Non-pharmacological management for patients with frontotemporal dementia: a systematic review.
Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by changes in behavior and language caused by focal degeneration of the frontal and anterior temporal lobes. The behavioral symptoms are distressing to patients and their caregivers. Non-pharmacological management is important as no disease-specific pharmacological treatment for FTD is currently available. The primary objective is to review the literature on non-pharmacological management for FTD and to propose directions for future research, with reference to findings. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included "frontotemporal dementia", and words related to non-pharmacological management, and it identified a total of 858 articles. Results revealed that very few randomized controlled trials exist on non-pharmacological management interventions for FTD. These interventions have been proposed by literature based on clinical experience. A small number of studies have supported behavioral management techniques that exploit disease-specific behaviors and preserved functions in patients with FTD, along with the management of caregivers' distress. These limitations warrant well-designed large-scale research to examine effects of non-pharmacological interventions on behavioral symptoms of FTD.


Eosinophilic oesophagitis: clinical presentation and pathogenesis.
Eosinophilic oesophagitis (EoE) is an inflammatory disorder of the oesophagus which has become increasingly recognised over recent years, although it remains underdiagnosed in many centres. It is characterised histologically by a significant eosinophilic infiltration of the oesophageal mucosa (>15 eosinophils per high powered field), and clinically with features of oesophageal dysfunction such a dysphagia, food impaction, and proton pump inhibitor (PPI) resistant dyspepsia. Fibrosis and oesophageal remodelling may occur and lead to oesophageal strictures. An allergic predisposition is common in the EoE population, which appears to be primarily food antigen driven in children and aeroallergen driven in adults. Evidence suggests that the pathogenesis of EoE is due to a dysregulated immunological response to an environmental allergen, resulting in a T helper type 2 (Th2) inflammatory disease and remodelling of the oesophagus in genetically susceptible individuals. Allergen elimination and anti-inflammatory therapy with corticosteroids are currently the mainstay of treatment; however, an increasing number of studies are now focused on targeting different stages in the disease pathogenesis. A greater understanding of the underlying mechanisms resulting in EoE will allow us to improve the therapeutic options available.


HIF-1alpha dysfunction in diabetes.
Diabetic wounds are a significant public health burden, with slow or nonhealing diabetic foot ulcers representing the leading cause of non-traumatic lower limb amputation in developed countries. These wounds heal poorly as a result of compromised blood vessel formation in response to ischemia. We have recently shown that this impairment in neovascularization results from a high glucose-induced defect in transactivation of hypoxia-inducible factor-1alpha (HIF-1alpha), the transcription factor regulating vascular endothelial growth factor (VEGF) expression. HIF-1 dysfunction is the end result of reactive oxygen species-induced modification of its coactivator p300 by the glycolytic metabolite methylglyoxal. Use of the iron chelator-antioxidant deferoxamine (DFO) reversed these effects and normalized healing of humanized diabetic wounds in mice. Here, we present additional data demonstrating that HIF-1alpha activity, not stability, is impaired in the high glucose environment. We demonstrate that high glucose-induced impairments in HIF-1alpha transactivation persist even in the setting of constitutive HIF-1alpha protein overexpression. Further, we show that high glucose-induced hydroxylation of the C-terminal transactivation domain of HIF-1alpha (the primary pathway regulating HIF-1alpha/p300 binding) does not alter HIF-1alpha activity. We extend our study of DFO's therapeutic efficacy in the treatment of impaired wound healing by demonstrating improvements in tissue viability in diabetic mice with DFO-induced increases in VEGF expression and vascular proliferation. Since DFO has been in clinical use for decades, the potential of this drug to treat a variety of ischemic conditions in humans can be evaluated relatively quickly.


General anaesthetic and airway management practice for obstetric surgery in England: a prospective, multicentre observational study.
There are no current descriptions of general anaesthesia characteristics for obstetric surgery, despite recent changes to patient baseline characteristics and airway management guidelines. This analysis of data from the direct reporting of awareness in maternity patients' (DREAMY) study of accidental awareness during obstetric anaesthesia aimed to describe practice for obstetric general anaesthesia in England and compare with earlier surveys and best-practice recommendations. Consenting patients who received general anaesthesia for obstetric surgery in 72 hospitals from May 2017 to August 2018 were included. Baseline characteristics, airway management, anaesthetic techniques and major complications were collected. Descriptive analysis, binary logistic regression modelling and comparisons with earlier data were conducted. Data were collected from 3117 procedures, including 2554 (81.9%) caesarean deliveries. Thiopental was the induction drug in 1649 (52.9%) patients, compared with propofol in 1419 (45.5%). Suxamethonium was the neuromuscular blocking drug for tracheal intubation in 2631 (86.1%), compared with rocuronium in 367 (11.8%). Difficult tracheal intubation was reported in 1 in 19 (95%CI 1 in 16-22) and failed intubation in 1 in 312 (95%CI 1 in 169-667). Obese patients were over-represented compared with national baselines and associated with difficult, but not failed intubation. There was more evidence of change in practice for induction drugs (increased use of propofol) than neuromuscular blocking drugs (suxamethonium remains the most popular). There was evidence of improvement in practice, with increased monitoring and reversal of neuromuscular blockade (although this remains suboptimal). Despite a high risk of difficult intubation in this population, videolaryngoscopy was rarely used (1.9%).


Development of oriented ocular dominance bands as a consequence of areal geometry.
It has been hypothesized that the different appearance of ocular dominance bands in the cat and the monkey is a consequence of the different mapping geometries in these species (LeVay et al. 1985; Anderson et al. 1988). Here I investigate the impact of areal geometries on the preferred direction of ocular dominance bands in two adaptive map formation models, the self-organizing feature map and the elastic net algorithm. In the case of the self-organizing feature map, the occurrence of instabilities that correspond to ocular dominance bands can be analytically investigated. The instabilities automatically yield stripes of correct orientation. These analytic results are complemented by simulations. In the case of the elastic net algorithm, simulations reveal two different parameter regimes of the algorithm, only one of which leads to stripes of correct orientation. The results suggest that neighborhood preservation in visual maps is enforced in the backward direction, such that neighboring cells in the cortex have neighboring receptive fields, and not vice versa.


Time of Grain Supplementation and Social Dominance Modify Feeding Behavior of Heifers in Rotational Grazing Systems.
Social hierarchy affects the access of animals to feed resources. On daily rotational pasture systems, supplementation time may influence feeding behavior. This trial was designed to test the effect of grain delivery time on the feeding behavior of heifers. Heifers divided into two groups according to breed (n = 15 Braford and n = 19 Jersey) were tested in a crossover design with two treatments: INITIAL-supplement at 8 am (entry time to a fresh paddock), and MIDDLE-supplement at 4 pm (middle time of paddock use). Animals entered a new paddock every morning, and grain supplement at 2 kg/animal/day was offered at the fence line (1 m/animal). Then, ingestive and other behaviors were registered by direct visual observation through scan sampling at 2-min intervals for 1 h after grain supply. Agonistic interactions were recorded continuously (instigator-victim) to build a social matrix whereby each heifer was defined as dominant, intermediate, or subordinate. Weekly pasture samples were collected according to the order that animals left the feeding area, using the hand-plucking technique, to determine crude protein and fiber content. Heifers spent more time grazing on the INITIAL treatment (p < 0.0001) but exhibited more behaviors on the MIDDLE treatment (p < 0.0001). Dominant heifers spent more time eating grain (p = 0.0008), whereas subordinate heifers spent more time grazing along the paddock (p = 0.0067), but not along the fence (p = 0.0008). The crude protein content of pasture samples was higher for the INITIAL treatment (p < 0.0001). Behavioral interaction occurred with respect to the order of leaving the feeding area, social rank, and crude protein consumed (p = 0.04). Subordinate heifers consistently grazed more and ate less grain supplement than dominant and intermediate heifers. However, when grain supplement was offered at the time animals entered the paddock, more grazing activity took place during supplement feeding, and subordinate heifers could select a high-protein diet. In the INITIAL treatment, this means that subordinate animals could benefit from the better pasture available, keeping a distance from dominant heifers, reducing agonistic interactions and likely improving their welfare.


Muscadine grape (Vitis rotundifolia) and wine phytochemicals prevented obesity-associated metabolic complications in C57BL/6J mice.
The objective of this study was to determine the effects of muscadine grape or wine (cv. Noble) phytochemicals on obesity and associated metabolic complications. Muscadine grape or wine phytochemicals were extracted using Amberlite FPX66 resin. Male C57BL/6J mice were given a low-fat diet (LF, 10% kcal fat), high-fat diet (HF, 60% kcal fat), HF + 0.4% muscadine grape phytochemicals (HF+MGP), or HF + 0.4% muscadine wine phytochemicals (HF+MWP) for 15 weeks. At 7 weeks, mice fed HF+MGP had significantly decreased body weights by 12% compared to HF controls. Dietary MGP or MWP supplementation reduced plasma content of free fatty acids, triglycerides, and cholesterol in obese mice. Inflammation was alleviated, and activity of glutathione peroxidase was enhanced. Consumption of MGP or MWP improved insulin sensitivity and glucose control in mice. Thus, consumption of muscadine grape and wine phytochemicals in the diet may help to prevent obesity-related metabolic complications.


Nutrient control of neural stem cells.
The physiological status of an organism is able to influence stem cell behaviour to ensure that stem cells meet the needs of the organism during growth, and in response to injury and environmental changes. In particular, the brain is sensitive to metabolic fluctuations. Here we discuss how nutritional status is able to regulate systemic and local insulin/IGF signalling so as to control aspects of neural stem behaviour. Recent results have begun to reveal how systemic signals are relayed to neural stem cells through local interactions with a glial niche. Although much still remains to be discovered, emerging parallels between the regulation of Drosophila and mammalian stem cells suggest a conserved mechanism for how the brain responds to changes in nutritional state.


Immunodominant HIV-1-specific HLA-B- and HLA-C-restricted CD8+ T cells do not differ in polyfunctionality.
HIV-1 specific HLA-B-restricted CD8+ T cell responses differ from HLA-C-restricted responses in antiviral effectiveness. To investigate possible reasons for these differences, we characterized the frequency and polyfunctionality of immmunodominant HLA-B*57/B5801- and HLA-Cw*07-restricted CD8+ T cells occurring concurrently in nine study subjects assessing IFN-gamma, TNF-alpha, IL-2, MIP-1beta, and CD107a by flow cytometry and analyzed sequence variation in targeted epitopes. HLA-B*57/5801 and HLA-Cw*07 restricted CD8+ T cells did not differ significantly in polyfunctionality (p=0.84). Possession of three or more functions correlated positively with CD4+ T cell counts (r=0.85; p=0.006) and monofunctional CD8+ T cells inversely correlated with CD4 cell counts (r=-0.79; p=0.05). There were no differences in polyfunctionality of CD8+ T cells specific to wildtype versus mutated epitopes. These results suggest that loss of polyfunctionality and increase in monofunctional HIV-1-specific CD8+ T cells are associated with disease progression independent of restricting HLA allele. Furthermore, sequence variation does not appear to significantly impact CD8+ T cell polyfunctionality in chronic HIV-1 infection.


Nanoenzymology of the 20S proteasome: proteasomal actions are controlled by the allosteric transition.
The proteasome is a major cytosolic proteolytic assembly, essential for the physiology of eukaryotic cells. Both the architecture and enzymatic properties of the 20S proteasome are relatively well understood. However, despite longstanding interest, the integration of structural and functional properties of the proteasome into a coherent model explaining the mechanism of its enzymatic actions has been difficult. Recently, we used tapping mode atomic force microscopy (AFM) in liquid to demonstrate that the alpha-rings of the proteasome imaged in a top-view position repeatedly switched between their open and closed conformations, apparently to control access to the central channel. Here, we show with AFM that the molecules in a side-view position acquired two stable conformations. The overall shapes of the 20S particles were classified as either barrel-like or cylinder-like. The relative abundance of the two conformers depended on the nature of their interactions with ligands. Similarly to the closed molecules in top view, the barrels predominated in control or inhibited molecules. The cylinders and open molecules prevailed when the proteasome was observed in the presence of peptide substrates. Based on these data, we developed the two-state model of allosteric transitions to explain the dynamics of proteasomal structure. This model helps to better understand the observed properties of the 20S molecule, and sets foundations for further studies of the structural dynamics of the proteasome.


Response of complex networks to stimuli.
We consider the response of complex systems to stimuli and argue for the importance of both sensitivity, the possibility of large response to small stimuli, and robustness, the possibility of small response to large stimuli. Using a dynamic attractor network model for switching of patterns of behavior, we show that the scale-free topologies often found in nature enable more sensitive response to specific changes than do random networks. This property may be essential in networks where appropriate response to environmental change is critical and may, in such systems, be more important than features, such as connectivity, often used to characterize network topologies. Phenomenologically observed exponents for functional scale-free networks fall in a range corresponding to the onset of particularly high sensitivities, while still retaining robustness.


Distinct Classes of Negative Alcohol-Related Consequences in a National Sample of Incoming First-Year College Students: A Latent Class Analysis.
: First-year college students are at particular risk for experiencing negative alcohol-related consequences that may set the stage for experiencing such consequences in later life. Latent class analysis is a person-centered approach that, based on observable indicator variables, divides a population into mutually exclusive and exhaustive groups ('classes'). To date, no studies have examined the latent class structure of negative alcohol-related consequences experienced by first-year college students just before entering college. The aims of this study were to (a) identify classes of first-year college students based on the patterns of negative alcohol-related consequences they experienced just before entering college, and (b) determine whether specific covariates were associated with class membership. Incoming freshmen from 148 colleges and universities (N = 54,435) completed a baseline questionnaire as part of an alcohol education program they completed just prior to their first year of college. Participants answered questions regarding demographics and other personal characteristics, their alcohol use in the past 2 weeks, and the negative alcohol-related consequences they had experienced during that time. Four distinct classes of students emerged: (a) No Problems, (b) Academic Problems, (c) Injured Self and (d) Severe Problems. Average number of drinks per drinking day, total number of drinking days, age of drinking initiation, intention to join a fraternity or sorority and family history of alcohol problems were associated with membership in all of the problem classes relative to the No Problems class. These results can inform future campus-based prevention efforts.


Health outcomes associated with methamphetamine use among young people: a systematic review.
Methamphetamine (MA) use among young people is of significant social, economic and public health concern to affected communities and policy makers. While responses have focused upon various perceived severe harms of MA use, effective public health interventions require a strong scientific evidence base. We conducted a systematic review to identify scientific studies investigating health outcomes associated with MA use among young people aged 10-24 years. The International Classification of Diseases (ICD-10) was used to categorize outcomes and determine the level of evidence for each series of harms. We identified 47 eligible studies for review. Consistent associations were observed between MA use and several mental health outcomes, including depression, suicidal ideation and psychosis. Suicide and overdose appear to be significant sources of morbidity and mortality among young MA users. Evidence for a strong association between MA use and increased risk of human immunodeficiency virus (HIV) and other sexually transmitted infections is equivocal. Finally, we identified only weak evidence of an association between MA use and dental diseases among young people. Available evidence indicates a consistent relationship between MA use and mental health outcomes (e.g. depression, psychosis) and an increased risk of mortality due to suicide and overdose. We found insufficient evidence of an association between MA use and other previously cited harms, including infectious diseases and dental outcomes. As such, future research of higher methodological quality is required to further investigate possible associations. Current interventions should focus attention upon MA-related health outcomes for which sound scientific evidence is available.


Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study.
The outcome of patients receiving mechanical ventilation for particular indications has been studied, but the outcome in a large number of unselected, heterogeneous patients has not been reported. To determine the survival of patients receiving mechanical ventilation and the relative importance of factors influencing survival. Prospective cohort of consecutive adult patients admitted to 361 intensive care units who received mechanical ventilation for more than 12 hours between March 1, 1998, and March 31, 1998. Data were collected on each patient at initiation of mechanical ventilation and daily throughout the course of mechanical ventilation for up to 28 days. All-cause mortality during intensive care unit stay. Of the 15 757 patients admitted, a total of 5183 (33%) received mechanical ventilation for a mean (SD) duration of 5.9 (7.2) days. The mean (SD) length of stay in the intensive care unit was 11.2 (13.7) days. Overall mortality rate in the intensive care unit was 30.7% (1590 patients) for the entire population, 52% (120) in patients who received ventilation because of acute respiratory distress syndrome, and 22% (115) in patients who received ventilation for an exacerbation of chronic obstructive pulmonary disease. Survival of unselected patients receiving mechanical ventilation for more than 12 hours was 69%. The main conditions independently associated with increased mortality were (1) factors present at the start of mechanical ventilation (odds ratio [OR], 2.98; 95% confidence interval [CI], 2.44-3.63; P<.001 for coma), (2) factors related to patient management (OR, 3.67; 95% CI, 2.02-6.66; P<.001 for plateau airway pressure >35 cm H(2)O), and (3) developments occurring over the course of mechanical ventilation (OR, 8.71; 95% CI, 5.44-13.94; P<.001 for ratio of PaO(2) to fraction of inspired oxygen <100). Survival among mechanically ventilated patients depends not only on the factors present at the start of mechanical ventilation, but also on the development of complications and patient management in the intensive care unit.


Refractive error and visual functions in children with special needs compared with the first grade school students in oman.
We evaluated the refractive status and visual function of children with special needs (other handicap) in 2010 and compared them with healthy 1(st) grade school students in Oman. This was a cohort study. Optometrists recorded vision using a logarithm of minimum angle of resolution (LogMAR) chart. Preferential looking method was used for testing 31 children. Cycloplegic refraction was performed on all children. Contrast sensitivity was tested using 2.5%, 10%, and 100% contrast charts. Ocular movement, alignment, and anterior segment were also assessed. A pediatrician reviewed the health records of all the children at the time of their enrollment in this study to determine if the child had been diagnosed with a systemic condition or syndromes. The visual functions were assessed by study investigators. We estimated the rates and the risk of different visual function defects in children with special needs. The prevalence of refractive error in 70 children (4.7 ± 0.8 years) with special needs (group 1) and 175 normal healthy first grade students (group 2) were 58.5% and 2.9%, respectively. The risk of refractive error was significantly higher in children with special needs [relative risk, 48.1 (95% confidence interval, 17.54-131.8)]. Hyperopia (>1.00 D), myopia (≥ 1.00D) and astigmatism (≥ ±1.00 D) were found in 18.6%, 24.3%, and 27.1%, respectively, in group 1. Six children in this group had defective near vision. Sixteen (80%) children with Down syndrome had refractive error. Seven (50%) children with developmental disorder showed decreased contrast sensitivity. Prevalence of uncorrected refractive error was much higher in children with special needs. Prevalence of strabismus, nystagmus, and reduced contrast sensitivity was also higher in children with special needs. Early vision screening, visual function assessment, correction of refractive error, and frequent follow-up are recommended.


Hyponatremia presenting with hourly fluctuating urine osmolality.
The etiology of hyponatremia is assessed based on urine osmolality and sodium. We herein describe a 35-year-old Asian man with pulmonary tuberculosis and perforated duodenal ulcer who presented with hyponatremia with hourly fluctuating urine osmolality ranging from 100 to 600 mosmol/kg, which resembled urine osmolality observed in typical polydipsia and SIADH simultaneously. Further review revealed correlation of body temperature and urine osmolality. Since fever is a known non-osmotic stimulus of ADH secretion, we theorized that hyponatremia in this patient was due to transient ADH secretion due to fever. In our case, empiric exogenous glucocorticoid suppressed transient non-osmotic ADH secretion and urine osmolality showed highly variable concentrations. Transient ADH secretion-related hyponatremia may be underrecognized due to occasional empiric glucocorticoid administration in patients with critical illnesses. Repeatedly monitoring of urine chemistries and interpretation of urine chemistries with careful review of non-osmotic stimuli of ADH including fever is crucial in recognition of this etiology. Hourly fluctuations in urine osmolality can be observed in patients with fever, which is a non-osmotic stimulant of ADH secretion. Repeated monitoring of urine chemistries aids in the diagnosis of the etiology underlying hyponatremia, including fever, in patients with transient ADH secretion. Glucocorticoid administration suppresses ADH secretion and improves hyponatremia even in the absence of adrenal insufficiency; the etiology of hyponatremia should be determined carefully in these patients.


Reactions of 4-hydroxy-2(E)-nonenal and related aldehydes with proteins studied by carbon-13 nuclear magnetic resonance spectroscopy.
In order to understand the modifications of proteins produced by aldehydes of lipid peroxidation, [1-13C]-2(E)-hexenal, [1-13C]-4-oxopentanal, and a mixture of [1-13C]- and [2-13C]-4-hydroxynon-2(E)-enal were synthesized and the reaction of each of the labeled aldehydes with bovine serum albumin was analyzed by 13C NMR spectroscopy. Protein nucleophiles add to the 3-position of hexenal, and the resulting propanal moieties appear to undergo aldol condensation, form imine cross-links with lysyl residues, or lead to pyridinium rings. During the reaction of 4-oxopentanal with the lysyl residues of bovine serum albumin, only 1-alkyl-2-methylpyrrole and a possible intermediate leading to the pyrrole were observed. Hydroxypyrrolidine cross-links such as 25 could not be detected, leaving the pyrrole as the mediator of protein cross-linking. The Michael adducts are the major products in the reaction between 4-hydroxynon-2-enal and proteins. They exist almost exclusively in the cyclic hemiacetal form and do not appear to cross-link through imine formation with lysyl residues. A minor pathway involves the reaction of 4-hydroxynon-2-enal with the lysyl amino groups of protein resulting in 2-pentylpyrrole adducts that may mediate protein cross-linking. The Michael adducts appear not to be the direct source of the pyrrole, but the imine 32 and the enamine 35 are likely intermediates toward the five-membered ring.


Real-time GPU-based 3D Deconvolution.
Confocal microscopy is an oft-used technique in biology. Deconvolution of 3D images reduces blurring from out-of-focus light and enables quantitative analyses, but existing software for deconvolution is slow and expensive. We present a parallelized software method that runs within ImageJ and deconvolves 3D images ~100 times faster than conventional software (few seconds per image) by running on a low-cost graphics processor board (GPU). We demonstrate the utility of this software by analyzing microclusters of T cell receptors in the immunological synapse of a CD4 + T cell and dendritic cell. This software provides a low-cost and rapid way to improve the accuracy of 3D microscopic images obtained by any method.


Rotatable diffractive gratings based on hybrid-aligned cholesteric liquid crystals.
This work proposes a thermally rotatable grating that is based on hybrid-aligned cholesteric liquid crystals (HBA-cholesteric LCs). Experiments reveal that the HBA-cholesteric texture has a uniformly striped domain, which forms a grating, when the ratio of the cell gap to the helical pitch (d/p) is in the range of 2≤d/p≤3. The stripe direction of the HBA-cholesteric grating is predicted by the proposed vertically aligned LC layer model. The stripe direction of the HBA-cholesteric grating rotates continuously under thermal and electrical effects. Furthermore, the HBA-cholesteric grating has a larger rotational angle under the thermal effect (~101°) than under the electrical effect (~48°). Potential applications of the proposed thermally rotatable cholesteric grating for beam steering devices are emphasized.


Structure of the ABL2/ARG kinase in complex with dasatinib.
ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases. ARG plays important roles in cell morphogenesis, motility, growth and survival, and many of these biological roles overlap with the cellular functions of the ABL kinase. Chronic myeloid leukemia (CML) is associated with constitutive ABL kinase activation resulting from fusion between parts of the breakpoint cluster region (BCR) and ABL1 genes. Similarly, fusion of the ETV6 (Tel) and ARG genes drives some forms of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Dasatinib is a tyrosine kinase inhibitor used for the treatment of CML by inhibiting ABL, and while it also inhibits ARG, there is currently no structure of ARG in complex with dasatinib. Here, the co-crystal structure of the mouse ARG catalytic domain with dasatinib at 2.5 Å resolution is reported. Dasatinib-bound ARG is found in the DFG-in conformation although it is nonphosphorylated on the activation-loop tyrosine. In this structure the glycine-rich P-loop is found in a relatively open conformation compared with other known ABL family-inhibitor complex structures.


Enantioselective, Convergent Synthesis of the Ineleganolide Core by a Tandem Annulation Cascade.
An enantioselective and diastereoselective approach toward the synthesis of the polycyclic norditerpenoid ineleganolide is disclosed. A palladium-catalyzed enantioselective allylic alkylation is employed to stereoselectively construct the requisite chiral tertiary ether and facilitate the synthesis of a 1,3-cis-cyclopentenediol building block. Careful substrate design enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold by a diastereoselective cyclopropanation-Cope rearrangement cascade under unusually mild conditions. Computational evaluation of ground state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures. This work represents the first successful synthesis of the core structure of any member of the polycyclic norcembranoid diterpene family of natural products. Advanced synthetic manipulations generated a series of natural product-like compounds that were shown to possess selective secretory antagonism of either interleukin-5 or interleukin-17. This bioactivity stands in contrast to the known antileukemic activity of ineleganolide and suggests the norcembranoid natural product core may serve as a useful scaffold for the development of diverse therapeutics.


Refractive index sensing characteristics in a D-shaped photonic quasi-crystal fiber sensor based on surface plasmon resonance.
A D-shaped photonic quasi-crystal fiber (PQF) sensor based on surface plasmon resonance is proposed for refractive index (RI) sensing. The influences of the width of the gold film, the diameter of the air holes, and the thickness of the gold film on the sensing performance are analyzed. When the RI of a liquid analyte gradually increases from 1.415 to 1.427, the average sensitivity is calculated as 10,250 nm/RIU, and the maximum sensitivity is up to 34,000 nm/RIU, which realizes the high-sensitivity sensing in the near-infrared band. The D-shaped PQF sensor proposed has great application potential in the detection of biochemical analytes and provides a new way to improve the sensing performance.


Pegylated interferon-alpha2a/ribavirin treatment of recurrent hepatitis C after liver transplantation.
Hepatitis C virus (HCV) infection invariably recurs after liver transplantation (LT), leading to significant morbidity and mortality. Although the combination of pegylated interferon-alpha (IFN-alpha)/ribavirin is the preferred treatment for these patients, the optimal schedule remains undetermined. In an uncontrolled trial, 19 patients with HCV infection recurring after LT received pegylated IFN-alpha(2a), 180 mug weekly, and ribavirin, 10 mg/kg body weight daily, for 48 weeks. The proportion of patients with undetectable HCV RNA in their serum after 12 weeks of treatment was 53%. Five patients (26%) dropped out of the study due to intolerance (in 2 cases), depression (in 1), or infectious complications (in 2). A sustained virological response (SVR), defined as undetectable serum HCV RNA 24 weeks after the end of treatment, was observed in 9/19 patients (47%). SVR was associated with an early virological response after 12 weeks of therapy (P<0.001) and a treatment duration >80% (P=0.02), but not with baseline HCV RNA level or a cumulative dose of pegylated IFN-alpha(2a) or ribavirin >80% of the scheduled dose. All 4 patients with genotype 2 or 3 reached SVR, as compared with 33% of patients with genotype 1 or 4 (P=0.03). A 48-week course of pegylated IFN-alpha(2a)/ribavirin therapy is effective in patients with recurrent HCV infection after LT.


An integrated simulation and optimization approach for managing human health risks of atmospheric pollutants by coal-fired power plants.
This research developed a simulation-aided nonlinear programming model (SNPM). This model incorporated the consideration of pollutant dispersion modeling, and the management of coal blending and the related human health risks within a general modeling framework In SNPM, the simulation effort (i.e., California puff [CALPUFF]) was used to forecast the fate of air pollutants for quantifying the health risk under various conditions, while the optimization studies were to identify the optimal coal blending strategies from a number of alternatives. To solve the model, a surrogate-based indirect search approach was proposed, where the support vector regression (SVR) was used to create a set of easy-to-use and rapid-response surrogates for identifying the function relationships between coal-blending operating conditions and health risks. Through replacing the CALPUFF and the corresponding hazard quotient equation with the surrogates, the computation efficiency could be improved. The developed SNPM was applied to minimize the human health risk associated with air pollutants discharged from Gaojing and Shijingshan power plants in the west of Beijing. Solution results indicated that it could be used for reducing the health risk of the public in the vicinity of the two power plants, identifying desired coal blending strategies for decision makers, and considering a proper balance between coal purchase cost and human health risk. A simulation-aided nonlinear programming model (SNPM) is developed. It integrates the advantages of CALPUFF and nonlinear programming model. To solve the model, a surrogate-based indirect search approach based on the combination of support vector regression and genetic algorithm is proposed. SNPM is applied to reduce the health risk caused by air pollutants discharged from Gaojing and Shijingshan power plants in the west of Beijing. Solution results indicate that it is useful for generating coal blending schemes, reducing the health risk of the public, reflecting the trade-offbetween coal purchase cost and health risk.


Isotopic homojunction band engineering from diamond.
Confinement of charge carriers in semiconductors by quantum wells is usually accomplished with layers that vary in elemental composition, such as aluminum gallium arsenide and gallium arsenide. We fabricated diamond superlattices by creating multilayer structures of isotopically pure carbon isotopes carbon-12 (12C) and carbon-13 (13C), which confine electrons by a difference in band-gap energy of 17 millielectron volts. Cathodoluminescence experiments performed at 80 kelvin showed that excitonic recombination in the higher-energy band of 13C vanishes in favor of increased recombination in the lower-energy 12C material. Carrier confinement was achieved in diamond superlattices made up of both thinner (30 nanometers) and thicker (up to 350 nanometers) layers.


Convection-enhanced delivery of a synthetic retinoid Am80, loaded into polymeric micelles, prolongs the survival of rats bearing intracranial glioblastoma xenografts.
Prognosis for the patients with glioblastoma, the most common malignant brain tumor, remains dismal. A major barrier to progress in treatment of glioblastoma is the relative inaccessibility of tumors to chemotherapeutic agents. Convection-enhanced delivery (CED) is a direct intracranial drug infusion technique to deliver chemotherapeutic agents to the central nervous system, circumventing the blood-brain barrier and reducing systemic side effects. CED can provide wider distribution of infused agents compared to simple diffusion. We have reported that CED of a polymeric micelle carrier system could yield a clinically relevant distribution of encapsulated agents in the rat brain. Our aim was to evaluate the efficacy of CED of polymeric micellar Am80, a synthetic agonist with high affinity to nuclear retinoic acid receptor, in a rat model of glioblastoma xenografts. We also used systemic administration of temozolomide, a DNA-alkylating agent, which has been established as the standard of care for newly diagnosed malignant glioma. U87MG human glioma cells were injected into the cerebral hemisphere of nude rats. Rats bearing U87MG xenografts were treated with CED of micellar Am80 (2.4 mg/m(2)) on day 7 after tumor implantation. Temozolomide (200 mg/m(2)/day) was intraperitoneally administered daily for 5 days, starting on day 7 after tumor implantation. CED of micellar Am80 provided significantly longer survival than the control. The combination of CED of micellar Am80 and systemic administration of temozolomide provided significantly longer survival than single treatment. In conclusion, temozolomide combined with CED of micellar Am80 may be a promising method for the treatment of malignant gliomas.


A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth.
SP/KLF (Specificity protein/Krüppel-like factor) transcription factors comprise an emerging group of proteins that may behave as tumour suppressors. Incidentally, many cancers that display alterations in certain KLF proteins are also associated with a high incidence of KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue) mutations. Therefore in the present paper we investigate whether SP/KLF proteins suppress KRAS-mediated cell growth, and more importantly, the potential mechanisms underlying these effects. Using a comprehensive family-wide screening of the 24 SP/KLF members, we discovered that SP5, SP8, KLF2, KLF3, KLF4, KLF11, KLF13, KLF14, KLF15 and KLF16 inhibit cellular growth and suppress transformation mediated by oncogenic KRAS. Each protein in this subset of SP/KLF members individually inhibits BrdU (5-bromo-2-deoxyuridine) incorporation in KRAS oncogenic-mutant cancer cells. SP5, KLF3, KLF11, KLF13, KLF14 and KLF16 also increase apoptosis in these cells. Using KLF11 as a representative model for mechanistic studies, we demonstrate that this protein inhibits the ability of cancer cells to form both colonies in soft agar and tumour growth in vivo. Molecular studies demonstrate that these effects of KLF11 are mediated, at least in part, through silencing cyclin A via binding to its promoter and leading to cell-cycle arrest in S-phase. Interestingly, similar to KLF11, KLF14 and KLF16 mechanistically share the ability to modulate the expression of cyclin A. Collectively, the present study stringently defines a distinct subset of SP/KLF proteins that impairs KRAS-mediated cell growth, and that mechanistically some members of this subset accomplish this, at least in part, through regulation of the cyclin A promoter.


Transcriptional and Epigenetic Changes Influencing Skeletal Muscle Metabolism in Women With Polycystic Ovary Syndrome.
Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). Despite this, the mechanisms underlying insulin resistance in PCOS are largely unknown. To investigate the genome-wide DNA methylation and gene expression patterns in skeletal muscle from women with PCOS and controls and relate them to phenotypic variations. In a case-control study, skeletal muscle biopsies from women with PCOS (n = 17) and age-, weight-, and body mass index‒matched controls (n = 14) were analyzed by array-based DNA methylation and mRNA expression profiling. Eighty-five unique transcripts were differentially expressed in muscle from women with PCOS vs controls, including DYRK1A, SYNPO2, SCP2, and NAMPT. Furthermore, women with PCOS had reduced expression of genes involved in immune system pathways. Two CpG sites showed differential DNA methylation after correction for multiple testing. However, an mRNA expression of ∼30% of the differentially expressed genes correlated with DNA methylation levels of CpG sites in or near the gene. Functional follow-up studies demonstrated that KLF10 is under transcriptional control of insulin, where insulin promotes glycogen accumulation in myotubes of human muscle cells. Testosterone downregulates the expression levels of COL1A1 and MAP2K6. PCOS is associated with aberrant skeletal muscle gene expression with dysregulated pathways. Furthermore, we identified specific changes in muscle DNA methylation that may affect gene expression. This study showed that women with PCOS have epigenetic and transcriptional changes in skeletal muscle that, in part, can explain the metabolic abnormalities seen in these women.


An assessment of bacterial small RNA target prediction programs.
Most bacterial regulatory RNAs exert their function through base-pairing with target RNAs. Computational prediction of targets is a busy research field that offers biologists a variety of web sites and software. However, it is difficult for a non-expert to evaluate how reliable those programs are. Here, we provide a simple benchmark for bacterial sRNA target prediction based on trusted E. coli sRNA/target pairs. We use this benchmark to assess the most recent RNA target predictors as well as earlier programs for RNA-RNA hybrid prediction. Moreover, we consider how the definition of mRNA boundaries can impact overall predictions. Recent algorithms that exploit both conservation of targets and accessibility information offer improved accuracy over previous software. However, even with the best predictors, the number of true biological targets with low scores and non-targets with high scores remains puzzling.


Sick leave due to musculoskeletal pain: determinants of distinct trajectories over 1 year.
This study aimed to identify sub-groups of workers with different trajectories of sick leave due to musculoskeletal pain over 1 year, and to investigate the extent to which the identified trajectories are associated with personal, occupational, lifestyle, and pain-related factors at baseline. Data on 981 blue- and white-collar workers were analyzed in the DPHACTO cohort (2012-2014). The number of days on sick leave due to pain was reported using text messages at 4-week intervals across 1 year. Latent class growth analysis was used to distinguish sub-groups with different trajectories of sick leave. A web-based questionnaire at baseline was used to assess personal, occupational (physical and psychosocial), lifestyle, and pain-related factors. Multinomial regression models were constructed to determine associations between baseline factors and trajectories of sick leave (referencing no sick leave), with adjustment for potential confounders. Four distinct sub-groups were identified, with trajectories of sick leave due to pain ranging from no sick leave (prevalence 76%; average 0.5 days/year) to some days and increasing sick leave due to pain over 1 year (2%; 89 days/year). The increasing trajectory of sick leave was associated with higher perceived physical exertion, more time in manual work, less social community and influence at work, less leisure-time physical activity, smoking, and more severe symptoms (e.g., multisite pain, low back pain intensity, and pain interference). We identified four distinct trajectories of sick leave due to musculoskeletal pain. The sub-group with increasing sick leave due to pain was associated with several modifiable physical and psychosocial factors at work and outside work, which may have implications for prevention.


Heat-not-burn tobacco, electronic cigarettes, and combustible cigarette use among Japanese adolescents: a nationwide population survey 2017.
From among the global public health concerns, smoking remains one of the most crucial challenges. Especially for adolescents, the increase in the use of electronic cigarettes is controversial, as its use may lead to established smoking. In Japan, where a unique tobacco regulation system exists, the heat-not-burn tobacco market has been growing. However, the prevalence and association of combustible cigarettes and new tobacco-related products have not yet been closely investigated among Japanese adolescents. This study aimed to clarify the prevalence of smoking among adolescents, including new types of tobacco-related products, and to compare the characteristics of their users. The 2017 Lifestyle Survey of Adolescents is a nationally-representative survey collected in Japan. From the national school directory, 98 junior high schools and 86 high schools were randomly sampled throughout Japan. The students completed an anonymous questionnaire at school. We calculated the prevalence of use for each type of tobacco product. Then, the use of a combination of products and the characteristics of different types of products were examined. In total, 64,152 students from 48 junior high schools and 55 high schools were included the analysis (school response rate = 56%, Mage = 15.7 years, 53.9% boys). The age-adjusted rate of ever (current) use of electronic cigarettes was 2.1% (0.7%) in junior high school and 3.5% (1.0%) in high school; that of combustible cigarettes was 2.6% (0.6%) in junior high school and 5.1% (1.5%) in high school. The rate of heat-not-burn tobacco use was lower relative to other products: 1.1% (0.5%) in junior high school and 2.2% (0.9%) in high school. An examination of the combined use of the three products identified a high number of dual users. Comparisons between different types of users indicated different backgrounds for combustible cigarette users and new product users. The prevalence of new tobacco-alternative products is growing in popularity among Japanese adolescents. Dual use is common, and many adolescents use new products only. Moreover, e-cigarettes might attract a broader range of groups to smoking. Continuous monitoring and research are needed to investigate their influence as a possible gateway to tobacco smoking.


Matrix metalloproteinases inhibition attenuates tobacco smoke-induced emphysema in Guinea pigs.
To evaluate the effect of CP-471,474 (Pfizer Global Research and Development; Groton, CT), a broad-spectrum inhibitor of matrix metalloproteinases (MMPs) in an experimental model of emphysema. Randomized, double-blinded, controlled experiment. Biochemistry and morphology laboratories and animal research facility. Guinea pigs were exposed to cigarette smoke over 1 month, 2 months, and 4 months, and half of the animals received CP-471,474. Age-matched guinea pigs exposed to room air were used as control animals. After death, the lungs were lavaged with saline solution, and MMPs in the lavage fluid were determined by zymography and immunoblot. Lungs were fixed for histology, immunohistochemistry, and morphometry. Following a 1-month exposure to tobacco smoke, semiquantitative histologic assessment showed moderate lung inflammation, which progressed in extent and severity and reached a peak at 2 months. CP-471,474 significantly reduced both the extent (p < 0.002) and severity (p < 0.05) of inflammation at 2 months. At 4 months, a spontaneous reduction of the inflammatory response was observed in both treated and untreated animals, and consequently no difference was observed between both. Emphysematous changes, revealed by a significant increase in the average size of alveoli, were detected at 2 months and 4 months of tobacco smoke exposure. The inhibitor significantly decreased the destructive lesions mainly at 2 months (p < 0.0001) and also at 4 months (p < 0.02). Smoking increased MMP-9 and MMP-1 activities as shown by zymography and immunoblot. Immunoreactive MMP-9 was mainly localized in alveolar and bronchiolar epithelial cells, macrophages, and airways smooth-muscle cells. These findings support a role for MMPs in the early inflammatory response and in the emphysematous lesions provoked by cigarette smoking.


Specifying and comparing implementation strategies across seven large implementation interventions: a practical application of theory.
The use of implementation strategies is an active and purposive approach to translate research findings into routine clinical care. The Expert Recommendations for Implementing Change (ERIC) identified and defined discrete implementation strategies, and Proctor and colleagues have made recommendations for specifying operationalization of each strategy. We use empirical data to test how the ERIC taxonomy applies to a large dissemination and implementation initiative aimed at taking cardiac prevention to scale in primary care practice. EvidenceNOW is an Agency for Healthcare Research and Quality initiative that funded seven cooperatives across seven regions in the USA. Cooperatives implemented multi-component interventions to improve heart health and build quality improvement capacity, and used a range of implementation strategies to foster practice change. We used ERIC to identify cooperatives' implementation strategies and specified the actor, action, target, dose, temporality, justification, and expected outcome for each. We mapped and compiled a matrix of the specified ERIC strategies across the cooperatives, and used consensus to resolve mapping differences. We then grouped implementation strategies by outcomes and justifications, which led to insights regarding the use of and linkages between ERIC strategies in real-world scale-up efforts. Thirty-three ERIC strategies were used by cooperatives. We identified a range of revisions to the ERIC taxonomy to improve the practical application of these strategies. These proposed changes include revisions to four strategy names and 12 definitions. We suggest adding three new strategies because they encapsulate distinct actions that were not described in the existing ERIC taxonomy. In addition, we organized ERIC implementation strategies into four functional groupings based on the way we observed them being applied in practice. These groupings show how ERIC strategies are, out of necessity, interconnected, to achieve the work involved in rapidly taking evidence to scale. Findings of our work suggest revisions to the ERIC implementation strategies to reflect their utilization in real-work dissemination and implementation efforts. The functional groupings of the ERIC implementation strategies that emerged from on-the-ground implementers will help guide others in choosing among and linking multiple implementation strategies when planning small- and large-scale implementation efforts. Registered as Observational Study at www.clinicaltrials.gov ( NCT02560428 ).


A Modeling Study of the Cost-Effectiveness of a Risk-Stratified Surveillance Program for Melanoma in the United Kingdom.
Population-wide screening for melanoma is unlikely to be cost-effective. Nevertheless, targeted surveillance of high-risk individuals may be. To estimate the cost-effectiveness of various surveillance strategies in the UK population, stratified by risk using a simple self-assessment tool scoring between 0 and 67. A decision model comparing alternative surveillance policies from the perspective of the UK National Health Service over 30 years was developed. The strategy with the highest expected net benefit for each risk score was identified, resulting in a compound risk-stratified policy describing the most cost-effective population-wide strategy. The overall expected cost and quality-adjusted life-years (QALYs), the incremental cost-effectiveness ratio, and associated uncertainty were reported. The most cost-effective strategy is for those with a Williams score of 15 to 21 (relative risk [RR] of 0.79-1.60 vs. a mean score of 17 in the United Kingdom) to be offered a one-off full-body skin examination, and for those with a score of 22 or more (RR 1.79+) to be enrolled into a quinquennial monitoring program, rising to annual recall for those with a risk score greater than 43 (RR 20.95+). Expected incremental cost would be £164 million per annum (~0.1% of the National Health Service budget), gaining 15,947 additional QALYs and yielding an incremental cost-effectiveness ratio of £10,199/QALY gained (51.3% probability <£30,000). The risk-stratified policy would be expensive to implement but cost-effective compared with typical UK thresholds (£20,000-£30,000/QALY gained), although decision uncertainty is high. Phased implementation enrolling only higher risk individuals would be substantially less expensive, but with consequent foregone health gain.


Cytoskeletal architecture and immunocytochemical localization of microtubule-associated proteins in regions of axons associated with rapid axonal transport: the beta,beta'-iminodipropionitrile-intoxicated axon as a model system.
Axons from rats treated with the neurotoxic agent beta,beta'-iminodipropionitrile (IDPN) were examined by quick-freeze, deep-etch electron microscopy. Microtubules formed bundles in the central region of the axons, whereas neurofilaments were segregated to the periphery. Most membrane-bounded organelles, presumably including those involved in rapid axonal transport, were associated with the microtubule domain. The high resolution provided by quick-freeze, deep-etch electron microscopy revealed that the microtubules were coated with an extensive network of fine strands that served both to cross-link the microtubules and to interconnect them with the membrane-bounded organelles. The strands were decorated with granular materials and were irregular in dimension. They appeared either singly or as an extensive anastomosing network in fresh axons. The microtubule-associated strands were observed in fresh, saponin-extracted, or aldehyde-fixed tissue. To explore further the identity of the microtubule-associated strands, microtubules purified from brain tissue and containing the high molecular weight microtubule-associated proteins MAP 1 and MAP 2 were examined by quick-freeze, deep-etch electron microscopy. The purified microtubules were connected by a network of strands quite similar in appearance to those observed in the IDPN axons. Control microtubule preparations consisting only of tubulin and lacking the MAPs were devoid of associated strands. To learn which of the MAPs were present in the microtubule bundles in the axon, sections of axons from IDPN-treated rats were examined by immunofluorescence microscopy using antibodies to MAP 1A, MAP 1B, MAP 2, and tubulin. Anti-MAP 2 staining was only marginally detectable in the IDPN-treated axons, consistent with earlier observations. Anti-MAP 1A and anti-MAP 1B brightly stained the IDPN-treated axons, with the staining exclusively limited to the microtubule domains. Furthermore, thin section-immunoelectron microscopy using colloidal gold-labeled second antibodies revealed that both anti-MAP 1A and anti-MAP 1B stained fuzzy filamentous structures between microtubules. In view of earlier work indicating that rapid transport is associated with the microtubule domain in the IDPN-treated axon, it now appears that MAP 1A and MAP 1B may play a role in this process. We believe that MAP 1A and MAP 1B are major components of the microtubule-associated fibrillar matrix in the axon.


Microtubule Dynamics, Kinesin-1 Sliding, and Dynein Action Drive Growth of Cell Processes.
Recent experimental studies of the role of microtubule sliding in neurite outgrowth suggested a qualitative model, according to which kinesin-1 motors push the minus-end-out microtubules against the cell membrane and generate the early cell processes. At the later stage, dynein takes over the sliding, expels the minus-end-out microtubules from the neurites, and pulls in the plus-end-out microtubules that continue to elongate the nascent axon. This model leaves unanswered a number of questions: why is dynein unable to generate the processes alone, whereas kinesin-1 can? What is the role of microtubule dynamics in process initiation and growth? Can the model correctly predict the rates of process growth in control and dynein-inhibited cases? What triggers the transition from kinesin-driven to dynein-driven sliding? To answer these questions, we combine computational modeling of a network of elastic dynamic microtubules and kinesin-1 and dynein motors with measurements of the process growth kinetics and pharmacological perturbations in Drosophila S2 cells. The results verify quantitatively the qualitative model of the microtubule polarity sorting and suggest that dynein-powered elongation is effective only when the processes are longer than a threshold length, which explains why kinesin-1 alone, but not dynein, is sufficient for the process growth. Furthermore, we show that the mechanism of process elongation depends critically on microtubule dynamic instability. Both modeling and experimental measurements show, surprisingly, that dynein inhibition accelerates the process extension. We discuss implications of the model for the general problems of cell polarization, cytoskeletal polarity emergence, and cell process protrusion.


A pilot study of preoperative continuous infusion 5-fluorouracil, external microwave hyperthermia, and external beam radiotherapy for treatment of locally advanced, unresectable, or recurrent rectal cancer.
To determine the feasibility of combining external beam radiotherapy, continuous infusion 5-fluorouracil (5-FU), and external microwave hyperthermia in patients with locally advanced, unresectable, or recurrent adenocarcinoma of the rectum. From 7/95 through 2/99, 15 patients were enrolled in the study. The treatment regimen consisted of continuous infusion 5-FU 250 mg/m(2)/d 7 days/week beginning on day 1, external beam radiotherapy to the pelvis, 4500 cGy, 180 cGy/d 5 days/week using a 3 or 4-field technique, and external microwave hyperthermia on days 3, 8, 15, 22, and 29. Chemotherapy was stopped on the last day of radiotherapy. Surgical resection, if feasible, was scheduled 3-6 weeks after completing thermochemoradiotherapy. For this regimen to be considered feasible, no more than 2 of the 15 patients should fail to complete therapy due to life-threatening toxicity. Toxicity was scored using National Cancer Institute Criteria. All patients completed the chemoradiotherapy portion of the protocol. Eleven of the 15 patients completed all 5 hyperthermia treatments. Of the 4 patients who did not receive the full course of hyperthermia, only 1 patient had treatment stopped due to life-threatening toxicity. The other 3 patients did not complete hyperthermia due to scheduling errors (n = 2) or patient request (n = 1). Five of 15 patients required a treatment interruption due to toxicity > or = Grade 3. Seven patients experienced lesser degrees of toxicity which did not require treatment interruption. Three patients experienced no side effects. The most common toxicities were dermatitis and diarrhea. Of the 14 patients in whom surgery was planned, 11 (79%) were resectable. There was one pathologic complete response. It is feasible to deliver thermochemoradiotherapy, as prescribed in this study, to patients with locally advanced, unresectable, or recurrent rectal cancer. The therapy is moderately toxic, with one-third of patients requiring temporary treatment interruptions. The regimen appears active against rectal cancer, and appears to warrant further consideration as a treatment option for this patient population.


Emotional support, instrumental support, and gambling participation among Filipino Americans.
Using representative survey data of Filipino Americans in Honolulu and San Francisco (SF) (N = 2,259), we examined the roles of emotional support and instrumental support on gambling participation. With considerable difference in gambling environments between two regions, we conducted two sets of hierarchical regression analyses for Honolulu sample, which has restricted gambling laws, and SF sample, which has legal gambling environment, and compared the effects of two types of social support on gambling participation. The results indicated that emotional support was positively and instrumental support was negatively associated with gambling participation among Filipino Americans in Honolulu. However, neither type of social support was significantly associated with gambling participation among Filipino Americans living in SF. This study highlights the differing roles and effects of instrumental and emotional support on gambling where gambling is restricted. It also suggests that gambling behaviors of Filipino Americans are subject to situation- and environment-specific factors.


Lifestyle factors and primary care specialty selection: comparing 2012-2013 graduating and matriculating medical students' thoughts on specialty lifestyle.
To compare how first-year (MS1) and fourth-year students (MS4) ascribe importance to lifestyle domains and specialty characteristics in specialty selection, and compare students' ratings with their primary care (PC) interest. In March 2013, MS4s from 11 U.S. MD-granting medical schools were surveyed. Using a five-point Likert-type scale (1 = not important at all; 5 = extremely important), respondents rated the importance of 5 lifestyle domains and 21 specialty selection characteristics. One-way analysis of variance was used to assess differences by PC interest among MS4s. Using logistic regression, ratings from MS4s were compared with prior analyses of ratings by MS1s who matriculated to the same 11 schools in 2012. The response rate was 57% (965/1,701). MS4s, as compared with MS1s, rated as more important to good lifestyle: time off (4.3 versus 4.0), schedule control (4.2 versus 3.9), and financial compensation (3.4 versus 3.2). More MS4s than MS1s selected "time-off" (262/906 [30%] versus 136/969 [14%]) and "control of work schedule" (169/906 [19%] versus 146/969 [15%]) as the most important lifestyle domains. In both classes, PC interest was associated with higher ratings of working with the underserved and lower ratings of prestige and salary. In the 2012-2013 academic year, matriculating students and graduating students had similar perceptions of lifestyle and specialty characteristics associated with PC interest. Graduating students placed more importance on schedule control and time off than matriculating students. Specialties should consider addressing a perceived lack of schedule control or inadequate time off to attract students.


Digital image correlation and finite element modelling as a method to determine mechanical properties of human soft tissue in vivo.
The mechanical properties of human soft tissue are crucial for impact biomechanics, rehabilitation engineering, and surgical simulation. Validation of these constitutive models using human data remains challenging and often requires the use of non-invasive imaging and inverse finite element (FE) analysis. Post-processing data from imaging methods such as tagged magnetic resonance imaging (MRI) can be challenging. Digital image correlation (DIC), however, is a relatively straightforward imaging method. DIC has been used in the past to study the planar and superficial properties of soft tissue and excised soft tissue layers. However, DIC has not been used to non-invasive study of the bulk properties of human soft tissue in vivo. Thus, the goal of this study was to assess the use of DIC in combination with FE modelling to determine the bulk material properties of human soft tissue. Indentation experiments were performed on a silicone gel soft tissue phantom. A two camera DIC setup was then used to record the 3D surface deformation. The experiment was then simulated using a FE model. The gel was modelled as Neo-Hookean hyperelastic, and the material parameters were determined by minimising the error between the experimental and FE data. The iterative FE analysis determined material parameters (micro=1.80kPa, K=2999kPa) that were in close agreement with parameters derived independently from regression to uniaxial compression tests (micro=1.71kPa, K=2857kPa). Furthermore the FE model was capable of reproducing the experimental indentor force as well as the surface deformation found (R(2)=0.81). It was therefore concluded that a two camera DIC configuration combined with FE modelling can be used to determine the bulk mechanical properties of materials that can be represented using hyperelastic Neo-Hookean constitutive laws.


The impact of sex and smoking status on the mutational spectrum of epidermal growth factor receptor gene in non small cell lung cancer.
Mutation of epidermal growth factor receptor (EGFR) gene has been reported to be present in non-small cell lung cancer (NSCLC) and significantly associated with female sex and never-smoking status. In this study, we extensively investigated the impact of sex and smoking on the EGFR mutation. We examined EGFR exons 18 to 21 status in 1,467 NSCLC patients by direct sequencing to study the impact of sex and smoking status on the EGFR mutational spectrum. Among 1,467 patients, 197 mutations were found at exon 19, 176 at exon 21, 21 at exon 18, and 24 at exon 20. To examine the independent effect of sex and smoking, the mutational status of each exon was compared between smokers and never smokers in each sex and between males and females stratified by smoking status. In females, exon 19 (P = 0.001) and exon 21 (P < 0.001) mutations were significantly less frequent in ever smokers compared with never smokers. In males, exon 19 (P < 0.001), exon 21 (P < 0.001), and exon 18 (P = 0.003) mutations were significantly less frequent in ever smokers compared with never smokers. In analysis stratified by smoking, there was no difference in sex among never smokers. However, exon 19 mutations were significantly less frequent in males compared with females among ever smokers (P = 0.003). In addition, the interactive effect of male sex and ever smoking status significantly decreased the frequency of exon 19 mutations (P = 0.047) when female never smoker was set as a reference. Both sex and smoking status could influence the EGFR mutational spectrum. Our findings suggest that individual EGFR exons may have differing susceptibilities for mutagenesis.


Detection of Chlamydia pneumoniae but not Helicobacter pylori in atherosclerotic plaques of aortic aneurysms.
Recent reports suggest an association between Chlamydia pneumoniae and Helicobacter pylori bacteria and atherosclerosis. We studied 51 patients (mean age, 68.3 years) who underwent abdominal aortic aneurysm surgery. For each patient we performed a microimmunofluorescence test for immunoglobulin G (IgG), IgA, and IgM antibodies to C. pneumoniae specific antigen (TW-183). Anti-H. pylori antibodies were determined by means of an EIA-G test. Each aortic aneurysm surgical specimen was sampled into multiple sections of 0.3 cm2 each and frozen at -20 degrees C. Two samples of each aneurysm were used for a nested PCR with two sets of C. pneumoniae and two sets of H. pylori specific primers. Specimens were treated with a solution containing 20 mM Tris-HCl, Tween 20-Nonidet P-40 (0.5% [vol/vol] each), and 100 micrograms of proteinase K per ml and incubated at 60 degrees C for 1 h and at 98 degrees C for 10 min. DNA was extracted twice with phenol-chloroform-isoamylic alcohol and precipitated with sodium acetate-ethanol by standard methods. Forty-one patients were seropositive for C. pneumoniae with past-infection patterns in 32 patients (16 < or = IgG < 512; 32 < or = IgA < 256) and high antibody titers in 9 patients (IgG > or = 512). In 26 of 51 patients, C. pneumoniae DNA was detected in aortic aneurysm plaque specimens. Of these patients, 23 had a serologic past-infection pattern, 2 had an acute reinfection pattern, and 1 was seronegative. Forty-seven of 51 patients were seropositive for H. pylori. In all cases PCR showed no evidence of H. pylori presence in plaque specimens. This study provides data on a possible C. pneumoniae involvement in the pathogenesis of aortic aneurysm and additional evidence for an association between this agent and atherosclerosis. Conversely, notwithstanding a high H. pylori seroprevalence observed, our results tend to rule out the possibility of a direct involvement of H. pylori in atherosclerosis.


fMRI evidence for areas that process surface gloss in the human visual cortex.
Surface gloss is an important cue to the material properties of objects. Recent progress in the study of macaque's brain has increased our understating of the areas involved in processing information about gloss, however the homologies with the human brain are not yet fully understood. Here we used human functional magnetic resonance imaging (fMRI) measurements to localize brain areas preferentially responding to glossy objects. We measured cortical activity for thirty-two rendered three-dimensional objects that had either Lambertian or specular surface properties. To control for differences in image structure, we overlaid a grid on the images and scrambled its cells. We found activations related to gloss in the posterior fusiform sulcus (pFs) and in area V3B/KO. Subsequent analysis with Granger causality mapping indicated that V3B/KO processes gloss information differently than pFs. Our results identify a small network of mid-level visual areas whose activity may be important in supporting the perception of surface gloss.


The demonstration of serum interleukin 6-8, tumor necrosis factor-alpha, complement, and immunoglobulin levels in Behçet's disease with ocular involvement.
To investigate whether there are alterations in the humoral immune system in patients with Behçet's disease (BD) with ocular involvement. Twenty-four BD patients with active uveitis and without any other manifestations of the disease were included in Group I-a. The same patients were reassessed during the convalescence period and assigned to Group I-c. Moreover, 24 age- and sex-matched healthy controls (Group II) were included in the study. Serum levels of immunoglobulin (Ig) A, IgM, complement (C) 3, C4, interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) in Groups I-a, I-c, and II were measured and compared. IgA, C3, C4, IL-6, IL-8, and TNF-alpha levels were higher in Group I-a than in Groups I-c and II. IgA-, C3-, C4-, IL6-, IL8-, and TNF-alpha-mediated mechanisms might be responsible for ocular lesions in BD.


Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions.
Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacologic approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutrient-restricted conditions to exert broad biological effects, protecting normal cells, organs, and systems, while sensitizing a wide variety of cancer cells to cytotoxic therapies. On the other hand, drugs targeting enzymes or metabolites of crucial metabolic pathways can be highly specific and effective, but must be matched with a responsive tumor, which might rapidly adapt. In this review, we illustrate how dietary and pharmacologic therapies differ in their effect on tumor growth, proliferation, and metabolism and discuss the available preclinical and clinical evidence in favor of or against each of them. We also indicate, when appropriate, how to optimize future investigations on metabolic therapies on the basis of tumor- and patient-related characteristics. To our knowledge, this is the first review article that comprehensively analyzes the preclinical and preliminary clinical experimental foundations of both dietary and pharmacologic metabolic interventions in cancer therapy. Among several promising therapies, we propose treatment personalization on the basis of tumor genetics, tumor metabolism, and patient systemic metabolism.Cancer Discov; 6(12); 1315-33. ©2016 AACR.


Measuring the distribution of spitefulness.
Spiteful, antisocial behavior may undermine the moral and institutional fabric of society, producing disorder, fear, and mistrust. Previous research demonstrates the willingness of individuals to harm others, but little is understood about how far people are willing to go in being spiteful (relative to how far they could have gone) or their consistency in spitefulness across repeated trials. Our experiment is the first to provide individuals with repeated opportunities to spitefully harm anonymous others when the decision entails zero cost to the spiter and cannot be observed as such by the object of spite. This method reveals that the majority of individuals exhibit consistent (non-)spitefulness over time and that the distribution of spitefulness is bipolar: when choosing whether to be spiteful, most individuals either avoid spite altogether or impose the maximum possible harm on their unwitting victims.


Aggressive diets and lipid responses.
Poor diet and physical inactivity, the two major contributors to the development of overweight and obesity, have recently been identified as the second most common actual cause of death in the United States. With the increasing awareness of the strong link between obesity and chronic disease, in particular cardiovascular disease, a myriad of diets have surfaced and many of them claim weight loss depends more on the macronutrient composition of the diet than the number of calories consumed. Long-term outcome data, particularly cardiovascular outcome data, on these diets are sparse. This article summarizes previous and recent reports of popular and aggressive diets, such as low-carbohydrate diets, low-fat diets, and very low-calorie diets, addressing their effects on weight loss and focusing on their effects on lipids and lipoproteins.


FcRgamma activation regulates inflammation-associated squamous carcinogenesis.
Chronically activated leukocytes recruited to premalignant tissues functionally contribute to cancer development; however, mechanisms underlying pro- versus anti-tumor programming of neoplastic tissues by immune cells remain obscure. Using the K14-HPV16 mouse model of squamous carcinogenesis, we report that B cells and humoral immunity foster cancer development by activating Fcgamma receptors (FcgammaRs) on resident and recruited myeloid cells. Stromal accumulation of autoantibodies in premalignant skin, through their interaction with activating FcgammaRs, regulate recruitment, composition, and bioeffector functions of leukocytes in neoplastic tissue, which in turn promote neoplastic progression and subsequent carcinoma development. These findings support a model in which B cells, humoral immunity, and activating FcgammaRs are required for establishing chronic inflammatory programs that promote de novo carcinogenesis.


Publishers' Responsibilities in Promoting Data Quality and Reproducibility.
Scholarly publishers can help to increase data quality and reproducible research by promoting transparency and openness. Increasing transparency can be achieved by publishers in six key areas: (1) understanding researchers' problems and motivations, by conducting and responding to the findings of surveys; (2) raising awareness of issues and encouraging behavioural and cultural change, by introducing consistent journal policies on sharing research data, code and materials; (3) improving the quality and objectivity of the peer-review process by implementing reporting guidelines and checklists and using technology to identify misconduct; (4) improving scholarly communication infrastructure with journals that publish all scientifically sound research, promoting study registration, partnering with data repositories and providing services that improve data sharing and data curation; (5) increasing incentives for practising open research with data journals and software journals and implementing data citation and badges for transparency; and (6) making research communication more open and accessible, with open-access publishing options, permitting text and data mining and sharing publisher data and metadata and through industry and community collaboration. This chapter describes practical approaches being taken by publishers, in these six areas, their progress and effectiveness and the implications for researchers publishing their work.


Neuroendocrine and immune contributors to fatigue.
Central fatigue, a persistent and subjective sense of tiredness, generally correlates poorly with traditional markers of disease. It is frequently associated with psychosocial factors, such as depression, sleep disorder, anxiety, and coping style, which suggest that dysregulation of the body's stress systems may serve as an underlying mechanism in the maintenance of chronic fatigue (CF). This article addresses the endocrine, neural, and immune factors that contribute to fatigue and describes research regarding the role of these factors in chronic fatigue syndrome as a model for addressing the biology of CF. In general, hypoactivity of the hypothalamic-pituitary-adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF. Noninvasive methods for evaluating endocrine, neural, and immune function are also discussed. Simultaneous evaluation of neuroendocrine and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems, their role in disease susceptibility, and progression of stress-related disorders.


Turn-taking in Human Communication--Origins and Implications for Language Processing.
Most language usage is interactive, involving rapid turn-taking. The turn-taking system has a number of striking properties: turns are short and responses are remarkably rapid, but turns are of varying length and often of very complex construction such that the underlying cognitive processing is highly compressed. Although neglected in cognitive science, the system has deep implications for language processing and acquisition that are only now becoming clear. Appearing earlier in ontogeny than linguistic competence, it is also found across all the major primate clades. This suggests a possible phylogenetic continuity, which may provide key insights into language evolution.


Prevalence and clinical consequences of cytomegalovirus DNA in the aqueous humour and corneal transplants.
To determine the prevalence and clinical consequences of cytomegalovirus (CMV) DNA in the aqueous and corneal tissues obtained at the time of corneal transplantation to evaluate the diagnostic value of PCR analysis in identifying patients at risk of postkeratoplasty CMV endotheliitis. Thirty patients who underwent corneal transplantation were included in 2011. The aqueous, excised recipient corneas and donor corneoscleral rims were analysed by PCR for the presence of CMV DNA. The medical records of the patients were retrospectively reviewed and linked with PCR results. CMV DNA was detected in three (10%) aqueous, eight (26.7%) recipient corneas and six (20.0%) donor corneas obtained during keratoplasty from the 30 patients. Postoperatively, four patients, who had CMV DNA in either aqueous (3) or recipient cornea (1), were diagnosed with CMV endotheliitis based on clinical features and repeat aqueous tapping for real-time PCR analysis. At the median 60.5 months follow-up, 8 (72.7%), including 4 with postkeratoplasty CMV endotheliitis, of the 11 patients with CMV positivity in any one sample had graft failure, while 9 (47.3%) of the 19 patients without evidence of CMV DNA experienced graft failure. We found a relatively high prevalence of CMV DNA in the aqueous and corneas obtained during keratoplasty. All the patients who had CMV positivity in aqueous developed CMV endotheliitis postoperatively and experienced graft failure eventually. Aqueous tapping at the time of corneal transplantation for PCR analysis may help to improve the diagnosis and follow-up management of postkeratoplasty CMV endotheliitis.


The minimal important difference of the hospital anxiety and depression scale in patients with chronic obstructive pulmonary disease.
Interpretation of the Hospital Anxiety and Depression Scale (HADS), commonly used to assess anxiety and depression in COPD patients, is unclear. Since its minimal important difference has never been established, our aim was to determine it using several approaches. 88 COPD patients with FEV1 </= 50% predicted completed the HADS and other patient-important outcome measures before and after an inpatient respiratory rehabilitation. For the anchor-based approach we determined the correlation between the HADS and the anchors that have an established minimal important difference (Chronic Respiratory Questionnaire [CRQ] and Feeling Thermometer). If correlations were >/= 0.5 we performed linear regression analyses to predict the minimal important difference from the anchors. As distribution-based approach we used the Effect Size approach. Based on CRQ emotional function and mastery domain as well as on total scores, the minimal important difference was 1.41 (95% CI 1.18-1.63) and 1.57 (1.37-1.76) for the HADS anxiety score and 1.68 (1.48-1.87) and 1.60 (1.38-1.82) for the HADS total score. Correlations of the HADS depression score and CRQ domain and Feeling Thermometer scores were < 0.5. Based on the Effect Size approach the MID of the HADS anxiety and depression score was 1.32 and 1.40, respectively. The minimal important difference of the HADS is around 1.5 in COPD patients corresponding to a change from baseline of around 20%. It can be used for the planning and interpretation of trials.


The transmissibility of novel Coronavirus in the early stages of the 2019-20 outbreak in Wuhan: Exploring initial point-source exposure sizes and durations using scenario analysis.
Background: The current novel coronavirus outbreak appears to have originated from a point-source exposure event at Huanan seafood wholesale market in Wuhan, China. There is still uncertainty around the scale and duration of this exposure event. This has implications for the estimated transmissibility of the coronavirus and as such, these potential scenarios should be explored. Methods: We used a stochastic branching process model, parameterised with available data where possible and otherwise informed by the 2002-2003 Severe Acute Respiratory Syndrome (SARS) outbreak, to simulate the Wuhan outbreak. We evaluated scenarios for the following parameters: the size, and duration of the initial transmission event, the serial interval, and the reproduction number (R0). We restricted model simulations based on the number of observed cases on the 25th of January, accepting samples that were within a 5% interval on either side of this estimate. Results: Using a pre-intervention SARS-like serial interval suggested a larger initial transmission event and a higher R0 estimate. Using a SARs-like serial interval we found that the most likely scenario produced an R0 estimate between 2-2.7 (90% credible interval (CrI)). A pre-intervention SARS-like serial interval resulted in an R0 estimate between 2-3 (90% CrI). There were other plausible scenarios with smaller events sizes and longer duration that had comparable R0 estimates. There were very few simulations that were able to reproduce the observed data when R0 was less than 1. Conclusions: Our results indicate that an R0 of less than 1 was highly unlikely unless the size of the initial exposure event was much greater than currently reported. We found that R0 estimates were comparable across scenarios with decreasing event size and increasing duration. Scenarios with a pre-intervention SARS-like serial interval resulted in a higher R0 and were equally plausible to scenarios with SARs-like serial intervals.


Effects of anorexia nervosa on clinical, hematologic, biochemical, and bone density parameters in community-dwelling adolescent girls.
Anorexia nervosa (AN) is an eating disorder that leads to a number of medical sequelae in adult women and has a mortality rate of 5.6% per decade; known complications include effects on hematologic, biochemical, bone density, and body composition parameters. Few data regarding medical and developmental consequences of AN are available for adolescents, in particular for an outpatient community-dwelling population of girls who have this disorder. The prevalence of AN is increasing in adolescents, and it is the third most common chronic disease in adolescent girls. Therefore, it is important to determine the medical effects of this disorder in this young population. We examined clinical characteristics and performed hematologic, biochemical, hormonal, and bone density evaluations in 60 adolescent girls with AN (mean age: 15.8 +/- 1.6 years) and 58 healthy adolescent girls (mean age: 15.2 +/- 1.8 years) of comparable maturity. Nutritional and pubertal status; vital signs; a complete blood count; potassium levels; hormonal profiles; bone density at the lumbar and lateral spine; total body, hip, and femoral neck (by dual-energy x-ray absorptiometry) and body composition (by dual-energy x-ray absorptiometry) were determined. All measures of nutritional status such as weight, percentage of ideal body weight, body mass index, lean body mass, fat mass, and percentage of fat mass were significantly lower in girls with AN than in control subjects. Girls with AN had significantly lower heart rates, lower systolic blood pressure, and lower body temperature compared with control subjects. Total red cell and white cell counts were lower in AN than in control subjects. Among girls with AN, 22% were anemic and 22% were leukopenic. None were hypokalemic. Mean age at menarche did not differ between the groups. However, the proportion of girls who had AN and were premenarchal was significantly higher compared with healthy control subjects who were premenarchal, despite comparable maturity as determined by bone age. Ninety-four percent of premenarchal girls with AN versus 28% of premenarchal control subjects were above the mean age at menarche for white girls, and 35% of premenarchal AN girls versus 0% of healthy adolescents were delayed >2 SD above the mean. The ratio of bone age to chronological age, a measure of delayed maturity, was significantly lower in girls with AN versus control subjects and correlated positively with duration of illness and markers of nutritional status. Serum estradiol values were lower in girls with AN than in control subjects, and luteinizing hormone values trended lower in AN. Levels of insulin-like growth factor-I were also significantly lower in girls with AN. Estradiol values correlated positively with insulin-like growth factor-I, a measure of nutritional status essential for growth (r = 0.28). All measures of bone mineral density (z scores) were lower in girls with AN than in control subjects, with lean body mass, body mass index, and age at menarche emerging as the most important predictors of bone density. Bone density z scores of <-1 at any one site were noted in 41% of girls with AN, and an additional 11% had bone density z scores of <-2. A high prevalence of hemodynamic, hematologic, endocrine, and bone density abnormalities are reported in this large group of community-dwelling adolescent girls with AN. Although a number of these consequences of AN are known to occur in hospitalized adolescents, the occurrence of these findings, including significant bradycardia, low blood pressure, and pubertal delay, in girls who are treated for AN on an outpatient basis is of concern and suggests the need for vigilant clinical monitoring, including that of endocrine and bone density parameters.


Differential disruption of blood-brain barrier in severe traumatic brain injury.
Traumatic brain injury (TBI) is a significant cause of death and disability in young adults, but not much is known about the incidence and characteristics of blood-brain barrier (BBB) dysfunction in this group. In this proof of concept study, we sought to quantify the incidence of BBB dysfunction (defined as a cerebrospinal fluid (CSF)-plasma albumin quotient of ≥0.007) and examine the relationship between plasma and CSF levels of proteins and electrolytes, in patients with severe TBI. We recruited 30 patients, all of whom were receiving hypertonic 20 % saline infusion for intracranial hypertension and had external ventricular drains in situ. Simultaneous CSF and blood samples were obtained. Biochemical testing was performed for sodium, osmolality, potassium, glucose, albumin, immunoglobulin-G, and total protein. Eleven patients (37 %) showed evidence of impairment of passive BBB function, with a CSF-plasma albumin quotient of ≥0.007. There were strong positive correlations seen among CSF-plasma albumin quotient and CSF-plasma immunoglobulin-G quotient and CSF-plasma total protein quotient (r = 0.967, P < 0.001 and r = 0.995, P < 0.001, respectively). We also found a higher maximum intracranial pressure (24 vs. 21 mmHg, P = 0.029) and a trend toward increased mortality (27 vs. 11 %, P = 0.33) in patients with BBB disruption. In summary, passive BBB dysfunction is common in patients with severe TBI, and may have important implications for effectiveness of osmotherapy and long-term outcomes. Also, our results suggest that the CSF-plasma total protein quotient, a measurement which is readily available, can be used instead of the CSF-plasma albumin quotient for evaluating BBB dysfunction.


Reduced β-amyloid pathology in an APP transgenic mouse model of Alzheimer's disease lacking functional B and T cells.
In Alzheimer's disease, accumulation and pathological aggregation of amyloid β-peptide is accompanied by the induction of complex immune responses, which have been attributed both beneficial and detrimental properties. Such responses implicate various cell types of the innate and adaptive arm of the immunesystem, both inside the central nervous system, and in the periphery. To investigate the role of the adaptive immune system in brain β-amyloidosis, PSAPP transgenic mice, an established mouse model of Alzheimer's disease, were crossbred with the recombination activating gene-2 knockout (Rag2 ko) mice lacking functional B and T cells. In a second experimental paradigm, aged PSAPP mice were reconstituted with bone marrow cells from either Rag2 ko or wildtype control mice. Analyses from both experimental approaches revealed reduced β-amyloid pathology and decreased brain amyloid β-peptide levels in PSAPP mice lacking functional adaptive immune cells. The decrease in brain β-amyloid pathology was associated with enhanced microgliosis and increased phagocytosis of amyloid β-peptide aggregates. The results of this study demonstrate an impact of the adaptive immunity on cerebral β-amyloid pathology in vivo and suggest an influence on microglia-mediated amyloid β-peptide clearance as a possible underlying mechanism.


Treatment of Other Nontuberculous Mycobacteria.
Nontuberculous mycobacteria (NTM) are numerous, and for the vast majority of them, randomized studies are lacking and data regarding optimal treatment are limited. When Mycobacterium avium complex (MAC) and M. abscessus are excluded, the main NTM are M. xenopi, M. kansasii, M. malmoense, M. szulgai, and M. simiae. Treatment is long (at least 12 months after culture conversion according to recommendations by scientific societies) and difficult (at least three drugs are required, each of which have potential adverse events). Moreover, optimal treatment is unknown for the vast majority of NTM and efficacy of treatment is not 100%. That is why, balance between benefit and risk is fundamental. For M. xenopi, the second most common NTM isolated in Europe, treatment is classically based on macrolides or fluoroquinolones, associated with ethambutol and rifampicin. For M. kansasii, the cornerstone of treatment is rifampicin, which should be associated with two other drugs: ethambutol plus isoniazid or clarithromycin. M. malmoense, which is common in Northern Europe, can be treated by rifampicin, ethambutol, and clarithromycin and/or fluoroquinolones.


Multisensor Imaging-From Sample Preparation to Integrated Multimodal Interpretation of LA-ICPMS and MALDI MS Imaging Data.
Laterally resolved chemical analysis (chemical imaging) has increasingly attracted attention in the Life Sciences during the past years. While some developments have provided improvements in lateral resolution and speed of analysis, there is a trend toward the combination of two or more analysis techniques, so-called multisensor imaging, for providing deeper information into the biochemical processes within one sample. In this work, a human malignant pleural mesothelioma sample from a patient treated with cisplatin as a cytostatic agent has been analyzed using laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). While LA-ICPMS was able to provide quantitative information on the platinum distribution along with the distribution of other elemental analytes in the tissue sample, MALDI MS could reveal full information on lipid distributions, as both modes of polarity, negative and positive, were used for measurements. Tandem MS experiments verified the occurrence of distinct lipid classes. All imaging analyses were performed using a lateral resolution of 40 μm, providing information with excellent depth of details. By analyzing the very same tissue section, it was possible to perfectly correlate the obtained analyte distribution information in an evaluation approach comprising LA-ICPMS and MALDI MS data. Correlations between platinum, phosphorus, and lipid distributions were found by the use of advanced statistics. The present proof-of-principle study demonstrates the benefit of data combination for outcomes beyond one method imaging modality and highlights the value of advanced chemical imaging in the Life Sciences.


A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukaemia cell lines.
The response of the CML-BC cell line, K562, the myelomonocytic cell line MM6 and the promyelocytic leukaemia cell line HL-60, to a 15 mer WT1 antisense oligonucleotide, targeted to the translation initiation site of the WT1 mRNA was examined. K562 cells exposed to 0.4 microM antisense oligonucleotide showed markedly reduced proliferation which was associated with reduced cell viability. Sense, scrambled and mutant antisense oligonucleotides had no effect on the proliferation of K562 cells. MM6 cells exposed to 0.4 microM antisense oligonucleotide also showed significantly reduced cellular proliferation which was also accompanied by loss of cell viability. In the K562 and MM6 antisense cultures that exhibited reduced cell viability, both DNA fragmentation and morphological features consistent with apoptosis could be identified. In contrast the growth of HL-60 cells was unaffected by exposure to 0.4 microM antisense oligonucleotide. In each of the cell lines examined, WT1 antisense oligonucleotide abrogated WT1 protein expression, and analysis of WT1 coding sequence in these cells showed that no oncogenic point mutations in the gene were present. We propose therefore that in some myeloid leukaemia cell lines, the expression of a normal WT1 protein is necessary for cell proliferation and that it plays a role in maintaining the viability of some leukaemia cells.


Retinoids synergize with insulin to induce hepatic Gck expression.
Hepatic GK (glucokinase) plays a key role in maintaining glucose homoeostasis. Many stimuli regulate GK activity by controlling its gene transcription. We hypothesized that endogenous lipophilic molecules modulate hepatic Gck expression. Lipophilic molecules were extracted from rat livers, saponified and re-constituted as an LE (lipophilic extract). LE synergized with insulin to induce primary hepatocyte, but not beta-cell, Gck expression in an SREBP-1c (sterol-regulatory-element-binding protein-1c)-independent manner. The dramatic induction of Gck mRNA resulted in a significant increase in GK activity. Subsequently, the active molecules were identified as retinol and retinal by MS after the purification of the active LE fractions. Retinoids synergized with insulin to induce Gck expression by the activation of both RAR [RA (retinoic acid) receptor] and RXR (retinoid X receptor). Inhibition of RAR activation completely abolished the effect of retinal. The hepatic GK specific activity and Gck mRNA levels of Zucker lean rats fed with a VAD [VA (vitamin A)-deficient] diet were significantly lower than those of rats fed with VAS (VA-sufficient) diet. Additionally, the hepatic Gck mRNA expression of Sprague-Dawley rats fed with a VAD diet was lower than that of rats fed with VA-marginal, -adequate or -supplemented diets. The reduced expression of Gck mRNA was increased after an intraperitoneal dose of RA in VAD rats. Furthermore, an intravenous injection of RA rapidly raised hepatic Gck expression in rats fed with a VAS control diet. Understanding the underlying mechanism that mediates the synergy may be helpful for developing a treatment strategy for patients with diabetes.