In vivo MRI-derived measurements of human cerebral cortex thickness are providing novel insights into normal and abnormal neuroanatomy, but little is known about their reliability. We investigated how the reliability of cortical thickness measurements is affected by MRI instrument-related factors, including scanner field strength, manufacturer, upgrade and pulse sequence. Several data processing factors were also studied. Two test-retest data sets were analyzed: 1) 15 healthy older subjects scanned four times at 2-week intervals on three scanners; 2) 5 subjects scanned before and after a major scanner upgrade. Within-scanner variability of global cortical thickness measurements was <0.03 mm, and the point-wise standard deviation of measurement error was approximately 0.12 mm. Variability was 0.15 mm and 0.17 mm in average, respectively, for cross-scanner (Siemens/GE) and cross-field strength (1.5 T/3 T) comparisons. Scanner upgrade did not increase variability nor introduce bias. Measurements across field strength, however, were slightly biased (thicker at 3 T). The number of (single vs. multiple averaged) acquisitions had a negligible effect on reliability, but the use of a different pulse sequence had a larger impact, as did different parameters employed in data processing. Sample size estimates indicate that regional cortical thickness difference of 0.2 mm between two different groups could be identified with as few as 7 subjects per group, and a difference of 0.1 mm could be detected with 26 subjects per group. These results demonstrate that MRI-derived cortical thickness measures are highly reliable when MRI instrument and data processing factors are controlled but that it is important to consider these factors in the design of multi-site or longitudinal studies, such as clinical drug trials.

Alzheimer's disease (AD) is associated with neurodegeneration in vulnerable limbic and heteromodal regions of the cerebral cortex, detectable in vivo using magnetic resonance imaging. It is not clear whether abnormalities of cortical anatomy in AD can be reliably measured across different subject samples, how closely they track symptoms, and whether they are detectable prior to symptoms. An exploratory map of cortical thinning in mild AD was used to define regions of interest that were applied in a hypothesis-driven fashion to other subject samples. Results demonstrate a reliably quantifiable in vivo signature of abnormal cortical anatomy in AD, which parallels known regional vulnerability to AD neuropathology. Thinning in vulnerable cortical regions relates to symptom severity even in the earliest stages of clinical symptoms. Furthermore, subtle thinning is present in asymptomatic older controls with brain amyloid binding as detected with amyloid imaging. The reliability and clinical validity of AD-related cortical thinning suggests potential utility as an imaging biomarker. This "disease signature" approach to cortical morphometry, in which disease effects are mapped across the cortical mantle and then used to define ROIs for hypothesis-driven analyses, may provide a powerful methodological framework for studies of neuropsychiatric diseases.

Despite its widespread use in aquaculture, the impact of chemical anti-sea lice treatment on salmonids following application in a commercial farm has not been previously reported. This work reports the cumulative effect of three consecutive anti-sea lice treatments using azamethiphos on the health status of aquaculture reared rainbow trout through the investigation of clinical chemistry, histopathology and proteome expression. The serum biomarkers showed decreasing trends in total protein, albumin and potassium concentrations and an average increase of total bilirubin and phosphate concentration towards the end of the treatment period. Principal component analysis clearly distinguished correlated pairs of biomarkers and also demonstrates a shift from acute to chronic effects as treatment progresses. Proteomic analysis confirmed alterations of proteins involved in clot formation, immune reaction and free heme binding. Tissue damage after the series of delousing treatments, exhibited increased deposits of hemosiderin. Results from this study suggest an impact of azamethiphos on trout health through intravascular haemolysis and consequently from pathophysiologic process of haemoglobin metabolism and its products, causing chronic kidney injury from iron deposits. This is the first report to demonstrate in fish the impact of active iron accumulation in different organs from physiological processes that can seriously impair normal function.

Pesticides are a safety issue globally and cause serious concerns for the environment, wildlife and human health. The handheld detection of four pesticide residues widely used in Basmati rice production using surface-enhanced Raman spectroscopy (SERS) is reported. Different SERS substrates were synthesised and their plasmonic and Raman scattering properties evaluated. Using this approach, detection limits for pesticide residues were achieved within the range of 5 ppb-75 ppb, in solvent. Various extraction techniques were assessed to recover pesticide residues from spiked Basmati rice. Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERs) acetate extraction was applied and characteristic spectral data for each pesticide was obtained from the spiked matrix and analysed using handheld-SERS. This approach allowed detection limits within the matrix conditions to be markedly improved, due to the rapid aggregation of nanogold caused by the extraction medium. Thus, detection limits for three out of four pesticides were detectable below the Maximum Residue Limits (MRLs) of 10 ppb in Basmati rice. Furthermore, the multiplexing performance of handheld-SERS was assessed in solvent and matrix conditions. This study highlights the great potential of handheld-SERS for the rapid on-site detection of pesticide residues in rice and other commodities.

Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure.

Gaucher disease is caused by mutations in GBA1 encoding acid β-glucosidase (GCase). Saposin C enhances GCase activity and protects GCase from intracellular proteolysis. Structure simulations indicated that the mutant GCases, N370S (0 S), V394L (4L) and D409V(9V)/H(9H), had altered function. To investigate the in vivo function of Gba1 mutants, mouse models were generated by backcrossing the above homozygous mutant GCase mice into Saposin C deficient (C*) mice. Without saposin C, the mutant GCase activities in the resultant mouse tissues were reduced by ~50% compared with those in the presence of Saposin C. In contrast to 9H and 4L mice that have normal histology and life span, the 9H;C* and 4L;C* mice had shorter life spans. 9H;C* mice developed significant visceral glucosylceramide (GC) and glucosylsphingosine (GS) accumulation (GC»GS) and storage macrophages, but lesser GC in the brain, compared to 4L;C* mice that presents with a severe neuronopathic phenotype and accumulated GC and GS primarily in the brain. Unlike 9V mice that developed normally for over a year, 9V;C* pups had a lethal skin defect as did 0S;C* mice resembled that of 0S mice. These variant Gaucher disease mouse models presented a mutation specific phenotype and underscored the in vivo role of Saposin C in the modulation of Gaucher disease.

Surveillance of Staphylococcus aureus infections in 3 northern remote communities of Saskatchewan was undertaken. Rates of methicillin-resistant infections were extremely high (146-482/10,000 population), and most (98.2%) were caused by USA400 strains. Although USA400 prevalence has diminished in the United States, this strain is continuing to predominate throughout many northern communities in Canada.

A mid-level data fusion coupled with multivariate analysis approach is applied to dual-platform mass spectrometry data sets using Rapid Evaporative Ionization Mass Spectrometry and Inductively Coupled Plasma Mass Spectrometry to determine the correct classification of salmon origin and production methods. Salmon (n = 522) from five different regions and two production methods are used in the study. The method achieves a cross-validation classification accuracy of 100% and all test samples (n = 17) have their origins correctly determined, which is not possible with single-platform methods. Eighteen robust lipid markers and nine elemental markers are found, which provide robust evidence of the provenance of the salmon. Thus, we demonstrate that our mid-level data fusion - multivariate analysis strategy greatly improves the ability to correctly identify the geographical origin and production method of salmon, and this innovative approach can be applied to many other food authenticity applications.

Previous research revealed that the basal ganglia play a critical role in category learning [Ell, S. W., Marchant, N. L., & Ivry, R. B. (2006). Focal putamen lesions impair learning in rule-based, but not information-integration categorization tasks. Neuropsychologia, 44(10), 1737-1751; Maddox, W. T. & Filoteo, J. V. (2007). Modeling visual attention and category learning in amnesiacs, striatal-damaged patients and normal aging. In Advances in Clinical-cognitive science: formal modeling and assessment of processes and symptoms (pp. 113-146). Washington DC: American Psychological Association] but less is known about the specific role of prefrontal cortical (PFC) regions in category learning. The current study examined rule-based (RB) and information-integration (II) category learning in 13 patients with damage primarily to ventral PFC regions. After 600 learning trials with feedback, patients were significantly less accurate than matched controls on both RB and II learning. Model-based analysis identified subgroups of patients whose impaired performance in each task was due to the use of sub-optimal learning strategies. Those patients impaired at either II or RB learning, performed significantly worse on the Wisconsin Card Sorting Test, a test of abstract rule formation and the ability to shift and maintain rules. Lesion analysis pointed to damage in a fairly circumscribed region of ventral medial prefrontal cortex as common to the impaired group of patients and those patients without ventral PFC damage mostly performed normally. These results provide further evidence that the ventromedial prefrontal cortex is critically important for the ability to monitor and integrate feedback in order to select and maintain optimal learning strategies.

Gaucher disease results from GBA1 mutations that lead to defective acid β-glucosidase (GCase) mediated cleavage of glucosylceramide (GC) and glucosylsphingosine as well as heterogeneous manifestations in the viscera and CNS. The mutation, tissue, and age-dependent accumulations of different GC species were characterized in mice with Gba1 missense mutations alone or in combination with isolated saposin C deficiency (C*). Gba1 heteroallelism for D409V and null alleles (9V/null) led to GC excesses primarily in the visceral tissues with preferential accumulations of lung GC24∶0, but not in liver, spleen, or brain. Age-dependent increases of different GC species were observed. The combined saposin C deficiency (C*) with V394L homozygosity (4L;C*) showed major GC18:0 degradation defects in the brain, whereas the analogous mice with D409H homozygosity and C* (9H;C*) led to all GC species accumulating in visceral tissues. Glucosylsphingosine was poorly degraded in brain by V394L and D409H GCases and in visceral tissues by D409V GCase. The neonatal lethal N370S/N370S genotype had insignificant substrate accumulations in any tissue. These results demonstrate age, organ, and mutation-specific quantitative differences in GC species and glucosylsphingosine accumulations that can have influence in the tissue/regional expression of Gaucher disease phenotypes.

The pharmacological chaperone, isofagomine (IFG), enhances acid β-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFα levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates.

Automated MRI-derived measurements of in-vivo human brain volumes provide novel insights into normal and abnormal neuroanatomy, but little is known about measurement reliability. Here we assess the impact of image acquisition variables (scan session, MRI sequence, scanner upgrade, vendor and field strengths), FreeSurfer segmentation pre-processing variables (image averaging, B1 field inhomogeneity correction) and segmentation analysis variables (probabilistic atlas) on resultant image segmentation volumes from older (n=15, mean age 69.5) and younger (both n=5, mean ages 34 and 36.5) healthy subjects. The variability between hippocampal, thalamic, caudate, putamen, lateral ventricular and total intracranial volume measures across sessions on the same scanner on different days is less than 4.3% for the older group and less than 2.3% for the younger group. Within-scanner measurements are remarkably reliable across scan sessions, being minimally affected by averaging of multiple acquisitions, B1 correction, acquisition sequence (MPRAGE vs. multi-echo-FLASH), major scanner upgrades (Sonata-Avanto, Trio-TrioTIM), and segmentation atlas (MPRAGE or multi-echo-FLASH). Volume measurements across platforms (Siemens Sonata vs. GE Signa) and field strengths (1.5 T vs. 3 T) result in a volume difference bias but with a comparable variance as that measured within-scanner, implying that multi-site studies may not necessarily require a much larger sample to detect a specific effect. These results suggest that volumes derived from automated segmentation of T1-weighted structural images are reliable measures within the same scanner platform, even after upgrades; however, combining data across platform and across field-strength introduces a bias that should be considered in the design of multi-site studies, such as clinical drug trials. The results derived from the young groups (scanner upgrade effects and B1 inhomogeneity correction effects) should be considered as preliminary and in need for further validation with a larger dataset.

The volume of parcellated cortical regions is a composite measure related to both thickness and surface area. It is not clear whether volumetric decreases in medial temporal lobe (MTL) cortical regions in aging and Alzheimer's disease (AD) are due to thinning, loss of surface area, or both, nor is it clear whether aging and AD differ in their effects on these properties. Participants included 28 Younger Normals, 47 Older Normals, and 29 patients with mild AD. T1-weighted MRI data were analyzed using a novel semi-automated protocol (presented in a companion article) to delineate the boundaries of entorhinal (ERC), perirhinal (PRC), and posterior parahippocampal (PPHC) cortical regions and calculate their mean thickness, surface area, and volume. Compared to Younger Normals, Older Normals demonstrated moderately reduced ERC and PPHC volumes, which were due primarily to reduced surface area. In contrast, the expected AD-related reduction in ERC volume was produced by a large reduction in thickness with minimal additional effect (beyond that of aging) on surface area. PRC and PPHC also showed large AD-related reductions in thickness. Of all these MTL morphometric measures, ERC and PRC thinning were the best predictors of poorer episodic memory performance in AD. Although the volumes of MTL cortical regions may decrease with both aging and AD, thickness is relatively preserved in normal aging, while even in its mild clinical stage, AD is associated with a large degree of thinning of MTL cortex. These differential morphometric effects of aging and AD may reflect distinct biologic processes and ultimately may provide insights into the anatomic substrates of change in memory-related functions of MTL cortex.

This study used desorption electrospray ionisation mass spectrometry (DESI-MS) to analyse and detect and classify biomarkers in five different animal and plant sources of milk for the first time. A range of differences in terms of features was observed in the spectra of cow milk, goat milk, camel milk, soya milk, and oat milk. Chemometric modelling was then used to classify the mass spectra data, enabling unique or significant markers for each milk source to be identified. The classification of different milk sources was achieved with a cross-validation percentage rate of 100% through linear discriminate analysis (LDA) with high sensitivity to adulteration (0.1-5% v/v). The DESI-MS results from the milk samples analysed show the methodology to have high classification accuracy, and in the absence of complex sample clean-up which is often associated with authenticity testing, to be a rapid and efficient approach for milk fraud control.

External dose rates were measured 1 m away from 230 Lu-177 patients to characterise the variability in normalised dose rates as a function of administered activity, body mass index (BMI) and sex. The largest dose rate observed was 0.07 mSv/h associated with an administered activity of 7.2 GBq. Substantial variability was found in the distribution of the normalised dose rate associated that had an average of 0.0037 mSv/h per GBq and a 95% confidence interval of 0.0024-0.0058 mSv/h per GBq. Based on this study, estimating the patient dose rate based on the Lu-177 gamma exposure factor overestimates the dose rate by a factor of 2. A statistically significant inverse relationship was found between the patient dose rate and patient BMI and an empirically derived equation relating these two quantities was reported. On average, male patient dose rates were 3.5% lower than female dose rates, which may be attributed to the larger average BMI of the male patient group.