Relationship between sialic acid and metabolic variables in Indian type 2 diabetic patients.
Plasma sialic acid is a marker of the acute phase response. Objective is to study the relationship between sialic acid relationship with metabolic variables in Indian type 2 diabetes with and without microvascular complications. Fasting Venous blood samples were taken from 200 subjects of which 50 were of diabetes mellitus (DM) and nephropathy patients, 50 patients with type 2 diabetes and retinopathy, 50 patients with type 2 diabetes without any complications and 50 healthy individuals without diabetes. The Indian subject's aged 15-60 years with type 2 diabetes were recruited for the study. Simultaneously urine samples were also collected from each of the subjects. All the blood samples were analyzed for total cholesterol, triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), fasting and postprandial glucose on fully automated analyzer. Serum and urine sialic acid along with microalbumin levels were also estimated. There was a significantly increasing trend of plasma and urine sialic acid with severity of nephropathy (P < 0.001) and with degree of urinary albumin excretion (P < 0.001). Serum sialic acid correlated with increasing serum creatinine concentration (P < 0.001). Elevated serum sialic acid concentrations were also associated with several risk factors for diabetic vascular disease: diabetes duration, HbA1c, serum triglyceride and cholesterol concentrations, waist-to-hip ratio and hypertension. Significant correlations were found between sialic acid concentration and cardiovascular risk factors like LDL and TG in the diabetic subjects. The main finding of this study is that elevated serum and urinary sialic acid and microalbumin concentrations were strongly related to the presence of microvascular complications like diabetic nephropathy and retinopathy and cardiovascular risk factors in Indian type 2 diabetic subjects. Further study of acute-phase response markers and mediators as indicators or predictors of diabetic microvascular complications is therefore justified.


RNA Editing, ADAR1, and the Innate Immune Response.
RNA editing, particularly A-to-I RNA editing, has been shown to play an essential role in mammalian embryonic development and tissue homeostasis, and is implicated in the pathogenesis of many diseases including skin pigmentation disorder, autoimmune and inflammatory tissue injury, neuron degeneration, and various malignancies. A-to-I RNA editing is carried out by a small group of enzymes, the adenosine deaminase acting on RNAs (ADARs). Only three members of this protein family, ADAR1-3, exist in mammalian cells. ADAR3 is a catalytically null enzyme and the most significant function of ADAR2 was found to be in editing on the neuron receptor GluR-B mRNA. ADAR1, however, has been shown to play more significant roles in biological and pathological conditions. Although there remains much that is not known about how ADAR1 regulates cellular function, recent findings point to regulation of the innate immune response as an important function of ADAR1. Without appropriate RNA editing by ADAR1, endogenous RNA transcripts stimulate cytosolic RNA sensing receptors and therefore activate the IFN-inducing signaling pathways. Overactivation of innate immune pathways can lead to tissue injury and dysfunction. However, obvious gaps in our knowledge persist as to how ADAR1 regulates innate immune responses through RNA editing. Here, we review critical findings from ADAR1 mechanistic studies focusing on its regulatory function in innate immune responses and identify some of the important unanswered questions in the field.


Identifying Physical Activity Profiles in COPD Patients Using Topic Models.
With the growing amount of physical activity (PA) measures, the need for methods and algorithms that automatically analyze and interpret unannotated data increases. In this paper, PA is seen as a combination of multimodal constructs that can cooccur in different ways and proportions during the day. The design of a methodology able to integrate and analyze them is discussed, and its operation is illustrated by applying it to a dataset comprising data from COPD patients and healthy subjects acquired in daily life. The method encompasses different stages. The first stage is a completely automated method of labeling low-level multimodal PA measures. The information contained in the PA labels are further structured using topic modeling techniques, a machine learning method from the text processing community. The topic modeling discovers the main themes that pervade a large set of data. In our case, topic models discover PA routines that are active in the assessed days of the subjects under study. Applying the designed algorithm to our data provides new learnings and insights. As expected, the algorithm discovers that PA routines for COPD patients and healthy subjects are substantially different regarding their composition and moments in time in which transitions occur. Furthermore, it shows consistent trends relating to disease severity as measured by standard clinical practice.


[Hemodynamics of congestive cardiomyopathy].
202 patients with congestive cardiomyopathy have been classified according to their hemodynamic, angiographic, echocardiographic and scintigraphic findings: 72 patients were in the late stage (LS), 103 patients in an early stage (ES) and 17 patients showed a latent form of the disease. 48% of the hemodynamic ES were found to be clinically in stage IV NYHA and 53% of ES fell in class III. 40% of the patients with LS showed a stationary clinical course whereas 46% could improve their classification by one grade. The mortality in hemodynamic LS was 46% within an interval of 18 +/- 14 months after the diagnosis. In ES 64% showed a stable clinical course, where a 22% were deteriorating. Mortality in this group was 10%. Sensitivity and specificity of echocardiography (93 vs 80%) and radionuclide methods (80 vs 71%) were quite good in the late stage whereas in ES specificity was only 71% vs 80%. There was a discrepancy between the degree of myocardial impairment and clinical symptoms in the late stage whereas in the early stage there was no correlation between exercise capacity and LV-hemodynamics. Non-invasive methods allow the hemodynamic evaluation of the disease; invasive methods are required for clarification of diagnosis or establishing prognosis.


Temperature and leaf wetness duration affect phenotypic expression of Rlm6-mediated resistance to Leptosphaeria maculans in Brassica napus.
Near-isogenic Brassica napus lines carrying/lacking resistance gene Rlm6 were used to investigate the effects of temperature and leaf wetness duration on phenotypic expression of Rlm6-mediated resistance. Leaves were inoculated with ascospores or conidia of Leptosphaeria maculans carrying the effector gene AvrLm6. Incubation period to the onset of lesion development, number of lesions and lesion diameter were assessed. Symptomless growth of L. maculans from leaf lesions to stems was investigated using a green fluorescent protein (GFP) expressing isolate carrying AvrLm6. L. maculans produced large grey lesions on Darmor (lacking Rlm6) at 5-25 degrees C and DarmorMX (carrying Rlm6) at 25 degrees C, but small dark spots and 'green islands' on DarmorMX at 5-20 degrees C. With increasing temperature/wetness duration, numbers of lesions/spots generally increased. GFP-expressing L. maculans grew from leaf lesions down leaf petioles to stems on DarmorMX at 25 degrees C but not at 15 degrees C. We conclude that temperature and leaf wetness duration affect the phenotypic expression of Rlm6-mediated resistance in leaves and subsequent L. maculans spread down petioles to produce stem cankers.


Vitamin D and the risk of dementia and Alzheimer disease.
To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease. One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria. During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25 to <50 nmol/L) were 2.25 (95% CI: 1.23-4.13) and 1.53 (95% CI: 1.06-2.21) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95% CI: 1.02-4.83) and 1.69 (95% CI: 1.06-2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L. Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.


Experimental rat models of chronic allograft nephropathy: a review.
Chronic allograft nephropathy (CAN) is the leading cause of late allograft loss after renal transplantation (RT), which continues to remain an unresolved problem. A rat model of CAN was first described in 1969 by White et al. Although the rat model of RT can be technically challenging, it is attractive because the pathogenesis of CAN is similar to that following human RT and the pathological features of CAN develop within months as compared with years in human RT. The rat model of RT is considered as a useful investigational tool in the field of experimental transplantation research. We have reviewed the literature on studies of rat RT reporting the donor and recipient strain combinations that have investigated resultant survival and histological outcomes. Several different combinations of inbred and outbred rat combinations have been reported to investigate the multiple aspects of transplantation, including acute rejection, cellular and humoral rejection mechanisms and their treatments, CAN, and potential targets for its prevention.


High-irradiance reactors with unfolded aplanatic optics.
Reconstituting the intense irradiance of short-arc discharge lamps at a remote target, at high radiative efficiency, represents a central challenge in the design of high-temperature chemical reactors, heightened by the need for high numerical aperture at both the target and the source. Separating the optical system from both the source and the reactor allows pragmatic operation, monitoring, and control. We explore near-field unfolded aplanats as feasible solutions and report measurements for a prototype that constitutes a double-ellipsoid mirror. We also propose compound unfolded aplanats that collect lamp emission over all angles (in lieu of light recycling optics) and irradiate the reactor over nearly its full circumference.


Detection of methane with high spatial resolution with photothermal deflection spectroscopy.
We demonstrate the use of photothermal deflection spectroscopy for detection and measurement of methane with very high spatial resolution. A high spatial resolution may be important for some applications, and other techniques in current use do not provide this resolution. To the best of our knowledge, this is the first application of photothermal spectroscopy to methane detection. We have succeeded in detecting a signal even from a very weak combination-overtone band of methane in the visible region of the spectrum. If used in conjunction with a strongly absorbing fundamental band, the technique is capable of yielding high sensitivity along with very high spatial and temporal resolutions.


An EGSnrc investigation of cavity theory for ion chambers measuring air kerma.
The EGSnrc system is used to compare the response of an aluminum-walled thimble chamber to that of a graphite-walled thimble chamber for a 60Co beam. When compared to previous experimental results, the EGSnrc values of the ratios of chamber response differ by as much as 0.7% from the experiment. However, it is shown that this difference can be more than accounted for by switching from using the graphite mean excitation energy of 78 eV used in dosimetry protocols to the value of 86.8 eV suggested by more recent stopping-power experiments. This suggests that the uncertainty analysis of Monte Carlo results must be done more carefully, by taking into account uncertainties in the underlying basic data such as the electron and photon cross sections. In comparison to Spencer-Attix cavity theory for a thick-walled ion chamber, the Monte Carlo calculated values of the chamber response differ from the expected ones by 0.15% and 0.01% for the graphite and aluminum chambers, respectively, which are comparable to previously reported values for the Spencer-Attix correction factors. EGSnrc is also used to investigate the effect on the chamber response of thin dag layers on the inside of the aluminum wall. There is good agreement between the calculated and measured changes in chamber response versus the thickness of the dag. The results are compared to the predictions of the Almond-Svensson extension of cavity theory and show that the theory does not correctly predict the chamber response in the presence of thin dag layers. This finding is in agreement with previously reported experimental results. It is demonstrated that the values of alpha, the fraction of ionizations in the gas arising from electrons generated in the dag layer, used in the theory, are not the source of the disagreement.


Welfare of pigs at slaughter.
The killing of pigs for human consumption (slaughtering) can take place in a slaughterhouse or on farm. The processes of slaughtering that were assessed for welfare, from the arrival of pigs until their death, were grouped into three main phases: pre-stunning (including arrival, unloading from the truck, lairage, handling and moving of pigs); stunning (including restraint); and bleeding. Stunning methods were grouped into three categories: electrical, controlled atmosphere and mechanical. Twelve welfare consequences the pigs can be exposed to during slaughter were identified: heat stress, cold stress, fatigue, prolonged thirst, prolonged hunger, impeded movement, restriction of movements, resting problem, negative social behaviour, pain, fear and respiratory distress. Welfare consequences and relevant animal-based measures were described. In total, 30 welfare hazards that could occur during slaughter were identified and characterised, most of them related to stunning and bleeding. Staff were identified as the origin of 29 hazards, which were attributed to the lack of appropriate skill sets needed to perform tasks or to fatigue. Corrective and preventive measures for these hazards were assessed: measures to correct hazards were identified, and management was shown to have a crucial role in prevention. Outcome tables linking hazards, welfare consequences, animal-based measures, origins and preventive and corrective measures were developed for each process. Mitigation measures to minimise welfare consequences are proposed.


Ischemic preconditioning and intermittent clamping confer protection against ischemic injury in the cirrhotic mouse liver.
Surgery on cirrhotic livers is fraught with complications, and many surgeons refrain from operating on patients with cirrhosis. Surgical procedures include temporal occlusion of blood flow resulting in ischemia. The mechanisms of protective strategies to prevent ischemic injury in patients with cirrhosis are not fully understood. The aim of this study was to evaluate how the cirrhotic liver tolerates an ischemic insult, whether mechanisms other than those observed in the normal liver are active, and whether intermittent clamping and preconditioning, which are known as safe surgical strategies in normal and steatotic livers, confer protection to the cirrhotic liver. We applied partial hepatic inflow occlusion to cirrhotic mice fed carbon tetrachloride according to different vascular occlusion protocols: intermittent clamping with 15 or 30 minute cycles of ischemia or ischemic preconditioning prior to 60 or 75 minutes of ischemia. Continuous ischemia (60 or 75 minutes) served as controls. The results showed that the cirrhotic liver was significantly more susceptible to 60 minutes of ischemia than the normal liver. Apoptosis was higher in the normal liver, whereas necrosis was a predominant feature in the cirrhotic liver. Both protocols of intermittent vascular occlusion and ischemic preconditioning dramatically prevented injury compared to continuous occlusion for 60 minutes. This protection was associated with reduced necrosis and apoptosis, and particularly reduced activation of the apoptotic pathway through mitochondria. In conclusion, this study extends the protective effects of ischemic preconditioning and intermittent clamping to the cirrhotic liver, highlighting a diminished apoptotic pathway with dramatic improvement in the development of necrosis.


Detection of myocardial infarction by immunohistological staining for C9 on formalin fixed, paraffin wax embedded sections.
To evaluate an immunohistological stain for complement component C9 as a method of detecting early myocardial infarction and to compare this with (1) an enzyme histochemical method and (2) conventional histological staining. (1) Eight hearts taken at necropsy were stained using the nitroblue tetrazolium/phenazine methosulphate method and an immunohistological stain for C9. (2) Twenty five hearts from cases of suspected or confirmed myocardial infarction and 25 from cases without conventional evidence of infarction were stained for C9 and by haematoxylin and eosin. (1) The histochemical method indicated myocardial necrosis in five hearts and the C9 method in seven, all of which had clinical evidence of myocardial damage or a reason for it. The histochemical method required fresh myocardium, was difficult to use and was difficult to interpret. (2) Of 25 hearts with suspected or confirmed infarction, 24 were stained by the C9 method. Staining with haematoxylin and eosin showed infarction in 16 of these, all with infarcts at least 24 hours old; the other eight had clinical evidence of infarction less than 24 hours old. The heart not stained by C9 was from a patient who, on review, had no evidence of infarction. Of the 25 control hearts, none had infarction on staining with haematoxylin and eosin, but three were stained by the C9 method. These three were from patients with septicaemia or another reason for myocardial damage. The immunohistological method for C9 is a simple, reliable and sensitive method for the detection of early myocardial necrosis that could be used on formalin fixed, paraffin wax embedded necropsy material. This had advantages over a histochemical method and conventional staining with haematoxylin and eosin.


Strategies of human corneal endothelial tissue regeneration.
Penetrating keratoplasty has previously been the only surgical treatment for patients with corneal endothelial disorders. Recently, posterior lamellar keratoplasty has become a viable and less aggressive alternative technique. However, both transplantation techniques have disadvantages, such as non-immunologic graft failure, allograft endothelial rejection or a global shortage of donor corneas. Over the past few years, several groups have established methods for the isolation, preservation, in vitro cultivation, transplantation, and in vivo stimulation of human corneal endothelial cells in animal models. It is hoped that these new strategies will allow the treatment of more than one patient with one donor cornea, performing autologous corneal endothelium transplantation from a surgical biopsy sample, or stimulating the growth of corneal endothelial cells in vivo. However, several aspects need to be addressed before commencing clinical trials.


Effects of yeast hydrolysate on hepatic lipid metabolism in high-fat-diet-induced obese mice: yeast hydrolysate suppresses body fat accumulation by attenuating fatty acid synthesis.
We observed whether the anti-obesity activity of yeast hydrolysate (YH) was due to the alteration of lipid-regulating enzyme activities. Male ICR mice were divided into four groups: a normal diet group (ND; 4.2% fat), a high-fat diet group (HF; 27.7% fat), an HF group treated orally with 0.5% or 1% YH in the drinking water (HF+YH0.5; 27.7% fat and HF+YH1; 27.7% fat). After 5 weeks, the YH groups (HF+YH0.5=3.92±0.17 g/100 g BW and HF+YH1=3.76±0.13 g/100 g BW) had significantly lower levels of epididymal fats compared to the HF group (4.91±0.29 g/100 g BW; p<0.05). YH supplementation produced a decrease in serum triglycerides and low-density lipoprotein cholesterol concentrations and body weight gain, and produced a dose-dependent significant increase in serum ghrelin compared with the HF group (p<0.05). Hepatic glucose-6-phosphate dehydrogenase (G6PD) activity was inhibited by YH supplementation compared with the HF group, and mice treated orally with 1% YH exhibited a significant decrease in hepatic malic enzyme (ME) activity compared to obese mice treated with the vehicle (HF=10.44±2.74 nmol/min/mg protein vs. HF+YH1=6.68±2.23 nmol/min/mg protein; p<0.05). YH supplementation suppressed body fat accumulation by attenuating fatty acid synthesis through the downregulation of hepatic G6PD and ME activities.


Influence of metformin on glucose intolerance and muscle catabolism following severe burn injury.
Hyperglycemia and accelerated muscle catabolism have been shown to adversely affect immune response and survival. The purpose of this study was to determine the effect of metformin on glucose kinetics and muscle protein metabolism in severely burned patients and assess any potential benefit of metformin in this clinical setting. In a double-blind, randomized manner, 8 adult burn patients received metformin (850 mg every 8 hours x 7 days), while 5 burn patients received placebo. Infusions of 6,6d2 glucose, d5 phenylalanine, sequential muscle biopsies, and femoral arterial, venous blood sampling allowed determination of glucose and muscle protein kinetics. Measurements were obtained immediately prior and at the conclusion of 7 days of treatment (metformin versus placebo). All patients received enteral feeds of comparable amounts during study. Patients receiving metformin had a significant decrease in their plasma glucose concentration, the rate of glucose production, and an increase in glucose clearance. Metformin administration was also associated with a significant increase in the fractional synthetic rate of muscle protein and improvement in net muscle protein balance. Glucose kinetics and muscle protein metabolism were not significantly altered in the patients receiving placebo. Metformin attenuates hyperglycemia and increases muscle protein synthesis in severely burned patients, thereby indicating a metabolic link between hyperglycemia and muscle loss following severe injury. Therefore, therapies that improve glucose tolerance such as metformin may be of clinical value in ameliorating muscle catabolism in critically injured patients.


Hereditary alpha-1-antitrypsin deficiency and its clinical consequences.
Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave.


Cancer stem cells and their niche.
The unique characteristics of stem cells, specifically pluripotency and self-renewal, are critical for sustaining the lifelong functionality of organs. Stem cells reside in a special microenvironment called the niche. Stem cells interact with the niche via adhesion molecules and exchange molecular signals that maintain the specific features of stem cells. A better understanding of the nature of stem cells and their niches is expected to provide an alternative approach to the treatment of various serious diseases, including cancer, in clinical practice. It has been suggested that tumor tissue contains a type of stem cell referred to as a cancer stem cell. Interestingly, there are a number of molecules that are commonly expressed in normal and cancer stem cells that lead to different phenomena depending on the local conditions. In this review, the hematopoietic system is used as an example to show how stem cells interact with different niches. The regulatory mechanisms of two kinds of bone marrow niche, osteoblastic and vascular, are covered in this review. Furthermore, the involvement of the niche in cancer stem cell regulation, tumor invasion and metastasis, and its response to oxidative stress is described, and novel therapeutic approaches involving the interactions between cancer stem cells and their niches are addressed.


Birth weight in relation to leisure time physical activity in adolescence and adulthood: meta-analysis of results from 13 nordic cohorts.
Prenatal life exposures, potentially manifested as altered birth size, may influence the later risk of major chronic diseases through direct biologic effects on disease processes, but also by modifying adult behaviors such as physical activity that may influence later disease risk. We investigated the association between birth weight and leisure time physical activity (LTPA) in 43,482 adolescents and adults from 13 Nordic cohorts. Random effects meta-analyses were performed on categorical estimates from cohort-, age-, sex- and birth weight specific analyses. Birth weight showed a reverse U-shaped association with later LTPA; within the range of normal weight the association was negligible but weights below and above this range were associated with a lower probability of undertaking LTPA. Compared with the reference category (3.26-3.75 kg), the birth weight categories of 1.26-1.75, 1.76-2.25, 2.26-2.75, and 4.76-5.25 kg, had odds ratios of 0.67 (95% confidence interval: 0.47, 0.94), 0.72 (0.59, 0.88), 0.89 (0.79, 0.99), and 0.65 (0.50, 0.86), respectively. The shape and strength of the birth weight-LTPA association was virtually independent of sex, age, gestational age, educational level, concurrent body mass index, and smoking. The association between birth weight and undertaking LTPA is very weak within the normal birth weight range, but both low and high birth weights are associated with a lower probability of undertaking LTPA, which hence may be a mediator between prenatal influences and later disease risk.


Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression.
Tumor initiation and progression provide a multitude of occasions for the generation of DNA damage and the consequent activation of the DNA damage response (DDR) pathway. DDR signaling involves the engagement of key factors such as ATM, CHK2, 53BP1 and the phosphorylation of histone H2AX (gamma-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and gamma-H2AX were engaged in cancer but the extent of their activation was strongly affected by the organ and cell type involved, whereas 53BP1 loss was the most consistent feature among the tumor studied. Unexpectedly, we also observed activated DDR markers in morphologically normal tissues, also in association with inflammation. Analysis of the dynamic engagement of DDR along the different stages of lung tumorigenesis showed that 53BP1 loss occurs early at the transition from normal to dysplastic change whereas the activated forms of ATM and CHK2, but not gamma-H2AX, initially accumulate in pre-invasive lesions and are then lost during tumor progression. In individual lung tumors, the activation of ATM, CHK2 and the presence of 53BP1 were consistently correlated, whereas gamma-H2AX did not correlate with activated ATM. Finally, the study of associations between critical clinicopathological parameters and activated DDR factors highlighted a statistically meaningful correlation between reduced local tumor extension and the phosphorylation of ATM, CHK2 and the presence of 53BP1, whereas no significant correlations with parameters such as survival or relapse of early-stage lung carcinomas were found.


Diltiazem induces severe photodistributed hyperpigmentation: case series, histoimmunopathology, management, and review of the literature.
Diltiazem hydrochloride is a commonly prescribed benzothiazepine calcium channel blocker for the treatment of cardiovascular disease. Recently, 8 cases of diltiazem-induced photodistributed hyperpigmentation occurring predominantly in elderly African American women were reported. Here, we report occurrence for the first time in a light-skinned African American woman and a Hispanic woman. We also report this finding in an African American man. Biopsy specimens of hyperpigmented areas were obtained for histopathologic evaluation and marker studies. Photospectrometry analysis for diltiazem was performed to analyze the photoabsorption properties of this drug. Routine laboratory examination results were normal in all patients. Serologic test results for antinuclear antibodies, including Sjögren antibodies anti-Ro (SS-A) and anti-La (SS-B), were negative. Histopathologic analysis of the skin biopsy specimens revealed a sparse lichenoid infiltrate, prominent pigmentary incontinence, and numerous melanophages in the dermis. There was no increase in dermal mucin suggestive of lupus. The mononuclear cells in the specimens were strongly positive for CD3, weakly positive for CD68, and either weakly positive or negative for CD79a. All specimens were negative for Alcian blue staining. Photospectrometry analysis of diltiazem showed an absorption range within the UV-B spectrum. Photospectrometry analysis revealed diltiazem could demonstrate a photosensitizing effect within the UV-B range. Discontinuation of therapy with diltiazem is the most effective modality in resolving hyperpigmentation. Avoidance of sun exposure and consistent use of sunscreens and sun-protective clothing are indicated for patients undergoing diltiazem therapy.


Optimizing nanoporous materials for gas storage.
In this work, we address the question of which thermodynamic factors determine the deliverable capacity of methane in nanoporous materials. The deliverable capacity is one of the key factors that determines the performance of a material for methane storage in automotive fuel tanks. To obtain insights into how the molecular characteristics of a material are related to the deliverable capacity, we developed several statistical thermodynamic models. The predictions of these models are compared with the classical thermodynamics approach of Bhatia and Myers [Bhatia and Myers, Langmuir, 2005, 22, 1688] and with the results of molecular simulations in which we screen the International Zeolite Association (IZA) structure database and a hypothetical zeolite database of over 100,000 structures. Both the simulations and our models do not support the rule of thumb that, for methane storage, one should aim for an optimal heat of adsorption of 18.8 kJ mol(-1). Instead, our models show that one can identify an optimal heat of adsorption, but that this optimal heat of adsorption depends on the structure of the material and can range from 8 to 23 kJ mol(-1). The different models we have developed are aimed to determine how this optimal heat of adsorption is related to the molecular structure of the material.


Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 3: Vitamin C in severe burns.
A short-cut systematic review was carried out to establish whether high-dose vitamin C can lead to lower fluid requirements, faster recovery and lower mortality in adult patients with burns of over 15% total body surface area (TBSA). Four studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that preliminary evidence suggests vitamin C can reduce the volume required for fluid resuscitation, improve wound healing and reduce ventilation requirements in patients with severe burns. Further evidence from large trials is required to confirm this promising early evidence.


HIV-infected children in the Asia-Pacific region with baseline severe anemia: antiretroviral therapy and outcomes.
Severe anemia is common among children infected with human immunodeficiency virus (HIV). The choice of antiretroviral (ART) regimen needs careful consideration. No information is available regarding the initial ART regimens used in the Asia-Pacific region and the rate of switch of ART regimens in HIV-infected children with severe anemia. To study the initial ART regimens and the rate of switch of ART regimens used during the first 36 months in HIV-infected children with severe anemia and to evaluate their clinical and laboratory outcomes. We analyzed regional cohort data of 130 Asian children aged <18 years with baseline severe anemia (hemoglobin <7.5 g/dl) who started antiretroviral therapy (ART) between January 2003 and September 2013. At ART initiation, median age was 3.5 years old (interquartile range (IQR) 1.7 to 6.3) and median hemoglobin was 6.7 g/dL (IQR 5.9-7.1, range 3.0-7.4). Initial ART regimens included stavudine (85.4%), zidovudine (13.8%), and abacavir (0.8%). In 81 children with available hemoglobin data after 6 months of ART, 90% recovered from severe anemia with a median hemoglobin of 10.7 g/dL (IQR 9.6-11.7, range 4.4-13.5). Those starting AZT-based ART had a mortality rate of 10.8 (95% confidence interval (CI) 4.8-23.9) per 100 patient-years compared to 2.7 (95% CI 1.6-4.6) per 100 patient-years among those who started d4T-based ART. With the phase-out of stavudine, age-appropriate non-zidovudine options are needed for younger Asian children with severe anemia.


Advancing methodology in the study of HIV status disclosure: the importance of considering disclosure target and intent.
Disclosure of HIV status has been the focus of three decades of research, which have revealed its complex relations to many behaviors involved in HIV prevention and treatment, and exposed its central role in managing the HIV epidemic. The causes and consequences of disclosure acts have recently been the subject of several theoretical models. Although it is acknowledged that individual disclosure events are part of a broader process of disclosing one's HIV status to an increasing number of people, this process has received less theoretical attention. In quantitative studies of disclosure, researchers have often implicitly assumed that disclosure is a single unidimensional process appropriately measured via the total number of one's disclosure acts. However, there is also evidence that disclosure may have different causes and consequences depending on the types of actors involved (e.g. family members, friends) and on the presence or absence of the discloser's intention, suggesting that the unidimensionality assumption may not hold. We quantitatively examined the dimensionality of voluntary and involuntary disclosure to different categories of actors, using data collected via structured interviews in the spring of 2010 from 158 people living with HIV in Kilimanjaro, Tanzania. For voluntary disclosure, nonparametric item response analyses identified two multi-category clusters, family and community, and two single-category dimensions, partner and children. Involuntary disclosure consisted of several single- or two-category dimensions. Correlation analyses between the resulting disclosure dimensions and stigma and social support revealed distinct relationships for each disclosure dimension. Our results suggest that treating disclosure as a unidimensional construct is a simplification of disclosure processes that may lead to incorrect conclusions about disclosure correlates. We therefore recommend examining disclosure acts jointly to identify sample-specific dimensions before examining causes and consequences of disclosure. We propose a methodology for investigating disclosure processes, and recommend its adoption in future disclosure studies.


Si-photonics based passive device packaging and module performance.
We report a fully packaged silicon passive waveguide device designed for a tunable filter based on a ring-resonator. Polarization diversity circuits prevent polarization dependant issues in the silicon ring-resonator. For the device packaging, the YAG laser welding technique has been used for pigtailing both of the input and output fibers. Post welding misalignment was compensated by mechanical fine tuning using the seesaw effect via power monitoring. Packaging loss less than 1.5 dB with respect to chip measurement has been achieved using 10 µm-curvature radius lensed fibers. In addition, the packaging process and the module performance are presented.


Preschool executive control on the Shape School task: measurement considerations and utility.
Executive functions (EF) necessary for purposeful goal-directed activities undergo rapid change and development during the preschool years. However, of the few psychometrically valid measures of EF suitable for use with preschoolers, information on task sensitivity and predictive validity is scant. The neurodevelopmental correlates of early executive difficulties are also largely unknown. In this study, the discriminant and predictive validity of the recently developed Shape School task (Espy, Bull, Martin, & Stroup, 2006) was examined with data from a regional sample of 209 preschool children at age 4 years. A 2-tiered measurement approach was used, with task completion examined in addition to efficiency. Children's performance was also examined in relation to functioning in a range of neurodevelopmental domains. The Shape School task showed some usefulness in capturing expected differences between at-risk and typically developing children. Performance loaded heavily on language and global cognitive abilities. However, several other factors were also implicated, including attention, motor skills, and ocular control. In addition, task completion and efficiency scores appeared to reflect different aspects of performance, and their associations with neurodevelopmental function and later academic achievement on the Woodcock-Johnson Tests of Achievement at age 6 years also differed. Implications for the application of the Shape School task are discussed.


An exploration of alcohol use amongst undergraduate female psychology students at a South African university.
Alcohol use amongst tertiary education students, particularly female undergraduates, is increasing. Heavy alcohol use by tertiary students leads to a variety of alcohol-related problems such as damage to property, poor academic performance, problematic peer relationships, high dropout rates, unprotected sexual activity, physical injuries, date rape and suicide. Abuse of alcohol is attributed to curiosity and experimentation, peer pressure, low self-esteem, enjoyment, parental modelling, socio-cultural influences, stress and life events, self-medication and concerns about weight and appearance.Our study explores alcohol use and the reasons behind it amongst undergraduate female psychology students at the University of Limpopo. The findings will be important, as these students represent many future psychologists who are going to advise others on harms related to alcohol use. This was a descriptive survey, and the qualitative results are presented. The sample consists of 700 undergraduate female psychology students. A self-administered questionnaire included five open-ended questions which elicited the thoughts and experiences of these students about alcohol use. Responses to these questions were analysed using thematic content analysis. The themes that arose were as follows: fun and enjoyment, socio-cultural influences, alcohol use leads to negative behaviour(s), peer influence, destress, concerns about weight and appearance, abstinence from alcohol and it improves self-esteem. The themes were reasons that female students gave for consuming alcohol. The majority of participants reported responsible drinking behaviour, but a notable proportion of female students' drinking behaviours (across all year levels) are cause for concern in terms of negative impact at both social and academic levels.


Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation.
The planar cell polarity (PCP) pathway is conserved throughout evolution, but it mediates distinct developmental processes. In Drosophila, members of the PCP pathway localize in a polarized fashion to specify the cellular polarity within the plane of the epithelium, perpendicular to the apicobasal axis of the cell. In Xenopus and zebrafish, several homologs of the components of the fly PCP pathway control convergent extension. We have shown previously that mammalian PCP homologs regulate both cell polarity and polarized extension in the cochlea in the mouse. Here we show, using mice with null mutations in two mammalian Dishevelled homologs, Dvl1 and Dvl2, that during neurulation a homologous mammalian PCP pathway regulates concomitant lengthening and narrowing of the neural plate, a morphogenetic process defined as convergent extension. Dvl2 genetically interacts with Loop-tail, a point mutation in the mammalian PCP gene Vangl2, during neurulation. By generating Dvl2 BAC (bacterial artificial chromosome) transgenes and introducing different domain deletions and a point mutation identical to the dsh1 allele in fly, we further demonstrated a high degree of conservation between Dvl function in mammalian convergent extension and the PCP pathway in fly. In the neuroepithelium of neurulating embryos, Dvl2 shows DEP domain-dependent membrane localization, a pre-requisite for its involvement in convergent extension. Intriguing, the Loop-tail mutation that disrupts both convergent extension in the neuroepithelium and PCP in the cochlea does not disrupt Dvl2 membrane distribution in the neuroepithelium, in contrast to its drastic effect on Dvl2 localization in the cochlea. These results are discussed in light of recent models on PCP and convergent extension.


Do We Pronounce Quotation? An Analysis of Name-informing and Non-name-informing Contexts.
Quotation marks are a tool to refer to the linguistic form of an expression. For instance, in cases of so-called pure quotation as in "Hanover" has three syllables, they point to the syllabic characteristics of the name of the town of Hanover. Cases of this nature differ from sentences like Hanover is a town in New Hampshire, in which Hanover is used denotationally and, thus, refers to the town of Hanover itself. Apart from quotation marks, other means such as italics, bold, capitalization, or air quotes represent potential means to signal a non-stereotypical use of an item in the written or gestural mode. It is far less clear, however, whether acoustic correlates of quotation marks exist. The present contribution aims at investigating this issue by focusing on instances of quotation, in which the conventionalized name of a lexical concept is highlighted by means of quotation marks, either together with or without an additional lexical quotational marker, such as so-called, on the lexical level (cf. The so-called "vuvuzela" is an instrument from South Africa vs. The "vuvuzela" is an instrument from South Africa). The data clearly show that quotation marks are pronounced, primarily triggering a lengthening effect, independently of whether they appear together with or without a name-informing context. The results of the experiments are interpreted against the background of a pragmatic implementation of quotation marks in general as well as in spoken discourse in particular.


Nanochannels of two distinct cross-sections in a porous Al-based coordination polymer.
A new aluminum naphthalenedicarboxylate Al(OH)(1,4-NDC) x 2 H2O compound has been synthesized. The crystal structure exhibits a three-dimensional framework composed of infinite chains of corner-sharing octahedral Al(OH)2O4 with 1,4-naphthanedicarboxylate ligands forming two types of channels with squared-shape cross-section. The large channels present a cross-section of 7.7 x 7.7 A(2), while the small channels are about 3.0 x 3.0 A(2). When water molecules are removed, no structural transformation occurs, generating a robust structure with permanent porosity and remarkable thermal stability. 2D (1)H-(13)C heteronuclear correlation NMR measurements, together with the application of Lee-Goldburg homonuclear decoupling, were applied, for the first time, to porous coordination polymers revealing the spatial relationships between the (1)H and (13)C spin-active nuclei of the framework. To demonstrate the open pore structure and the easy accessibility of the nanochannels to the gas phase, highly sensitive hyperpolarized (HP) xenon NMR, under extreme xenon dilution, has been applied. Xenon can diffuse selectively into the large nanochannels, while the small ones show no substantial uptake of xenon due to severe restrictions along the channels that prevent the diffusion. Two-dimensional exchange experiments showed the exchange time to be as short as 15 ms. Through variable-temperature HP (129)Xe NMR experiments we were able to achieve an unprecedented description of the large nanochannel space and surface, a physisorption energy of 10 kJ mol(-1), and the chemical shift value of xenon probing the internal surfaces. The large pore channels are straight, parallel, and independent, allowing one-dimensional anisotropic diffusion of gases and vapors. Their walls are composed of the naphthalene moieties that create an unique environment for selective sorption. These results prompted us to measure the storage capacity toward methanol, acetone, benzene, and carbon dioxide. The selective adsorption of methanol and acetone vs that of water, together with the permanent porosity and high thermal stability, makes this compound a suitable matrix for separation and purification.


Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study.
The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy. CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival. In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events. The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL.


Relationship between self-care and health-related quality of life in older adults with moderate to advanced heart failure.
Heart failure (HF) patients who follow the treatment regimen and attend to symptoms before they escalate are assumed to have better health-related quality of life (HRQOL) than those with poor self-care, but there are few data available to support or refute this assumption. The objective of the study was to describe the relationship between HF self-care and HRQOL in older (≥65 years old) adults with moderate to advanced HF. Self-care was measured using the 3 scales (maintenance, management, and confidence) of the Self-care of Heart Failure Index. Scores range from 0 to 100, with higher numbers indicating better self-care. Health-related quality of life was measured with the Minnesota Living With Heart Failure Questionnaire, a 2-subscale (physical and emotional) instrument. Lower numbers on the Minnesota Living With Heart Failure Questionnaire indicate better HRQOL. Pearson correlations, independent-samples t-tests, and linear and logistic regression modeling were used in the analysis. In 207 adults (72.9 [SD, 6.3] years), New York Heart Association class III (82%) or IV, significant linear associations were observed between self-care confidence and total (r = -0.211; P = .002), physical (r = -0.189; P = .006), and emotional HRQOL (r = -0.201; P = .004). Patients reporting better (below median) HRQOL had higher confidence scores compared with patients reporting above-median HRQOL scores (58.8 [19.2] vs 52.8 [19.6]; P = .028). Confidence was an independent determinant of total (βs = -3.191; P = .002), physical (βs = -2.346; P = .002), and emotional (βs = -3.182; P = .002) HRQOL controlling for other Self-care of Heart Failure Index scores, age, gender, and New York Heart Association class. Each 1-point increase in confidence was associated with a decrease in the likelihood that patients had worse (above median) HRQOL scores (odds ratio, 0.980 [95% confidence interval, 0.963-0.998]) with the same controls. No significant associations were found between self-care maintenance or management and HRQOL. The degree of individual confidence in HF self-care is related to HRQOL, but self-reports of specific maintenance and management behaviors are not. Interventions that improve self-care confidence may be particularly important in older adults with moderate to advanced HF.


Dietary green and white teas suppress UDP-glucuronosyltransferase UGT2B17 mediated testosterone glucuronidation.
The anabolic steroid testosterone can be used by athletes to enhance athletic performance and muscle growth. UDP-glucuronosyltransferase (UGT2B17) is the key enzyme involved in the glucuronidation of testosterone to testosterone glucuronide, which also serves as a marker for the testosterone/epitestosterone (T/E) ratio used to detect testosterone abuse in sport. Inhibitors of testosterone glucuronidation could have an impact on circulating testosterone levels, thus aiding performance, as well as potentially affecting the urinary T/E ratio and therefore masking testosterone abuse. Previous reports have revealed that non-steroidal, anti-inflammatory drugs, diclofenac and ibuprofen, inhibit the UGT2B17 enzyme. The aim of this study is to analyse dietary tea samples for inhibition of testosterone glucuronidation and, where inhibition is present, to identify the active compounds. Analysis of testosterone glucuronidation was conducted by performing UGT2B17 assays with detection of un-glucuronidated testosterone using high performance liquid chromatography. The results from this study showed that testosterone glucuronidation was inhibited by the green and white tea extracts, along with specific catechin compounds, notably: epicatechin, epigallocatechin gallate (EGCG) and catechin gallate. The IC50 inhibition value for EGCG was determined, using a Dixon plot, to be 64 μM, equalling the most active NSAID inhibitor diclofenac. Thus, common foodstuffs and their constituents, for the first time, have been identified as inhibitors of a key enzyme involved in testosterone glucuronidation. Whilst these common compounds are not substrates of the UGT2B17 enzyme, we showed that they inhibit testosterone glucuronidation which may have implications on current doping control in sport.


AltitudeOmics: impaired pulmonary gas exchange efficiency and blunted ventilatory acclimatization in humans with patent foramen ovale after 16 days at 5,260 m.
A patent foramen ovale (PFO), present in ∼40% of the general population, is a potential source of right-to-left shunt that can impair pulmonary gas exchange efficiency [i.e., increase the alveolar-to-arterial Po2 difference (A-aDO2)]. Prior studies investigating human acclimatization to high-altitude with A-aDO2 as a key parameter have not investigated differences between subjects with (PFO+) or without a PFO (PFO-). We hypothesized that in PFO+ subjects A-aDO2 would not improve (i.e., decrease) after acclimatization to high altitude compared with PFO- subjects. Twenty-one (11 PFO+) healthy sea-level residents were studied at rest and during cycle ergometer exercise at the highest iso-workload achieved at sea level (SL), after acute transport to 5,260 m (ALT1), and again at 5,260 m after 16 days of high-altitude acclimatization (ALT16). In contrast to PFO- subjects, PFO+ subjects had 1) no improvement in A-aDO2 at rest and during exercise at ALT16 compared with ALT1, 2) no significant increase in resting alveolar ventilation, or alveolar Po2, at ALT16 compared with ALT1, and consequently had 3) an increased arterial Pco2 and decreased arterial Po2 and arterial O2 saturation at rest at ALT16. Furthermore, PFO+ subjects had an increased incidence of acute mountain sickness (AMS) at ALT1 concomitant with significantly lower peripheral O2 saturation (SpO2). These data suggest that PFO+ subjects have increased susceptibility to AMS when not taking prophylactic treatments, that right-to-left shunt through a PFO impairs pulmonary gas exchange efficiency even after acclimatization to high altitude, and that PFO+ subjects have blunted ventilatory acclimatization after 16 days at altitude compared with PFO- subjects.


A study of gender-based cytochrome P4501A2 variability: a possible mechanism for the male excess of bladder cancer.
One hypothesis for the well known gender difference in bladder cancer risk is that males and females metabolize carcinogens differently. The caffeine breath test (CBT) was performed on a group of healthy men and women to determine whether there was a gender difference in P4501A2 activity. Results consistent with previous data suggest an elevation of CBT in men were observed, although this increase was not statistically significant. Among women, however, there was a significant difference between nulliparous and parous women(P = 0.03). Parous women had CBT values similar to men, whereas the results of women who had never given birth were lower. Confirming earlier studies, women taking oral contraceptives had low CBT values. Our data suggest an effect of recent caffeine consumption, with heavy coffee drinkers having higher rates of caffeine clearance. Adjustment for other weak effects, such as age, exposure to environment cigarette smoke, history of smoking, recent meat and cruciferous vegetable consumption, and use of alcohol or other medications, did not alter these findings. The finding of a difference between parous and nulliparous women requires further study.


Copy number variation in pediatric multiple sclerosis.
Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.


The role of macrophages in the generation of T-helper cells. II. The genetic control of the macrophage-T-cell interaction for helper cell induction with soluble antigens.
Helper cell induction to nonparticle antigens in vitro requires the cooperation of T cells and macrophages, but does not occur if the macrophages are allogenic. The reasons for this were investigated. Malfunction of allogenic macrophages was excluded by cultures with their syngenic T cells; suppressor cell induction was excluded by admixture experiments. Thus, T cells and macrophages only cooperated if they were genetically similar. The genetic locus (loci) involved was mapped. Using congenic lines differing only at the H-2 complex, the genetic control of T-macrophage interaction was localized in the H-2 region. Mice with intra H-2 recombinants were used to map the T-macrophage interaction locus in the I-A region of the H-2 complex (formerly known as poly-D, L-ala-poly-L-lys. Recombinants were also used to exclude the presence of another T-macrophage locus either the K, I-B, or I-C, SS-Slp, or D regions of the H-2 complex. Genetic restrictions for T-macrophage interaction in helper cell induction was shown in mice of the H-2-k, d, b, q, s genotypes as well as in H-2 recombinants. The possible mechanisms and significance of this genetic restriction are discussed.


Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study.
Paliperidone extended-release tablet (paliperidone ER) is an oral psychotropic agent developed for schizophrenia treatment. Paliperidone (9-OH-risperidone, metabolite of risperidone), when used with OROS technology has a unique pharmacokinetic profile undergoing limited hepatic metabolism. The efficacy and safety of once-daily paliperidone ER (3 mg, 9 mg and 15 mg) were compared with placebo in 618 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. An assay sensitivity group with known efficacy was included to confirm trial validity (olanzapine 10 mg). All doses of paliperidone ER demonstrated significant improvements in PANSS total and PANSS factors scores (p<0.05) and in personal and social functioning (p<0.001) compared with placebo. Symptom improvement has been observed at the first observation assessment (Day 4) (p<0.001) compared with placebo, suggesting a rapid onset of action for paliperidone ER. Paliperidone ER was associated with a low incidence of treatment-emergent adverse events. The incidence of movement disorder-related adverse events and rating scale scores were similar in the paliperidone ER 3 mg and placebo groups and increased with dose. Increases in prolactin plasma levels and dose-related increases in body weight (<2 kg) were observed; there were no significant changes in serum lipid or glucose levels. In this study, all doses of paliperidone ER were effective in significantly improving the symptoms of schizophrenia and personal and social functioning and were generally well tolerated. As such, paliperidone ER may provide a valuable new treatment option for patients with schizophrenia.


Persistent ventricular asynchrony after coronary artery bypass surgery predicts cardiac events.
The aim of this study was to identify echocardiographic LV systolic and diastolic measurements that predict clinical events post-coronary artery bypass graft (CABG) surgery. We collected data from 27 patients (age 70 +/- 7 years) who underwent elective CABG, before and within 6 weeks after surgery. LV systolic function was assessed by conventional echocardiographic parameters. A number of LV filling measurements were also made, which included total isovolumic time (t-IVT), Tei index, and restrictive filling pattern. Postoperative cardiac events were death or hospitalization for chest pain, breathlessness, or arrhythmia. Patient's follow-up period was 17 +/- 10 months. Of the 27 patients (age 70 +/- 7 years, 22 male), 10 had postoperative cardiac events. LV ejection fraction (EF) and fractional shortening (FS) were lower (P = 0.01, and P = 0.007, respectively), t-IVT longer (P < 0.001), and Tei index was higher (P < 0.001) preoperatively in patients with events compared to those without. The same differences between groups remained after surgery; EF (P = 0.002), FS (P = 0.002), t-IVT (P < 0.001), and Tei index (P < 0.001). T-IVT was the only preoperative predictor of events (P = 0.038) but its postoperative value as well as that of FS predicted events (P = 0.034, and P = 0.042, respectively). T-IVT of 12.2 s/min and FS of 26% were 80% sensitive and 88% specific for predicting postoperative events. Despite successful surgical revascularization residual impairment of LV systolic function and persistent asynchrony in the form of prolonged t-IVT are associated with postoperative events. Since these abnormalities remained despite full medical therapy, they may thus suggest a need for electrical resynchronization therapy.


Preplant Biofumigation with Sorghum or Methyl Bromide Compared for Managing Criconemoides xenoplax in a Young Peach Orchard.
Sorghum as a preplant green manure biofumigant management system of Criconemoides xenoplax was investigated from 1998 to 2003. The study was conducted on a site infested with C. xenoplax and having a previous history of peach tree short life (PTSL). Plots consisted of five preplant treatments: (i) nonfumigated soil without tarp and urea, (ii) nonfumigated soil with tarp and urea, (iii) sorghum as a green manure without tarp and urea, (iv) sorghum as a green manure with tarp and urea, and (v) preplant methyl bromide fumigation. Sorghum as a green manure with and without tarp was comparable with methyl bromide fumigation in suppressing the population of C. xenoplax in the early stages of this experiment. Nematode population densities were suppressed 11 months longer in sorghum with tarp and urea plots than in sorghum without tarp and urea plots. However, nematode population densities in sorghum with tarp and urea plots were not suppressed as long as in fumigated methyl bromide plots (19 versus 24 months, respectively).


Percutaneous left atrial appendage occlusion for stroke prevention in atrial fibrillation: an update.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. One of its most devastating complications is the development of thromboembolism leading to fatal or disabling stroke. Oral anticoagulation (OAC, warfarin) is the standard treatment for stroke prevention in patients with AF with an increased stroke risk. However, there are several obstacles to long-term OAC therapy, including the risk of serious bleeding, several drug-drug interactions and the need for frequent blood testing. Although newer oral anticoagulants have been developed, these drugs also face issues of major bleeding and non-compliance. Therefore, alternative treatment options for stroke prevention in patients with AF with a high stroke risk are needed. Percutaneous left atrial appendage (LAA) occlusion is an evolving therapy, which should be taken into consideration in those patients with non-valvular AF with a high stroke risk and contraindications for OAC. This article aims to discuss the rationale for LAA closure, the available LAA occlusion devices and their clinical evidence until now. Moreover, we discuss the importance of proper patient selection, the role of various imaging techniques and the need for a more tailored postprocedural antithrombotic therapy.


Perceptions of Tetanus-diphteria-acellular pertussis (Tdap) Vaccination among Korean Women of Childbearing Age.
The number of cases of pertussis reported has increased gradually in the last decade. Pertussis vaccination is the most effective strategy for the prevention of infection. Despite the fact that young infants are at the highest risk for pertussis, the rate of tetanus-diphtheria-acellular pertussis (Tdap) vaccination is presumed to be very low among women of childbearing age in Korea. The purpose of this study was to investigate the perceptions of women of childbearing age regarding Tdap vaccination in Korea. Women of childbearing age, who visited the Department of Obstetrics and Gynecology at 3 University hospitals in the Seoul and Gyeonggi-do provinces of Korea, were surveyed. Individual questionnaires were administered from April to May 2012. Demographic data, Tdap vaccination history, general knowledge about pertussis, and information on factors associated with decision on vaccination were collected. Of the 500 reproductive-age women enrolled, only 4 (0.8%) had received the Tdap. The most common reason for non-vaccination was the lack of awareness of pertussis and information about the Tdap. Totally, 171 (34.2%) responded that they would receive a Tdap vaccination in the future. By multivariate analysis, general confidence in the effectiveness of the vaccine (odds ratio [OR] = 1.88, 95% confidence interval [CI] 1.17 to 3.01) was indicated as an important factor for deciding whether to receive the Tdap vaccine (P < 0.01). The coverage of Tdap vaccination of women of childbearing age, including pregnant women, is very low because of the lack of awareness of pertussis and the Tdap. Education of women of childbearing age about pertussis is very important to increase Tdap vaccination rates among these women, particularly during the perinatal period.


Diagnostic thoracic ultrasound imaging - An exploration of respiratory physiotherapists' interest and use in clinical practice: A national survey.
Physiotherapists are learning to perform diagnostic thoracic ultrasound but it is currently unknown how they are learning, how they are using thoracic ultrasound in their practice, or any factors affecting the implementation of thoracic ultrasound into practice. The aim of this survey was to explore the use of thoracic ultrasound by physiotherapists. This information could be used to aid training and implementation strategies to assist physiotherapists to integrate thoracic ultrasound safely into their practice. A questionnaire comprising of open/closed questions was distributed to respiratory physiotherapist. Distribution was at three national study days and via a specialist newsletter containing a link to a SurveyMonkey™ questionnaire. A total of 133 questionnaires were returned with 31 reported that they used thoracic ultrasound imaging and 101 reporting they did not. The most common roles of thoracic ultrasound in practice were to: enhance the ability to differentially diagnose respiratory pathologies, aid respiratory assessment and support clinical reasoning. Of the 133 respondents, 58 reported that they had undertaken training in thoracic ultrasound imaging and 75 had not. The most common factors identified regarding thoracic ultrasound implementation were team support, ultrasound machine availability/cost, time pressures and mentor availability. This survey has provided an understanding of thoracic ultrasound practice amongst respiratory physiotherapists in the UK. The survey results demonstrated the barriers that inhibit current practice and highlighted the importance of mentor support. There was a good understanding by all respondents regarding the clinical application of thoracic ultrasound. These findings are being used to develop professional guidance and ensure safe practice of thoracic ultrasound.


Ginsenoside Rg3 attenuates microglia activation following systemic lipopolysaccharide treatment in mice.
Neuroinflammation, characterized by activation of microglia and expression of major inflammatory mediators, contributes to neuronal damage in addition to acute and chronic central nervous system (CNS) disease progression. The present study investigated the immune modulatory effects of ginsenoside Rg3, a principle active ingredient in Panax ginseng, on pro-inflammatory cytokines and microglia activation in brain tissue induced by systemic lipopolysaccharide (LPS) treatment in C57BL/6 mice. Systemic LPS treatment induces immediate microglia activation in the brain. Based on this information, ginsenoside Rg3 was treated orally with 10, 20, and 30 mg/kg 1 h prior to the LPS (3 mg/kg, intraperitoneally (i.p.)) injection. Ginsenoside Rg3 at 20 and 30 mg/kg oral doses significantly attenuated up-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and IL-6 mRNA in brain tissue at 4 h after LPS injection. Morphological activation of microglia and Iba1 protein expression by systemic LPS injection were reduced with ginsenoside Rg3 (30 mg/kg) treatment. In addition, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in brain tissue were also attenuated with oral treatment of ginsenoside Rg3 at 30 mg/kg. These results indicate that ginsenoside Rg3 plays a modulatory role in neuroinflammation. This study shows that ginsenoside Rg3 attenuates microglia activation using an in vivo animal model.


OvAd1, a Novel, Potent, and Selective Chimeric Oncolytic Virus Developed for Ovarian Cancer by 3D-Directed Evolution.
Effective therapeutics for ovarian cancer continue to be urgently needed, particularly for chemotherapy-resistant cases. Here we present both a 3D-Matrigel culture-based expansion of our directed evolution method for generation of oncolytic virotherapies and two promising ovarian-cancer targeted oncolytic viruses, OvAd1 and OvAd2. OvAd1 was developed using Matrigel cell cultures, whereas OvAd2 was developed in parallel using traditional monolayer tissue culture methods. Both viruses are potent against a panel of platinum-resistant ovarian cancer cell lines and are attenuated on normal cells in vitro, resulting in therapeutic windows of ∼200-fold. We observed two benefits of the use of Matrigel-based cultures for directed evolution of these oncolytics: (1) use of Matrigel generated a bioselected pool that was more strongly attenuated on normal cells while retaining its potency against ovarian cancer cells, and (2) in an ovarian carcinomatosis model, the Matrigel-derived virus OvAd1 suppressed all tumor growth while the non-Matrigel-derived virus was 50% effective. Neither virus stimulated formation of peritoneal adhesions as seen for Ad5-based therapies. Consequently, these viruses are novel candidates for development as new effective treatments for aggressive ovarian cancer.


Photoinducible Oncometabolite Detection.
Dysregulated metabolism can fuel cancer by altering the production of bioenergetic building blocks and directly stimulating oncogenic gene-expression programs. However, relatively few optical methods for the direct study of metabolites in cells exist. To address this need and facilitate new approaches to cancer treatment and diagnosis, herein we report an optimized chemical approach to detect the oncometabolite fumarate. Our strategy employs diaryl tetrazoles as cell-permeable photoinducible precursors to nitrileimines. Uncaging these species in cells and cell extracts enables them to undergo 1,3-dipolar cycloadditions with endogenous dipolarophile metabolites such as fumarate to form pyrazoline cycloadducts that can be readily detected by their intrinsic fluorescence. The ability to photolytically uncage diaryl tetrazoles provides greatly improved sensitivity relative to previous methods, and enables the facile detection of dysregulated fumarate metabolism through biochemical activity assays, intracellular imaging, and flow cytometry. Our studies showcase an intersection of bioorthogonal chemistry and metabolite reactivity that can be applied for biological profiling, imaging, and diagnostics.


Absolute calibration of an ultraviolet spectrometer using a stabilized laser and a cryogenic cavity radiometer.
We carry out the calibration of an ultraviolet spectrometer by using a cryogenic electrical-substitution radiometer and intensity-stabilized laser sources. A comparison of the error budgets for the laser-based calibration described here and for a calibration using a type-FEL tungsten spectral-irradiance standard indicates that this technique could provide an improvement of a factor of ~3 in the uncertainty of the spectrometer calibration, resulting in an absolute accuracy (standard deviation of 3) of ~1% at 257 nm. The technique described here might significantly improve the accuracy of calibrations on NASA ozone-monitoring and solar ultraviolet-monitoring spectrophotometers when used to complement present procedures that employ lamps and the SURF II synchrotron ultraviolet radiation facility at the National Institute of Standards and Technology.


Intestinal explant barrier chip: long-term intestinal absorption screening in a novel microphysiological system using tissue explants.
The majority of intestinal in vitro screening models use cell lines that do not reflect the complexity of the human intestinal tract and hence often fail to accurately predict intestinal drug absorption. Tissue explants have intact intestinal architecture and cell type diversity, but show short viability in static conditions. Here, we present a medium throughput microphysiological system, Intestinal Explant Barrier Chip (IEBC), that creates a dynamic microfluidic microenvironment and prolongs tissue viability. Using a snap fit mechanism, we successfully incorporated human and porcine colon tissue explants and studied tissue functionality, integrity and viability for 24 hours. With a proper distinction of transcellular over paracellular transport (ratio >2), tissue functionality was good at early and late timepoints. Low leakage of FITC-dextran and preserved intracellular lactate dehydrogenase levels indicate maintained tissue integrity and viability, respectively. From a selection of low to high permeability drugs, 6 out of 7 properly ranked according to their fraction absorbed. In conclusion, the IEBC is a novel screening platform benefitting from the complexity of tissue explants and the flow in microfluidic chips.


Specific inclusion bodies are associated with replication of lettuce infectious yellows virus RNAs in Nicotiana benthamiana protoplasts.
Nicotiana benthamiana mesophyll protoplasts, either mock-inoculated or inoculated using in vitro transcripts derived from lettuce infectious yellows virus (LIYV) RNA 1- and/or RNA 2-cloned cDNAs were analysed by transmission electron microscopy (TEM) and, in some cases, also by immunogold labelling. TEM revealed the main cytopathological effects of LIYV infections in N. benthamiana protoplasts infected with RNAs 1 and 2: (a) typical closterovirus-induced (beet yellows virus-type) accumulations of vesiculated cytoplasmic membranes as inclusion bodies, sometimes with associated virions; (b) scattered aggregations of virions within the cytoplasm; and (c) electron-dense plasmalemma deposits. These were not seen in mock-inoculated protoplasts. Protoplasts inoculated only with LIYV RNA 1 contained vesiculated cytoplasmic inclusion bodies, but not virions or plasmalemma deposits. Thus, infection by only LIYV RNA 1 is sufficient to induce characteristic closterovirus vesiculated cytoplasmic inclusion bodies. However, both LIYV RNAs 1 and 2 are needed for production of virions and plasmalemma deposits.


Good practices in migrant health: the European experience.
Migrants comprise a growing proportion of European populations. Although many are healthy, those who do need healthcare often face barriers and the care they receive may be inappropriate to their needs. This paper summarises good practices identified in a review of health services for migrants in Europe. Governments should ensure that migrants are entitled to health services, that the services are appropriate to their needs and that data systems are in place to monitor utilisation and detect inequities. Health services should adopt a 'whole organisation approach', in which cultural competence is viewed as much as a task for organisations as for individuals. Health workers should take steps to overcome language, social and cultural barriers to care. In each case, existing examples of good practice are provided. At a time when support is growing in some countries for political parties pursuing anti-immigrant agendas and governments in all countries are pursuing austerity policies, there is a greater need than ever for the public health community to ensure that migrants have access to services that are effective and responsive to their needs.


Surface Crystallization of Liquid Au-Si and Its Impact on Catalysis.
In situ transmission electron microscopy reveals that an atomically thin crystalline phase at the surface of liquid Au-Si is stable over an unexpectedly wide range of conditions. By measuring the surface structure as a function of liquid temperature and composition, a simple thermodynamic model is developed to explain the stability of the ordered phase. The presence of surface ordering plays a key role in the pathway by which the Au-Si eutectic solidifies and also dramatically affects the catalytic properties of the liquid, explaining the anomalously slow growth kinetics of Si nanowires at low temperature. A strategy to control the presence of the surface phase is discussed, using it as a tool in designing strategies for nanostructure growth.


Rediscovery of four narrow endemic Didymocarpus species (Gesneriaceae) from Mizoram, India, with revised species descriptions and lectotypifications.
Here we report the rediscovery of four endemic gesneriads from the state of Mizoram, India, after a span of 86 to 90 years since their last collection. The four species belong to the genus Didymocarpus Wall. and they are: D. adenocarpus, D. lineicapsa, D. parryorum, and D. wengeri. We present revised morphological descriptions, photographs, and designate lectotypes for D. parryorum and D. wengeri. During our study we came across several discrepancies between morphological characters assigned to these four species in the protologue and morphological characters present (or absent) in the type specimens and in plants recollected by us. We list these discrepancies in a section titled 'amendments to protologue'. Based on the high endemicity and critical conservation status of all the four rediscovered species, we suggest that floristic studies along with large-scale biogeographic studies should be prioritized in the Indo-Burmese region.


Invasive breast carcinoma cells from patients exhibit MenaINV- and macrophage-dependent transendothelial migration.
Metastasis is a complex, multistep process of cancer progression that has few treatment options. A critical event is the invasion of cancer cells into blood vessels (intravasation), through which cancer cells disseminate to distant organs. Breast cancer cells with increased abundance of Mena [an epidermal growth factor (EGF)-responsive cell migration protein] are present with macrophages at sites of intravasation, called TMEM sites (for tumor microenvironment of metastasis), in patient tumor samples. Furthermore, the density of these intravasation sites correlates with metastatic risk in patients. We found that intravasation of breast cancer cells may be prevented by blocking the signaling between cancer cells and macrophages. We obtained invasive breast ductal carcinoma cells of various subtypes by fine-needle aspiration (FNA) biopsies from patients and found that, in an in vitro transendothelial migration assay, cells that migrated through a layer of human endothelial cells were enriched for the transcript encoding Mena(INV), an invasive isoform of Mena. This enhanced transendothelial migration required macrophages and occurred with all of the breast cancer subtypes. Using mouse macrophages and the human cancer cells from the FNAs, we identified paracrine and autocrine activation of colony-stimulating factor-1 receptor (CSF-1R). The paracrine or autocrine nature of the signal depended on the breast cancer cell subtype. Knocking down Mena(INV) or adding an antibody that blocks CSF-1R function prevented transendothelial migration. Our findings indicate that Mena(INV) and TMEM frequency are correlated prognostic markers and CSF-1 and Mena(INV) may be therapeutic targets to prevent metastasis of multiple breast cancer subtypes.


Cotton Wool Spots after Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Associated with Central Retinal Vein Occlusion.
To report a case series, whereby we encountered a transient increase in retinal cotton wool spots (CWS) following anti-vascular endothelial growth factor (anti-VEGF) therapy for the treatment of macular edema secondary to central retinal vein occlusion (CRVO). Eighteen eyes were treated with intravitreal aflibercept (IVA), and 5 were treated with intravitreal ranibizumab (IVR). Fundus photographs obtained 1 month after initial IVA or IVR injections were retrospectively evaluated for the presence of CWS. Twenty-one (91.3%) patients had the following systemic diseases: hypertension, diabetes mellitus without retinopathy, dyslipidemia, or chronic renal failure requiring dialysis. One month after treatment, reduced macular edema was observed in 21 (91.3%) eyes. Initial injections facilitated complete resolution in 14 eyes, and CWS gradually became fainter with additional injections. Some eyes with CRVO-related macular edema can show a transient increase in CWS after initial anti-VEGF therapy; however, macular edema, retinal hemorrhage, and visual acuity were improved in almost every case.


Acupuncture-induced haemothorax: a rare iatrogenic complication of acupuncture.
This paper reports a rare iatrogenic complication of acupuncture-induced haemothorax and comments on the importance and need for special education of physicians and physiotherapists in order to apply safe and effective acupuncture treatment. A 37-year-old healthy woman had a session of acupuncture treatments for neck and right upper thoracic non-specific musculoskeletal pain, after which she gradually developed dyspnoea and chest discomfort. After some delay while trying other treatment, she was eventually transferred to the emergency department where a chest X-ray revealed a right pneumothorax and fluid collection. She was admitted to hospital and a chest tube inserted into the right hemithorax (under ultrasound guidance) drained 800 mL of bloody fluid (haematocrit (Hct) 17.8%) in 24 h and 1200 mL over the following 3 days. Her blood Hct fell from 39.0% to 30.8% and haemoglobin from 12.7 to 10.3 g/dL. The patient recovered completely and was discharged after 9 days of hospitalisation. When dyspnoea, chest pain and discomfort occur during or after an acupuncture treatment, the possibility of secondary (traumatic) pneumo- or haemopneumothorax should be considered and the patient should remain under careful observation (watchful waiting) for at least 48 h. To maximise the safety of acupuncture, specific training should be given for the safe use of acupuncture points of the anterior and posterior thoracic wall using dry needling, trigger point acupuncture or other advanced acupuncture techniques.


Warm water bath stimulates phase-shifts of the peripheral circadian clocks in PER2::LUCIFERASE mouse.
Circadian clocks in the peripheral tissues of mice are known to be entrained by pulse stimuli such as restricted feeding, novel wheel running, and several other agents. However, there are no reports on high temperature pulse-mediated entrainment on the phase-shift of peripheral clocks in vivo. Here we show that temperature treatment of mice for two days at 41°C, instead of 37°C, for 1-2 h during the inactive period, using a temperature controlled water bath stimulated phase-advance of peripheral clocks in the kidney, liver, and submandibular gland of PER2::LUCIFERASE mice. On the other hand, treatment for 2 days at 35°C ambient room temperature for 2 h did not cause a phase-advance. Maintenance of mice at 41°C in a water bath, sustained the core body temperature at 40-41°C. However, the use of 37°C water bath or the 35°C ambient room temperature elevated the core body temperature to 38.5°C, suggesting that at least a core body temperature of 40-41°C is necessary to cause phase-advance under light-dark cycle conditions. The temperature pulse stimulation at 41°C, instead of 37°C water bath for 2 h led to the elevated expression of Per1 and Hsp70 in the peripheral tissue of mice. In summary, the present study demonstrates that transient high temperature pulse using water bath during daytime causes phase-advance in mouse peripheral clocks in vivo. The present results suggest that hot water bath may affect the phase of peripheral clocks.


New Caledonian crows use tools for non-foraging activities.
Tool use is of great interest for cognitive research, largely because it can be particularly revealing about the underlying information processing mechanisms. Tool use that is inflexible or requires extensive experience to change, and that is only addressed towards specific targets such as food, is not likely to reflect unusual or particularly complex cognition. On the contrary, if tools are employed flexibly and for a variety of innovative purposes, then conventional combinations of inherited predispositions and associative learning are challenged and interesting questions emerge. Since New Caledonian crows (Corvus moneduloides) are especially adept at using and making tools for food extraction, we decided to examine their ability to generalise this to other contexts. We recorded how five pairs of New Caledonian crows interacted with novel objects that were not associated with food. We observed eight occasions in which the first contact with the novel object was mediated by a tool, suggesting that the function of the tool was for exploration. This is the first report of non-foraging tool use in New Caledonian crows, and it implies that the cognitive operations controlling tool-oriented behaviour in this species are more general than previously thought.


Phonemic-Morphemic dissociation in university students with dyslexia: an index of reading compensation?
A phonological deficit constitutes a primary cause of developmental dyslexia, which persists into adulthood and can explain some aspects of their reading impairment. Nevertheless, some dyslexic adults successfully manage to study at university level, although very little is currently known about how they achieve this. The present study investigated at both the individual and group levels, whether the development of another oral language skill, namely, morphological knowledge, can be preserved and dissociated from the development of phonological knowledge. Reading, phonological, and morphological abilities were measured in 20 dyslexic and 20 non-dyslexic university students. The results confirmed the persistence of deficits in phonological but not morphological abilities, thereby revealing a dissociation in the development of these two skills. Moreover, the magnitude of the dissociation correlated with reading level. The outcome supports the claim that university students with dyslexia may compensate for phonological weaknesses by drawing on morphological knowledge in reading.


Differentiation of calcium oxalate monohydrate and calcium oxalate dihydrate stones using quantitative morphological information from micro-computerized and clinical computerized tomography.
We differentiated calcium oxalate monohydrate and calcium oxalate dihydrate kidney stones using micro and clinical computerized tomography images. A total of 22 calcium oxalate monohydrate and 15 calcium oxalate dihydrate human kidney stones were scanned using a commercial micro-computerized tomography scanner with a pixel size of 7 to 23 μm. Under an institutional review board approved protocol, image data on 10 calcium oxalate monohydrate and 9 calcium oxalate dihydrate stones greater than 5 mm were retrieved from a total of 80 patients who underwent clinical dual energy computerized tomography for clinical indications and had stones available for infrared spectroscopic compositional analysis. Micro and clinical computerized tomography images were processed using in-house software, which quantified stone surface morphology with curvature based calculations. A shape index was generated as a quantitative shape metric to differentiate calcium oxalate monohydrate from calcium oxalate dihydrate stones. Statistical tests were used to test the performance of the shape index. On micro-computerized tomography images the shape index of calcium oxalate monohydrate and calcium oxalate dihydrate stones significantly differed (ROC curve AUC 0.92, p <0.0001). At the optimal cutoff sensitivity was 0.93 and specificity was 0.91. On clinical computerized tomography images a significant morphological difference was also detected (p = 0.007). AUC, sensitivity and specificity were 0.90, 1 and 0.73, respectively. On micro and clinical computerized tomography images a morphological difference was detectable in calcium oxalate monohydrate and calcium oxalate dihydrate stones larger than 5 mm. The shape index is a highly promising method that can distinguish calcium oxalate monohydrate and calcium oxalate dihydrate stones with reasonable accuracy.


Role of gut-brain axis in persistent abnormal feeding behavior in mice following eradication of Helicobacter pylori infection.
Bacterial infection can trigger the development of functional GI disease. Here, we investigate the role of the gut-brain axis in gastric dysfunction during and after chronic H. pylori infection. Control and chronically H. pylori-infected Balb/c mice were studied before and 2 mo after bacterial eradication. Gastric motility and emptying were investigated using videofluoroscopy image analysis. Gastric mechanical viscerosensitivity was assessed by cardioautonomic responses to distension. Feeding patterns were recorded by a computer-assisted system. Plasma leptin, ghrelin, and CCK levels were measured using ELISA. IL-1beta, TNF-alpha, proopiomelanocortin (POMC), and neuropeptide Y mRNAs were assessed by in situ hybridizations on frozen brain sections. Gastric inflammation was assessed by histology and immunohistochemistry. As shown previously, H. pylori-infected mice ate more frequently than controls but consumed less food per bout, maintaining normal body weight. Abnormal feeding behavior was accompanied by elevated plasma ghrelin and postprandial CCK, higher TNF-alpha (median eminence), and lower POMC (arcuate nucleus) mRNA. Infected mice displayed delayed gastric emptying and visceral hypersensitivity. Eradication therapy normalized gastric emptying and improved gastric sensitivity but had no effect on eating behavior. This was accompanied by persistently increased TNF-alpha in the brain and gastric CD3(+) T-cell counts. In conclusion, chronic H. pylori infection in mice alters gastric emptying and mechanosensitivity, which improve after bacterial eradication. A feeding pattern reminiscent of early satiety persists after H. pylori eradication and is accompanied by increased TNF-alpha in the brain. The results support a role for altered gut-brain pathways in the maintenance of postinfective gut dysfunction.


Transmission as an input boundary value for an analytical solution of a single-scatter lidar equation.
Single-scatter lidar signals carry information on the spatial atmospheric backscatter coefficient, attenuated by the path-integrated extinction. Assuming that the relationship between the backscatter and the extinction is known, the inverted extinction profile and the path-integrated extinction are uniquely related to the input boundary value. The integrated extinction over a certain range interval is a measure of the optical transmission along that path. In reverse, for a given transmission over the path of interest, the input boundary value is uniquely defined. An analytical expression is derived that describes the input boundary condition for the inversion of the single-scatter lidar equation in terms of the transmission losses over the path of interest. The proposed method is useful in situations in which independent transmission measurements are carried out or in situations in which targets such as multiple cloud layers or beam stops are available in the lidar path. Equations for both the forward and the backward integration method are presented. Compared with the widely accepted inversion schemes that are based on single-point reference extinction values, the proposed method is less sensitive to noise.


The Process of Constructing a Health Tourism Destination Index.
The purpose of the study is to identify a set of key indicators with weightings for health tourism destinations by using an advanced analytic hierarchy process (AHP) method, derived from the official, academic, and professional opinions of the experts. The AHP method allocated weightings to the evaluation criteria selected by the fifteen experts. After expert evaluations were conducted, the three dimensions and eleven sub-dimensions of the initial health tourism destination were obtained as follows: (1) special demands and indications-medical care, health promotion, and tourism and leisure; (2) natural environment-climate, air, water, and light; (3) leisure activities and general demands-sports, therapeutic activities, interactions with animals and plants, and diet. The results revealed that the dimensions of special demands and indications were given the most attention and that the sub-dimensions of sports promotion were the highest ranked by expert groups. The official and academic opinions suggested that health tourism destinations should focus on special demands and indications, while professionals tended to consider the natural environment as a primary concern. In particular, they considered that good air quality can help people release pressure, relax, activate lymphocytes, improve immune function, and enhance disease immunity. The health tourism destination index can contribute to the overall strategic planning process by identifying improvements in activities and enhancing competitiveness in health tourism management by using benchmarking to further improve tourists' experience and satisfaction.


Using explosive percolation in analysis of real-world networks.
We apply a variant of the explosive percolation procedure to large real-world networks and show with finite-size scaling that the university class, ordinary or explosive, of the resulting percolation transition depends on the structural properties of the network, as well as the number of unoccupied links considered for comparison in our procedure. We observe that in our social networks, the percolation clusters close to the critical point are related to the community structure. This relationship is further highlighted by applying the procedure to model networks with predefined communities.