Highly sensitive quantification of optic neuritis intrathecal biomarker CXCL13.

BACKGROUND: Elevation of CXCL13, a key regulator of B-cell recruitment in cerebrospinal fluid (CSF) is implicated in multiple sclerosis (MS). OBJECTIVE: to evaluate if measurement of CXCL13 using a highly sensitive assay is of value in acute optic neuritis (ON) patients for the prediction of later MS. METHOD: CXCL13 was measured by Simoa in two independent treatment-naïve ON cohorts, a training cohort (TC, n = 33) originating from a population-based cohort, a validation cohort (VC, n = 30) consecutively collected following principles for population studies. Prospectively, 14/33 TC and 12/30 VC patients progressed to MS (MS-ON) while 19/33 TC and 18/30 VC patients, remained as isolated ON (ION). RESULTS: CXCL13 was detectable in all samples and were higher in ON compared with healthy controls (HC) (p = 0.012). In the TC, CSF levels in MS-ON were higher compared with ION patients and HC (p = 0.0001 and p<0.0001). In the VC, we confirmed the increase of CXCL13 in MS-ON compared to ION (p = 0.0091). Logistic regression analysis revealed an area under receiver operating characteristic curve of 0.83 [95% C.I: 0.73-0.93]. CONCLUSIONS: The highly sensitive CXCL13 Simoa assay demonstrated ability to identify ON patients and separate MS-ON from ION, and predictive diagnostic values indicates a promising potential of this assay.

Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges.

Long-acting/extended-release drug formulations have proved very successful in diverse areas of medicine, including contraception, psychiatry and, most recently, human immunodeficiency virus (HIV) disease. Though challenging, application of this technology to anti-tuberculosis treatment could have substantial impact. The duration of treatment required for all forms of tuberculosis (TB) put existing regimens at risk of failure because of early discontinuations and treatment loss to follow-up. Long-acting injections, for example, administered every month, could improve patient adherence and treatment outcomes. We review the state of the science for potential long-acting formulations of existing tuberculosis drugs, and propose a target product profile for new formulations to treat latent tuberculous infection (LTBI). The physicochemical properties of some anti-tuberculosis drugs make them unsuitable for long-acting formulation, but there are promising candidates that have been identified through modeling and simulation, as well as other novel agents and formulations in preclinical testing. An efficacious long-acting treatment for LTBI, particularly for those co-infected with HIV, and if coupled with a biomarker to target those at highest risk for disease progression, would be an important tool to accelerate progress towards TB elimination.

Genetic relationships between boar feed efficiency and sow piglet production, body condition score, and stayability in Norwegian Landrace pigs.

Both feed efficiency and sow production are economically important traits in pig breeding. One challenge in a maternal line such as Norwegian Landrace is to breed for highly feed efficient fattening pigs and, at the same time, produce sows with high daily feed intake to maintain their BCS in multiple parities. The aim of this study was to estimate genetic correlations among novel feed efficiency measurements on Norwegian Landrace boars and piglet production, stayability, and body condition in Norwegian Landrace sows. The feed efficiency measurements were lean meat and fat efficiency. These measurements were calculated using an extended residual feed intake model where total feed intake in the test period was the response variable and fat (kg) and lean meat (kg) on the carcass were included as both fixed and random regressions. The random regression coefficients that resulted from this model were breeding values, which represented the amount of feed used to produce an extra kilogram of lean meat and fat. The sow traits were stayability of the sow from first to second parity, BCS at weaning, litter weight at 3 wk, and total number of piglets born. All traits were recorded on first parity purebred Norwegian Landrace and analyzed using multivariate animal models. All genetic correlations between fat efficiency and sow traits were low. Significant genetic correlations were found only between fat efficiency and stayability (0.21 ± 0.11) and between fat efficiency and total litter weight at 3 wk (0.21 ± 0.10). The results indicate that selection for efficient deposition of fat could give poor stayability and lower litter weight at 3 wk in first parity sows. The genetic correlations between lean meat efficiency and sow traits were not significantly different from 0 and signified no genetic relationships between these traits. Selection for efficient deposition of lean meat should not affect the sow traits and is, therefore, beneficial.

Genetic variation in efficiency to deposit fat and lean meat in Norwegian Landrace and Duroc pigs.

Feed costs amount to approximately 70% of the total costs in pork production, and feed efficiency is, therefore, an important trait for improving pork production efficiency. Production efficiency is generally improved by selection for high lean growth rate, reduced backfat, and low feed intake. These traits have given an effective slaughter pig but may cause problems in piglet production due to sows with limited body reserves. The aim of the present study was to develop a measure for feed efficiency that expressed the feed requirements per 1 kg deposited lean meat and fat, which is not improved by depositing less fat. Norwegian Landrace ( = 8,161) and Duroc ( = 7,202) boars from Topigs Norsvin's testing station were computed tomography scanned to determine their deposition of lean meat and fat. The trait was analyzed in a univariate animal model, where total feed intake in the test period was the dependent variable and fat and lean meat were included as random regression cofactors. These cofactors were measures for fat and lean meat efficiencies of individual boars. Estimation of fraction of total genetic variance due to lean meat or fat efficiency was calculated by the ratio between the genetic variance of the random regression cofactor and the total genetic variance in total feed intake during the test period. Genetic variance components suggested there was significant genetic variance among Norwegian Landrace and Duroc boars in efficiency for deposition of lean meat (0.23 ± 0.04 and 0.38 ± 0.06) and fat (0.26 ± 0.03 and 0.17 ± 0.03) during the test period. The fraction of the total genetic variance in feed intake explained by lean meat deposition was 12% for Norwegian Landrace and 15% for Duroc. Genetic fractions explained by fat deposition were 20% for Norwegian Landrace and 10% for Duroc. The results suggested a significant part of the total genetic variance in feed intake in the test period was explained by fat and lean meat efficiency. These new efficiency measures may give the breeders opportunities to select for animals with a genetic potential to deposit lean meat efficiently and at low feed costs in slaughter pigs rather than selecting for reduced the feed intake and backfat.

Multimodal approach to assess tumour vasculature and potential treatment effect with DCE-US and DCE-MRI quantification in CWR22 prostate tumour xenografts.

The aim of this study was to compare intratumoural heterogeneity and longitudinal changes assessed by dynamic contrast-enhanced ultrasound (DCE-US) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in prostate tumour xenografts. In vivo DCE-US and DCE-MRI were obtained 24 h pre- (day 0) and post- (day 2) radiation treatment with a single dose of 7.5 Gy. Characterization of the tumour vasculature was determined by Brix pharmacokinetic analysis of the time-intensity curves. Histogram analysis of voxels showed significant changes (p < 0.001) from day 0 to day 2 in both modalities for kep , the exchange rate constant from the extracellular extravascular space to the plasma, and kel , the elimination rate constant of the contrast. In addition, kep and kel values from DCE-US were significantly higher than those derived from DCE-MRI at day 0 (p < 0.0001) for both groups. At day 2, kel followed the same tendency for both groups, whereas kep showed this tendency only for the treated group in intermediate-enhancement regions. Regarding kep median values, longitudinal changes were not found for any modality. However, at day 2, kep linked to DCE-US was correlated to MVD in high-enhancement areas for the treated group (p = 0.05). In contrast, correlation to necrosis was detected for the control group in intermediate-enhancement areas (p < 0.1). Intratumoural heterogeneity and longitudinal changes in tumour vasculature were assessed for both modalities. Microvascular parameters derived from DCE-US seem to provide reliable biomarkers during radiotherapy as validated by histology. Furthermore, DCE-US could be a stand-alone or a complementary technique.

Numbers of coliforms, Escherichia coli, F-RNA phage, rotavirus, bovine enteric calicivirus and presence of non-O157 STEC on commercial vacuum packaged beef.

The numbers of coliforms, Escherichia coli, F-RNA coliphages, bovine enteric calicivirus (BEC) and rotavirus (RV) and presence of non-O157 shiga toxigenic E. coli (STEC) were determined on commercial vacuum packaged beef subprimals at the retail level from swabs obtained from the entire surfaces of 150 cuts that originated from federally and provincially registered plants. The prevalence and log mean numbers of E. coli were higher in provincially registered plants than in federally registered plants; 64% vs 20%, respectively, and -0.3 vs -1.22 log cfu/100 cm(2), respectively. In contrast, the prevalence and mean log numbers of F-RNA coliphages were lower for the provincially registered plants than for the federally registered plants; 31% vs 68% and -0.86 vs -0.13 log cfu/100 cm(2), respectively. One E. coli sample tested positive for stx2 and eae. F-RNA coliphages associated with human origin (GII/GIII) were detected in 12% and 30% of samples that originated from provincially and federally registered plants, respectively. RV RNA was detected in 4% of samples while BEC RNA was not detected. Although the infectivity of RV is unknown, the presence of viable F-RNA coliphages suggests that consumers could potentially be at risk when consuming undercooked meat that is contaminated with RV.

Protein corona fingerprinting predicts the cellular interaction of gold and silver nanoparticles.

Using quantitative models to predict the biological interactions of nanoparticles will accelerate the translation of nanotechnology. Here, we characterized the serum protein corona 'fingerprint' formed around a library of 105 surface-modified gold nanoparticles. Applying a bioinformatics-inspired approach, we developed a multivariate model that uses the protein corona fingerprint to predict cell association 50% more accurately than a model that uses parameters describing nanoparticle size, aggregation state, and surface charge. Our model implicates a set of hyaluronan-binding proteins as mediators of nanoparticle-cell interactions. This study establishes a framework for developing a comprehensive database of protein corona fingerprints and biological responses for multiple nanoparticle types. Such a database can be used to develop quantitative relationships that predict the biological responses to nanoparticles and will aid in uncovering the fundamental mechanisms of nano-bio interactions.

Genetic parameters for feed intake, litter weight, body condition and rebreeding success in primiparous Norwegian Landrace sows.

The aim of this study was to estimate genetic parameters for feed intake recorded as farmers' perception of young sows' appetite for the first 3 weeks of lactation (APP) and feed intake recorded for one day in the 3rd week of lactation (FEED), litter weight (LW) at 3 weeks, sow body condition at weaning (BC) and the following five reproduction traits: weaning-to-service interval of 1 to 7 days (WSI7), weaning-to-service interval of 1 to 50 days (WSI50), delayed service or not (DELAYED), pregnant on first service or not (PREGNANT) and litter size in 2nd parity (NBT2). The analyses included data on 4606 Norwegian Landrace 1st-parity sows and their litters. The Gibbs sampling method was used. The traits DELAYED and PREGNANT were analysed as threshold traits and APP, FEED, LW, BC, WSI7, WSI50 and NBT2 were analysed as linear traits. The heritability estimates for APP and FEED were low (<0.1), whereas the estimates for DELAYED and PREGNANT were rather high (0.4 and 0.3). The heritability estimate for BC was 0.2. The genetic correlations confirmed the complexity of breeding for sow performance; selection for heavy 1st litters may lead to lower body condition at weaning, which in turn leads to lower reproductive performance and smaller litters in 2nd parity. Selection for higher sow feed intake would improve body condition, but the simple way of measuring feed intake tested in this study (APP and FEED) cannot be recommended because of the low heritability obtained for these traits.

VEGFA variants are associated with pre-school lung function, but not neonatal lung function.

BACKGROUND: Vascular endothelial growth factor (VEGF) is implicated in airway remodelling and asthma development. We studied VEGFA gene variants and plasma levels and the development of lung function, bronchial hyperresponsiveness and asthma in childhood. METHODS: We analysed 13 SNPs in the VEGFA gene in 411 children from the COPSAC2000 high-risk birth cohort. Asthma was diagnosed prospectively, and lung function measurements were obtained at birth and 6 years of age. Plasma VEGF levels were measured at 18 months of age. We used a Bonferroni adjusted significance level. Findings were replicated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort at age 8. RESULTS: At age six, three SNPs from the same linkage block were associated with FEV1 (rs699947, P = 1.31E-05), independent of asthma, and there were suggestive associations between FEV1/FVC ratio and rs833052 and maximal mid-expiratory flow and rs6900017. Replication in the PIAMA cohort showed borderline association between FEV1 and rs699947 and significant meta-analysis result. SNPs upstream and nearby rs699947 were nominally associated with VEGF plasma levels. VEGF levels were not associated with asthmatic symptoms or lung function measures. CONCLUSIONS AND CLINICAL RELEVANCE: VEGF gene variants are associated with lung function at school age, but not at birth, suggesting a role of VEGF in post-natal lung function development.

Heritability of shoulder ulcers and genetic correlations with mean piglet weight and sow body condition.

The objective of this paper was to estimate the heritability for shoulder ulcers and the genetic correlations between shoulder ulcers, mean piglet weight and sow body condition. The analyses were based on information on 5549 Norwegian Landrace sows and their 7614 purebred litters. The genetic analysis was performed using the Gibbs sampling method. Shoulder ulcers were analyzed as a threshold trait. Sow body condition and mean piglet weight were analyzed as linear traits. The heritability of shoulder ulcers was estimated at 0.25 (s.d. = 0.03). The heritability for sow body condition was estimated at 0.14 (s.d. = 0.02) and that for mean piglet weight at 0.23 (s.d. = 0.02). The genetic correlation between shoulder ulcers and sow body condition was negative (-0.59, s.d. = 0.09). The genetic correlation between shoulder ulcers and mean piglet weight was positive (0.23, s.d. = 0.10) and the genetic correlation between sow body condition and mean piglet weight was negative (-0.24, s.d. = 0.10).

Dose distribution in the thyroid gland following radiation therapy of breast cancer--a retrospective study.

PURPOSE: To relate the development of post-treatment hypothyroidism with the dose distribution within the thyroid gland in breast cancer (BC) patients treated with loco-regional radiotherapy (RT). METHODS AND MATERIALS: In two groups of BC patients postoperatively irradiated by computer tomography (CT)-based RT, the individual dose distributions in the thyroid gland were compared with each other; Cases developed post-treatment hypothyroidism after multimodal treatment including 4-field RT technique. Matched patients in Controls remained free for hypothyroidism. Based on each patient's dose volume histogram (DVH) the volume percentages of the thyroid absorbing respectively 20, 30, 40 and 50 Gy were then estimated (V20, V30, V40 and V50) together with the individual mean thyroid dose over the whole gland (MeanTotGy). The mean and median thyroid dose for the included patients was about 30 Gy, subsequently the total volume of the thyroid gland (VolTotGy) and the absolute volumes (cm3) receiving respectively <30 Gy and ≥30 Gy were calculated (Vol<30 and Vol≥30) and analyzed. RESULTS: No statistically significant inter-group differences were found between V20, V30, V40 and V50Gy or the median of MeanTotGy. The median VolTotGy in Controls was 2.3 times above VolTotGy in Cases (ρ=0.003), with large inter-individual variations in both groups. The volume of the thyroid gland receiving<30 Gy in Controls was almost 2.5 times greater than the comparable figure in Cases. CONCLUSIONS: We concluded that in patients with small thyroid glands after loco-radiotherapy of BC, the risk of post-treatment hypothyroidism depends on the volume of the thyroid gland.

The effect of rowing on endothelial function and insulin action in healthy controls and in patients with type 2 diabetes.

Patients with type 2 diabetes (T2DM) have an increased risk for cardiovascular disease. We examined the effects of 8 weeks of home-based rowing training (heart rate corresponding to 65-70% of VO(2 peak) ) on endothelial function and glucose clearance (local and systemic effects) in male subjects with T2DM (n=9) and matched controls (n=8). Before and after training (30 min every other day), all subjects underwent sequential graded brachial artery infusions of non-insulin vasodilators (acetylcholine; sodium nitroprusside; adenosine). Forearm blood flow was improved by training in controls (without and with insulin: P=0.003 and 0.05, respectively) but not in subjects with T2DM. Likewise, whole body glucose clearance increased in response to training in controls (P=0.05) but not in T2DM. However, in both groups, the capacity for local forearm glucose extraction (controls: P=0.001; T2DM: P=0.002) and clearance (controls: P<0.001; T2DM: P=0.01) were positively affected by exercise. While the subjects with T2DM did not respond to the same degree as controls to 8 weeks of home-based exercise, there are clear benefits as illustrated by improvements in local glucose disposal. Training of higher intensity or duration may be required in order to elicit a response similar to controls.

Neoadjuvant chemotherapy in breast cancer-response evaluation and prediction of response to treatment using dynamic contrast-enhanced and diffusion-weighted MR imaging.

OBJECTIVE: To explore the predictive value of MRI parameters and tumour characteristics before neoadjuvant chemotherapy (NAC) and to compare changes in tumour size and tumour apparent diffusion coefficient (ADC) during treatment, between patients who achieved pathological complete response (pCR) and those who did not. METHODS: Approval by the Regional Ethics Committee and written informed consent were obtained. Thirty-one patients with invasive breast carcinoma scheduled for NAC were enrolled (mean age, 50.7; range, 37-72). Study design included MRI before treatment (Tp0), after four cycles of NAC (Tp1) and before surgery (Tp2). Data in pCR versus non-pCR groups were compared and cut-off values for pCR prediction were evaluated. RESULTS: Before NAC, HER2 overexpression was the single significant predictor of pCR (p = 0.006). At Tp1 ADC, tumour size and changes in tumour size were all significantly different in the pCR and non-pCR groups. Using 1.42 × 10(-3) mm(2)/s as the cut-off value for ADC, pCR was predicted with sensitivity and specificity of 88% and 80%, respectively. Using a cut-off value of 83% for tumour volume reduction, sensitivity and specificity for pCR were 91% and 80%. CONCLUSION: ADC, tumour size and tumour size reduction at Tp1 were strong independent predictors of pCR.

Adverse effects associated with arginine alpha-ketoglutarate containing supplements.

The athletic performance supplement industry is a multibillion-dollar business and one popular category claims to increase nitric oxide (NO) production. We report three patients presenting to the emergency department with adverse effects. A 33-year-old man presented with palpitations, dizziness, vomiting, and syncope, after the use of NO(2) platinum. His examination and electrocardiogram (ECG) were normal. The dizziness persisted, requiring admission overnight. A 21-year-old man with palpitations and near syncope had used a "nitric oxide" supplement. He was tachycardic to 115 bpm with otherwise normal examination. Laboratory values including methemoglobin, and ECG were unremarkable. He was treated with 1 L of saline with no change in heart rate. He was admitted for observation. A 24-year-old man presented after taking NO-Xplode with palpitations and a headache. His examination, laboratory values, and ECG were normal. He was discharged. The purported active ingredient in these products is arginine alpha-ketoglutarate (AAKG), which is claimed to increase NO production by supplying the precursor L-arginine. The symptoms could be due to vasodilation from increased levels of NO, though other etiologies cannot be excluded. AAKG containing supplements may be associated with adverse effects requiring hospital admission.

Cancer treatment by radiotherapy in Western Nepal: a hospital-based study.

OBJECTIVE: The aim of this study was to describe utilization of radiotherapy and treatment compliance in the context of Nepal. METHODS: A retrospective study was carried out on data collected from the radiotherapy treatment records of patients treated at Manipal Teaching Hospital (MTH), Pokhara, between 28 September 2000 and 30 May 2008. RESULTS: In the 944 patients, the gender distribution showed a slight female preponderance (53.7 vs. 46.3%). Curative treatment was given to 62.8% (n= 593) and palliative to the remaining 37.2% (n= 351). Patients older than 50 years were more likely to receive palliative radiotherapy (p= 0.001). The commonest cancers treated were head and neck at 23.7% (n= 224), followed by lung at 21.3% (n= 201) and cervix at 16.1% (n= 152). The majority of patients were between 50-70 years of age (n= 564). Nineteen percent (n= 179) did not complete the prescribed dose of radiation. Unplanned treatment interruptions were found in 35.6% (n= 336) and this was not affected by age (p= 0.1) or gender (p= 0.1). The most frequent treatment interruption compromising optimal effectiveness of cancer treatment was observed for head and neck cancers, constituting 43% (n= 96) of patients in the group. CONCLUSION: Head and neck in both sexes and cervix in females were the most common cancers treated with a curative intent. Lung cancer, the second most common in both genders, was treated with palliative intent in a large number of cases. This indicates the need for early diagnosis for a possible curative treatment.

Prediction of genetic growth curves in pigs.

Genetic growth curves of boars in a test station were predicted on daily weight records collected by automated weighing scales. The data contained 121 865 observations from 1477 Norwegian Landrace boars and 108 589 observations from 1300 Norwegian Duroc boars. Random regression models using Legendre polynomials up to second order for weight at different ages were compared for best predicting ability and Bayesian information criterion (BIC) for both breeds. The model with second-order polynomials had best predictive ability and BIC. The heritability for weight, based on this model, was found to vary along the growth trajectory between 0.32-0.35 for Duroc and 0.17-0.25 for Landrace. By varying test length possibility to use shorter test time and pre-selection was tested. Test length was varied and compared with average termination at 100 kg, termination of the test at 90 kg gives, e.g. 2% reduction in accuracy of estimated breeding values (EBV) for both breeds and termination at 80 kg gives 5% reduction in accuracy of EBVs for Landrace and 3% for Duroc. A shorter test period can decrease test costs per boar, but also gives possibilities to increase selection intensity as there will be room for testing more boars.

Reduction in dose from CT examinations of liver lesions with a new postprocessing filter: a ROC phantom study.

BACKGROUND: It is desirable to lower the dose from computed tomography (CT) examinations as much as possible without reducing diagnostic performance. Mathematical postprocessing filters are one tool to achieve dose reduction. PURPOSE: To evaluate the possibilities of reducing CT doses from liver examinations using a new postprocessing filter. MATERIAL AND METHODS: An anthropomorphic upper-abdomen phantom was used in receiver operating characteristic (ROC) studies of the detectability of liver lesions. A standard abdominal CT protocol was used. Only mA settings were changed; all other scan parameters were constant. The postprocessing filter used was SharpView CT, which provides context-controlled restoration of digital images using adaptive filters. Six readers were given a set of 10 images obtained at five different dose levels, each image with 32 predefined areas to be evaluated on a five-point scale. In total, 1920 areas were evaluated. At each dose level, the readers evaluated five images without enhancement and five images based on postprocessing filters. All images were randomized with respect to dose level. RESULTS: The postprocessing filter improved the diagnostic performance significantly compared to the unenhanced images at all dose levels. Radiation dose for abdominal CT examinations of liver lesions in the range 2-7 mm was reduced by 30% using postprocessing filters, while diagnostic performance of the examination was maintained or even improved. CONCLUSION: This study indicates great potential for lowering doses for CT examinations of liver lesions using the new postprocessing filter. The software must be fully tested clinically to reliably assess the benefits of this filtration.

The right-to-left shunt of crocodilians serves digestion.

Abstract All amniotes except birds and mammals have the ability to shunt blood past the lungs, but the physiological function of this ability is poorly understood. We studied the role of the shunt in digestion in juvenile American alligators in the following ways. First, we characterized the shunt in fasting and postprandial animals and found that blood was shunted past the lungs during digestion. Second, we disabled the shunt by surgically sealing the left aortic orifice in one group of animals, and we performed a sham surgery in another. We then compared postprandial rates of gastric acid secretion at body temperatures of 19 degrees and 27 degrees C and rates of digestion of bone at 27 degrees C. Twelve hours after eating, maximal rates of gastric acid secretion when measured at 19 degrees and 27 degrees C were significantly less in the disabled group than in sham-operated animals. Twenty-four hours postprandial, a significant decrease was found at 27 degrees C but not at 19 degrees C. For the first half of digestion, dissolution of cortical bone was significantly slower in the disabled animals. These data suggest the right-to-left shunt serves to retain carbon dioxide in the body so that it can be used by the gastrointestinal system. We hypothesize that the foramen of Panizza functions to enrich with oxygen blood that is destined for the gastrointestinal system to power proton pumps and other energy-demanding processes of digestion and that the right-to-left shunt serves to provide carbon dioxide to gastrointestinal organs besides the stomach, such as the pancreas, spleen, upper small intestine, and liver.