular diseases, independent of BMI, age, sex, race/ethnicity, smoking status, and alcohol intake. When WC and BMI were mutually adjusted in a model, WC was related to 1.37 fold increased risk of death from any cancer and 1.82 fold increase risk of death from cardiovascular disease, comparing the highest versus lowest WC categories. Importantly, WC, but not BMI showed statistically significant positive associations with deaths from lung cancer and chronic respiratory disease. Participants in the highest versus lowest WC category had a relative risk of death from lung cancer of 1.77 (95% CI, 1.41 to 2.23) and of death from chronic respiratory disease of 2.77 (95% CI, 1.95 to 3.95). In contrast, subjects in the highest versus lowest BMI category had a relative risk of death from lung cancer of 0.94 (95% CI, 0.75 to 1.17) and of death from chronic respiratory disease of 1.18 (95% CI, 0.89 to 1.56). Increased abdominal fat measured by WC was related to a higher risk of deaths from major specific causes, including deaths from lung cancer and chronic respiratory disease, independent of BMI.


Import of adenovirus DNA involves the nuclear pore complex receptor CAN/Nup214 and histone H1.
Adenovirus type 2 (Ad2) imports its DNA genome through the nuclear pore complex (NPC) of cells in interphase for viral production. Here we identify the NPC-filament protein CAN/Nup214 as a docking site for incoming Ad2 capsids. Binding to CAN is independent of cytosolic factors. Capsids disassemble at NPCs to free their DNA for import. This process requires binding of nuclear histone H1 to the stably docked capsids and involves H1-import factors, restricting this irreversible process to the proximity of the nucleus. Our results provide a molecular mechanism for disassembly of Ad2 and reveal an unexpected function of histone H1 in virus-mediated DNA import.


Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities.
Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.


Effectiveness of Using Enhanced Filters in Schools and Homes to Reduce Indoor Exposures to PM2.5 from Outdoor Sources and Subsequent Health Benefits for Children with Asthma.
Filters can reduce indoor concentrations of particulate matter (PM2.5), but their benefits have not been well-characterized. This study investigates exposure, health, and cost impacts of high efficiency filters in homes and schools, focusing on the asthma-related outcomes. Reductions in indoor exposures to PM2.5 from outdoor sources with enhanced filters (e.g., MERV 12) are estimated using probabilistic indoor air quality models, and avoided health impacts are quantified using health impact assessment. These methods are applied using data from Detroit, Michigan, an urban region with elevated asthma rates. Replacing inefficient filters with enhanced filters in schools would reduce the PM2.5-attributable asthma burden by 13% annually, with higher benefits for more efficient filters. Marginal costs average $63 per classroom or $32 per child with asthma per year. In homes, using efficient furnace filters or air cleaners yields 11 to 16% reductions in the asthma burden with an annualized marginal costs of $151-494 per household. Additional benefits include reductions in health risk for adults and lower exposures to other contaminants such as PM from indoor sources. On the basis of the included health outcomes, efficient filters in schools in particular is a potentially cost-efficient way to reduce the asthma-related health burden for children.


Localization of decay accelerating factor in normal and diseased kidneys.
Decay accelerating factor (DAF) is a cell membrane associated glycoprotein that inhibits C3 activation. In the present study we evaluated the presence of DAF in normal (N = 15) and diseased human kidneys (N = 76). Sections of frozen tissue were stained for DAF by immunoperoxidase, utilizing three mouse monoclonal anti-DAF anti-bodies. In normal kidneys, DAF was localized in the glomerular vascular pole, apparently in the juxtaglomerular apparatus (JGA). All other structures were negative for DAF. By contrast, in diseased kidneys, two types of abnormalities were detected. First, JGA-DAF was significantly decreased and this abnormality correlated with the pathologic diagnosis and with the presence of C3, IgM and/or fibrinogen in the glomeruli. Second, DAF was present in the glomerular mesangium (67%), renal interstitium (68%) and/or blood vessels (38%). The presence of DAF in the mesangium and interstitium of the kidney correlated with each other and correlated with C1q and C3 deposition in the glomerulus. Finally, vascular DAF was significantly more common in patients with electron dense deposits in the glomeruli. In summary, DAF is present in the normal kidney and is located exclusively in the glomerular vascular pole. In diseased kidneys, DAF tends to be lost from the JGA but is often present in glomerular mesangium, interstitium and blood vessels. This pattern is specially prominent in patients demonstrating complement deposition in the glomerulus. We speculate that kidney DAF may play a role in protecting the kidney against the products of complement activation.


Digital resources for transfusion education.
Regular training in the blood transfusion process is crucial for transfusion safety. Hospital transfusion committees have an obligation to provide this education to hospital employees through training activities. E-learning is positioning itself as a valid alternative to physical-presence courses. We describe a training course on blood transfusion to members of our hospital who are involved in the transfusion process, including technicians, nurses, and doctors. The course uses Moodle as the e-learning platform; it is evaluated using a satisfaction survey along with a knowledge-transfer and impact survey a year after taking the course. From 2015 to 2018, seven editions of the online transfusion course were developed. Six hundred and eighty students enrolled; of these, 124 did not take the final examination (18.2%); 60 never began the course (8.8%). Of the 556 students who completed the course, 546 passed (98.2%). The average score from the initial self-assessment was 7.3 while the average score from the final self-assessment was 9.2; the mean improvement was 1.9 (out of 10). The level of general course satisfaction was 9.27 (an average out of 10). More than 90% of the students stated that they were able to apply the acquired knowledge in the workplace after a year. E-learning has demonstrated itself as an affordable solution that could help in the training of all staff involved in the transfusion process at our hospital, with the advantage that it includes general knowledge and particular skills in local transfusion medical practice.


Diffusion-weighted MRI Enables to Accurately Grade Inflammatory Activity in Patients of Ileocolonic Crohn's Disease: Results from an Observational Study.
Diffusion-weighted imaging (DWI) is a novel technique to evaluate bowel inflammation in Crohn's disease (CD). It remains unclear whether DWI could differentiate grades of inflammation activity and add to the accuracy of conventional magnetic resonance enterography (MRE) in defining disease activity. We aimed to assess the accuracy of DWI for evaluating ileocolonic CD inflammation compared with conventional MRE, using ileocolonoscopy as reference standard. This was an observational study of CD patients who underwent both ileocolonoscopy and MRE with DWI. The conventional MRE and DWI findings of the ileocolon were scored from 0 to 3. The respective segment endoscopic disease activity was scored by simplified endoscopic score for Crohn's disease (SES-CD) and was graded as inactive (0-2), mild (3-6) or moderate-severe (≥7). One hundred eighty-five bowel segments from 43 consecutive CD patients were evaluated and included inactive (n = 86), mild (n = 72), and moderate-severe (n = 27) ileo-colonic segments. The area under the receiver operating characteristics curve (AUC) of 0.973 for apparent diffusion coefficient (ADC) to differentiate active from inactive CD was significantly higher than those of conventional MRE parameters (AUC between 0.840 and 0.940). Higher accuracy of ADC (AUC = 0.919) for differentiating inactive-mild from moderate-severe CD was also shown compared with that of conventional MRE parameters (AUC between 0.868 and 0.915). ADC values demonstrated strongest correlation with SES-CD (r = -0.880) comparing to DWI SI and conventional MRE parameters (r between 0.787 and 0.867). DWI enables to accurately grade inflammatory activity in patients of ileocolonic CD and may be better suited than conventional MRE for monitoring the activity of CD.


Analysis of color distortions in a transmission-type holographic screen.
Full-color transmission-type holographic screens for displaying stereoscopic and multiview images suffer color distortions, especially at their edges. These distortions arise because the reconstructed image of the diffuser appears not at a specified location at different locations for different parts of the screen. Analysis shows that the diffuser strip, which is an object that records the screen, should be extended further in the photoplate direction than in the conventional position to remove the distortions and that use of a short-wavelength laser in the blue spectral region, along with extending the diffuser, is recommended for recording large-sized screens. The analysis also allows the largest sizes of screens that can be recorded for a given set of parameters to be calculated. A comparison of the quality of the images displayed on the screens recorded in the conventional position and in the newly developed position has shown distinctive improvements for the new position.


Vision screening and photorefraction - the relation of refractive errors to strabismus and amblyopia.
Isotropic photorefraction is a technique well suited for screening infants and young children for refractive errors. The photorefractive measurements have been empirically calibrated against retinoscopic refractions, so errors exceeding selected criteria can be identified in screening and followed up. Such a screening programme is in progress for the population of 6-9 month infants in the City of Cambridge. In 1096 infants screened 5% have been found to have large hypermetropic errors, 1.3% to show a refractive difference between the eyes (anisometropia) and less than 1% to have significant myopia or manifest strabismus. These findings were generally confirmed on retinoscopic examinations. In subsequent follow up of the large hypermetropic errors, most decline with age but a few show little or no change up to age 2 years and some show more change in one eye than the other leading to anisometropia. A trial is underway to examine whether early correction with spectacles can reduce the later incidence of strabismus and amblyopia in hypermetropic infants. Significant astigmatism is found in a large fraction of the infant population; the predominant axis of this astigmatism shows marked and unexplained variations between different locations in England.


Haemoglobin management in acute brain injury.
Anaemia is common among patients in the neurocritical care unit (NCCU) and is thought to exacerbate brain injury. However, the optimal haemoglobin (Hgb) level still remains to be elucidated for traumatic brain injury (TBI), subarachnoid haemorrhage (SAH) and acute ischaemic stroke (AIS). This review outlines recent studies about anaemia and the effects of red blood cell transfusion (RBCT) on outcome in TBI, SAH and AIS patients admitted to the NCCU. Patients with severe SAH, AIS and TBI often develop anaemia and require RBCT. In general critical care, a restrictive RBCT strategy (Hgb ~7 g/dl) is preferable in patients without serious cardiac disease. In severe TBI, AIS and SAH, both anaemia and RBCT may negatively influence clinical outcome. However, the appropriate RBCT trigger remains unclear and there is great variance in how these patients are transfused. There is evidence from PET and microdialysis studies in humans that RBCT can favourably influence brain metabolism and oxygenation. This correction of hypoxia or altered metabolism rather than anaemia may be of greater importance. Results from general critical care should not be extrapolated to all patients with acute brain injury. Transfusion is not risk free, but RBCT use needs to be considered also in terms of potential benefit.


Simultaneous saccharification and co-fermentation for bioethanol production using corncobs at lab, PDU and demo scales.
While simultaneous saccharification and co-fermentation (SSCF) is considered to be a promising process for bioconversion of lignocellulosic materials to ethanol, there are still relatively little demo-plant data and operating experiences reported in the literature. In the current work, we designed a SSCF process and scaled up from lab to demo scale reaching 4% (w/v) ethanol using xylose rich corncobs. Seven different recombinant xylose utilizing Saccharomyces cerevisiae strains were evaluated for their fermentation performance in hydrolysates of steam pretreated corncobs. Two strains, RHD-15 and KE6-12 with highest ethanol yield and lowest xylitol yield, respectively were further screened in SSCF using the whole slurry from pretreatment. Similar ethanol yields were reached with both strains, however, KE6-12 was chosen as the preferred strain since it produced 26% lower xylitol from consumed xylose compared to RHD-15. Model SSCF experiments with glucose or hydrolysate feed in combination with prefermentation resulted in 79% of xylose consumption and more than 75% of the theoretical ethanol yield on available glucose and xylose in lab and PDU scales. The results suggest that for an efficient xylose conversion to ethanol controlled release of glucose from enzymatic hydrolysis and low levels of glucose concentration must be maintained throughout the SSCF. Fed-batch SSCF in PDU with addition of enzymes at three different time points facilitated controlled release of glucose and hence co-consumption of glucose and xylose was observed yielding 76% of the theoretical ethanol yield on available glucose and xylose at 7.9% water insoluble solids (WIS). With a fed-batch SSCF in combination with prefermentation and a feed of substrate and enzymes 47 and 40 g l-1 of ethanol corresponding to 68% and 58% of the theoretical ethanol yield on available glucose and xylose were produced at 10.5% WIS in PDU and demo scale, respectively. The strain KE6-12 was able to completely consume xylose within 76 h during the fermentation of hydrolysate in a 10 m3 demo scale bioreactor. The potential of SSCF is improved in combination with prefermentation and a feed of substrate and enzymes. It was possible to successfully reproduce the fed-batch SSCF at demo scale producing 4% (w/v) ethanol which is the minimum economical requirement for efficient lignocellulosic bioethanol production process.


Copper induced spin state change of heme-Aβ associated with Alzheimer's disease.
Heme binds Aβ to give a mixture of a mono-histidine bound high spin peroxidase type active site and a bis-histidine bound low spin cytochrome b type active site present in an equilibrium at physiological pH. Of these, the high spin mono-histidine bound complexes produce significant amounts of partially reduced oxygen species (PROS), catalyze the degradation of neurotransmitters and oxidize cytochrome c, with potentially detrimental effects. The presence of excess Aβ could lower these effects by creating a low spin bis-histidine cytochrome b type active site which exerts less oxidative stress by producing a much smaller amount of PROS. The presence of Cu(ii) reverses this effect and can convert the benign low spin heme-Aβ complex to the detrimental high spin form, even in the presence of excess Aβ. Data suggest that the histidine needed to form the bis-histidine site in the low spin heme-Aβ complex is likely to be involved in the high affinity Cu binding site in the heme-Cu-Aβ complex.


Dextran-lipase conjugates as tools for low molecular weight ligand immobilization in microarray development.
The development of effective array biosensors relies heavily on careful control of the density of surface-immobilized ligands on the transducing platform. In this paper we describe the synthesis of new dextran-lipase conjugates for use in immobilizing low molecular weight haptens onto glass planar waveguides for immunosensor development. The conjugates were synthesized by immobilizing bacterial thermoalkalophilic lipases (Geobacillus thermocatenulatus lipase 2, BTL2) on agarose macroporous beads, followed by covalent coupling to dextran networks of variable molecular weight (1500-40000). The chimeras were immobilized via nonspecific hydrophobic interactions onto glass planar waveguides modified with 1,1,1,3,3,3-hexamethyldisilazane to obtain highly ordered and homogeneous molecular architectures as confirmed by atomic force microscopy. Microcystin LR (MCLR) was covalently bound to the dextran-BTL2 conjugates. The usefulness of this approach in immunosensor development was demonstrated by determining amounts of MCLR down to a few picograms per liter with an automated array biosensor and evanescent wave excitation for fluorescence measurements of attached DyLight649-labeled secondary antibody. Modifying BTL2 with dextrans of an increased molecular weight (>6000) provided surfaces with an increased loading capacity that was ascribed to the production of three-dimensional surfaces by the effect of analyte binding deep in the volume, leading to expanded dynamic ranges (0.09-136.56 ng L(-1)), lower limits of detection (0.007 ± 0.001 ng L(-1)), and lower IC50 values (4.4 ± 0.7 ng L(-1)). These results confirm the effectiveness of our approach for the development of high-performance biosensing platforms.