Persistence and removal of trace organic compounds in centralized and decentralized wastewater treatment systems.

The persistence of trace organic chemicals in treated effluent derived from both centralized wastewater treatment plants (WWTPs) and decentralized wastewater treatment systems (DEWATS) is of concern due to their potential impacts on human and ecosystem health. Here, we utilize non-targeted analysis (NTA) with comprehensive two-dimensional gas chromatography coupled with time of flight mass spectrometry (GC × GC/TOF-MS) to conduct an evaluation of the common persistent and removed compounds found in two centralized WWTPs in the USA and South Africa and one DEWATS in South Africa. Overall, removal efficiencies of chemicals were similar between the treatment plants when they were compared according to the number of chemical features detected in the influents and effluents of each treatment plant. However, the DEWATS treatment train, which has longer solids retention and hydraulic residence times than both of the centralized WWTPs and utilizes primarily anaerobic treatment processes, was able to remove 13 additional compounds and showed a greater decrease in normalized peak areas compared to the centralized WWTPs. Of the 111 common compounds tentatively identified in all three influents, 11 compounds were persistent in all replicates, including 5 compounds not previously reported in effluents of WWTPs or water reuse systems. There were no significant differences among the physico-chemical properties of persistent and removed compounds, but significant differences were observed among some of the molecular descriptors. These results have important implications for the treatment of trace organic chemicals in centralized and decentralized WWTPs and the monitoring of new compounds in WWTP effluent.

Isothermal drying characteristics and kinetics of human faecal sludges.

Background: Drying is an important step for the thermochemical conversion of solid fuels, but it is energy-intensive for treating highly moist materials. Methods: To inform the thermal treatment of faecal sludge (FS), this study investigated the drying characteristics and kinetics of various faecal wastes using thermogravimetric analysis and isothermal heating conditions. Results: The findings show that FS from anaerobic baffled reactor (ABR) and ventilated improved pit (VIP) latrines exhibit similar drying characteristics, with maximum drying rates at 0.04 mg/min during a constant rate period that is followed by a distinct falling rate period. On the contrary, fresh human faeces (HF) and FS from urine-diverting dry toilets (UDDT) exhibited a falling rate period regime with no prior or intermittent constant rate periods. The absence of constant rate period in these samples suggested limited amounts of unbound water that can be removed by dewatering and vice versa for VIP and ABR faecal sludges. The activation energies and effective moisture diffusivity for the sludges varied from 20 to 30 kJ/mol and 3∙10 -7 to 1∙10 -5 m 2/s at 55°C and sludge thickness of 3mm. The Page model was consistent in modelling the different sludges across all temperatures. Conclusions: These results presented in this study can inform the design and development of innovative drying methods for FS treatment.

LC-MS/MS determination of antiretroviral drugs in influents and effluents from wastewater treatment plants in KwaZulu-Natal, South Africa.

South Africa has the largest occurrence of the human immune deficiency virus (HIV) in the world but has also implemented the largest antiretroviral (ARV) treatment programme. It was therefore of interest to determine the presence and concentrations of commonly used antiretroviral drugs (ARVDs) and, also, to determine the capabilities of wastewater treatment plants (WWTPs) for removing ARVDs. To this end, a surrogate standard based LC-MS/MS method was optimized and applied for the detection of thirteen ARVDs used in the treatment and management of HIV/acquired immune deficiency syndrome (HIV/AIDS) in two major and one modular WWTP in the eThekwini Municipality in KwaZulu-Natal, South Africa. The method was validated and the detection limits fell within the range of 2-20 ng L-1. The analytical recoveries for the ARVDs were mainly greater than 50% with acceptable relative standard deviations. The concentration values ranged from

Moving from laboratory to real life conditions: Influence on the assessment of variability and stability of gait.

The availability of wearable sensors allows shifting gait analysis from the traditional laboratory settings, to daily life conditions. However, limited knowledge is available about whether alterations associated to different testing environment (e.g. indoor or outdoor) and walking protocols (e.g. free or controlled), result from actual differences in the motor behaviour of the tested subjects or from the sensitivity to these changes of the indexes adopted for the assessment. In this context, it was hypothesized that testing environment and walking protocols would not modify motor control stability in the gait of young healthy adults, who have a mature and structured gait pattern, but rather the variability of their motor pattern. To test this hypothesis, data from trunk and shank inertial sensors were collected from 19 young healthy participants during four walking tasks in different environments (indoor and outdoor) and in both controlled (i.e. following a predefined straight path) and free conditions. Results confirmed what hypothesized: variability indexes (Standard deviation, Coefficient of variation and Poincaré plots) were significantly influenced by both environment and walking conditions. Stability indexes (Harmonic ratio, Short term Lyapunov exponents, Recurrence quantification analysis and Sample entropy), on the contrary, did not highlight any change in the motor control. In conclusion, this study highlighted an influence of environment and testing condition on the assessment of specific characteristics of gait (i.e. variability and stability). In particular, for young healthy adults, both environment and testing conditions affect gait variability indexes, whereas neither affect gait stability indexes.

Detection and characterisation of bone destruction in murine rheumatoid arthritis using statistical shape models.

Rheumatoid arthritis (RA) is an autoimmune disease in which chronic inflammation of the synovial joints can lead to destruction of cartilage and bone. Pre-clinical studies attempt to uncover the underlying causes by emulating the disease in genetically different mouse strains and characterising the nature and severity of bone shape changes as indicators of pathology. This paper presents a fully automated method for obtaining quantitative measurements of bone destruction from volumetric micro-CT images of a mouse hind paw. A statistical model of normal bone morphology derived from a training set of healthy examples serves as a template against which a given pathological sample is compared. Abnormalities in bone shapes are identified as deviations from the model statistics, characterised in terms of type (erosion / formation) and quantified in terms of severity (percentage affected bone area). The colour-coded magnitudes of the deviations superimposed on a three-dimensional rendering of the paw show at a glance the severity of malformations for the individual bones and joints. With quantitative data it is possible to derive population statistics characterising differences in bone malformations for different mouse strains and in different anatomical regions. The method was applied to data acquired from three different mouse strains. The derived quantitative indicators of bone destruction have shown agreement both with the subjective visual scores and with the previous biological findings. This suggests that pathological bone shape changes can be usefully and objectively identified as deviations from the model statistics.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to-or adding-another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.

Urine diversion dry toilets in eThekwini Municipality, South Africa: acceptance, use and maintenance through users' eyes.

This study was part of the VUNA project aimed to develop an affordable sanitation system that produces a valuable fertiliser, reduces pollution of water resources and promotes health. Urine diversion dry toilets (UDDTs) simplify the on-site hygienisation of faeces and allow for nutrient recovery from urine. Social acceptance is vital for the implementation of the UDDT, because sanitation is only effective if the system not only provides a well-designed toilet and effective waste management, but also offers users a facility that caters to their needs and is sensitive to their cultural lifestyle. This study used qualitative and quantitative methods to investigate acceptance, use and maintenance of UDDTs. Key findings indicate lower levels of acceptance of UDDTs among the elderly, who are accustomed to traditional pit toilets. The users aspire to own a flush toilet, perceived to be indicative of household wealth. A dominant concern was emptying the pit and the quality of the building material. Community interventions are required that will promote acceptance, understanding and encourage proper use and maintenance of the UDDT, and may need some technology modification. There is an urgent need for increased community participation to address users' perceptions, attitudes and behaviour concerning the UDDT.

Post-mortem histopathology underlying ß-amyloid PET imaging following flutemetamol F 18 injection.

In vivo imaging of fibrillar ß-amyloid deposits may assist clinical diagnosis of Alzheimer's disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [18F]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar ß-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of ß-amyloid pathology in AD and other dementing and non-dementing disease groups. The GE067-026 trial demonstrated 91% sensitivity and 90% specificity of [18F]flutemetamol PET by majority read for the presence of moderate or frequent plaques. The probability of an abnormal [18F]flutemetamol scan increased with neocortical plaque density and AD diagnosis. All dementia cases with non-AD neurodegenerative diseases and those without histopathological features of ß-amyloid deposits were [18F]flutemetamol negative. Majority PET assessments accurately reflected the amyloid plaque burden in 90% of cases. However, ten cases demonstrated a mismatch between PET image interpretations and post-mortem findings. Although tracer retention was best associated with amyloid in neuritic plaques, amyloid in diffuse plaques and cerebral amyloid angiopathy best explain three [18F]flutemetamol positive cases with mismatched (sparse) neuritic plaque burden. Advanced cortical atrophy was associated with the seven false negative [18F]flutemetamol images. The interpretation of images from pathologically equivocal cases was associated with low reader confidence and inter-reader agreement. Our results support that amyloid in neuritic plaque burden is the primary form of ß-amyloid pathology detectable with [18F]flutemetamol PET imaging. ClinicalTrials.gov NCT01165554. Registered June 21, 2010; NCT02090855. Registered March 11, 2014.

Perceptions of risk and predictive testing held by the first-degree relatives of patients with rheumatoid arthritis in England, Austria and Germany: a qualitative study.

OBJECTIVES: The family members of patients with rheumatoid arthritis (RA) are at increased risk of developing RA and are potential candidates for predictive testing. This study explored the perceptions of first-degree relatives of people with RA about being at risk of RA and engaging in predictive testing. METHODS: 34 first-degree relatives (siblings and offspring) of patients with RA from the UK, Germany and Austria participated in semistructured interviews about their perceptions of RA risk and the prospect of predictive testing. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: First-degree relatives were aware of their susceptibility to RA, but were unsure of the extent of their risk. When considering their future risk, some relatives were concerned about the potential impact that RA would have on their lives. Relatives were concerned that knowing their actual risk would increase their anxiety and would affect decisions about their future. Also, relatives were concerned about the levels of uncertainty associated with predictive testing. Those in favour of knowing their future risk felt that they would need additional support to understand the risk information and cope with the emotional impact of this information. CONCLUSIONS: Identifying individuals at risk of RA may allow targeted interventions to reduce the risk and consequence of future disease; however, relatives have concerns about predictive testing and risk information. The development of strategies to quantify and communicate risk needs to take these views into account and incorporate approaches to mitigate concerns and minimise the psychological impact of risk information.

Periodontitis prevalence and serum antibody reactivity to periodontal bacteria in primary Sjögren's syndrome: a pilot study.

AIMS: The aims of this study were as follows: (i) To assess the prevalence of periodontitis among patients with primary Sjögren's syndrome (pSS) and comparator groups of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). (ii) To perform a pilot study to compare serum antibody responses to 10 oral/periodontal bacteria in these patient groups and a historical comparator group of patients with periodontitis. MATERIALS AND METHODS: Standard clinical periodontal assessments were performed on 39 pSS, 36 RA and 23 OA patients and "In-house" antibody ELISAs for serum antibodies against 10 oral/periodontal bacteria were performed in these groups. RESULTS: Forty-six percent of the pSS group, 64% of the RA group and 48% of the OA group had moderate/severe periodontitis. These frequencies did not reach statistical significance between groups. Raised antibody levels to Prevotella denticola were found in the pSS, RA and periodontitis groups compared to the OA group. Significant between group differences were seen for Aggregatibacter actinomycetemcomitans, Prevotella intermedia and Campylobacter showae. None of these differences were specifically associated with pSS. CONCLUSION: This study showed no increase in periodontitis in pSS patients. Although the P. denticola data are of interest, identifying bacterial triggering factors for pSS will likely require alternative strategies including modern techniques such as microbiome analysis.

Parametric imaging and quantitative analysis of the PET amyloid ligand [(18)F]flutemetamol.

OBJECTIVES: The amyloid imaging PET tracer [(18)F]flutemetamol was recently approved by regulatory authorities in the US and EU for estimation of ß-amyloid neuritic plaque density in cognitively impaired patients. While the clinical assessment in line with the label is a qualitative visual assessment of 20 min summation images, the aim of this work was to assess the performance of various parametric analysis methods and standardized uptake value ratio (SUVR), in comparison with arterial input based compartment modeling. METHODS: The cerebellar cortex was used as reference region in the generation of parametric images of binding potential (BPND) using multilinear reference tissue methods (MRTMo, MRTM, MRTM2), basis function implementations of the simplified reference tissue model (here called RPM) and the two-parameter version of SRTM (here called RPM2) and reference region based Logan graphical analysis. Regionally averaged values of parametric results were compared with the BPND of corresponding regions from arterial input compartment modeling. Dynamic PET data were also pre-filtered using a 3D Gaussian smoothing of 5mm FWHM and the effect of the filtering on the correlation was investigated. In addition, the use of SUVR images was evaluated. The accuracy of several kinetic models were also assessed through simulations of time-activity curves based on clinical data for low and high binding adding different levels of statistical noise representing regions and individual voxels. RESULTS: The highest correlation was observed for pre-filtered reference Logan, with correction for individual reference region efflux rate constant k2' (R(2)=0.98), or using a cohort mean k2' (R(2)=0.97). Pre-processing filtered MRTM2, unfiltered SUVR over the scanning window 70-90 min and unfiltered RPM also demonstrated high correlations with arterial input compartment modeling (MRTM2 R(2)=0.97, RPM R(2)=0.96 and SUVR R(2)=0.95) Poorest agreement was seen with MRTM without pre-filtering (R(2)=0.68). CONCLUSIONS: Parametric imaging allows for quantification without introducing bias due to selection of anatomical regions, and thus enables objective statistical voxel-based comparisons of tracer binding. Several parametric modeling approaches perform well, especially after Gaussian pre-filtering of the dynamic data. However, the semi-quantitative use of SUVR between 70 and 90 min has comparable agreement with full kinetic modeling, thus supporting its use as a simplified method for quantitative assessment of tracer uptake.

To what extent can portable fluorescence spectroscopy be used in the real-time assessment of microbial water quality?

The intrinsic fluorescence of aquatic organic matter emitted at 350 nm when excited at 280 nm correlates widely with water quality parameters such as biochemical oxygen demand. Hence, in sewage-impacted rivers and groundwater, it might be expected that fluorescence at these wavelengths will also correlate with the microbial water quality. In this paper we use a portable fluorimeter to assess the relationship between fluorescence intensity at this wavelength pair and Escherichia coli enumeration in contrasting river catchments of poor water quality: in KwaZulu-Natal, S. Africa and the West Midlands, UK. Across all catchments we demonstrate a log correlation (r = 0.74) between fluorescence intensity and E. coli over a seven-log range in E. coli enumerations on non-perturbed (unfiltered) samples. Within specific catchments, the relationship between fluorescence intensity and E. coli is more variable, demonstrating the importance of catchment-specific interference. Our research demonstrates the potential of using a portable fluorimeter as an initial screening tool for indicative microbial water quality, and one that is ideally suited to simple pollution scenarios such as assessing the impact of faecal contamination in river or groundwater at specific sites.

Automated quantification of 18F-flutemetamol PET activity for categorizing scans as negative or positive for brain amyloid: concordance with visual image reads.

UNLABELLED: Clinical trials of the PET amyloid imaging agent (18)F-flutemetamol have used visual assessment to classify PET scans as negative or positive for brain amyloid. However, quantification provides additional information about regional and global tracer uptake and may have utility for image assessment over time and across different centers. Using postmortem brain neuritic plaque density data as a truth standard to derive a standardized uptake value ratio (SUVR) threshold, we assessed a fully automated quantification method comparing visual and quantitative scan categorizations. We also compared the histopathology-derived SUVR threshold with one derived from healthy controls. METHODS: Data from 345 consenting subjects enrolled in 8 prior clinical trials of (18)F-flutemetamol injection were used. We grouped subjects into 3 cohorts: an autopsy cohort (n = 68) comprising terminally ill patients with postmortem confirmation of brain amyloid status; a test cohort (n = 172) comprising 33 patients with clinically probable Alzheimer disease, 80 patients with mild cognitive impairment, and 59 healthy volunteers; and a healthy cohort of 105 volunteers, used to define a reference range for SUVR. Visual image categorizations for comparison were from a previous study. A fully automated PET-only quantification method was used to compute regional neocortical SUVRs that were combined into a single composite SUVR. An SUVR threshold for classifying scans as positive or negative was derived by ranking the PET scans from the autopsy cohort based on their composite SUVR and comparing data with the standard of truth based on postmortem brain amyloid status for subjects in the autopsy cohort. The derived threshold was used to categorize the 172 scans in the test cohort as negative or positive, and results were compared with categorization using visual assessment. Different reference and composite region definitions were assessed. Threshold levels were also compared with corresponding thresholds derived from the healthy group. RESULTS: Automated quantification (using pons as the reference region) demonstrated 91% sensitivity and 88% specificity and gave 3 false-positive and 4 false-negative scans. All 3 false-positive cases were either borderline-normal by standard of truth or had moderate to heavy cortical diffuse plaque burden. In the test cohort, the concordance between quantitative and visual read categorization ranged from 97.1% to 99.4% depending on the selection of reference and composite regions. The threshold derived from the healthy group was close to the histopathology-derived threshold. CONCLUSION: Categorization of (18)F-flutemetamol amyloid imaging data using an automated PET-only quantification method showed good agreement with histopathologic classification of neuritic plaque density and a strong concordance with visual read results.

Prospective flutemetamol positron emission tomography and histopathology in normal pressure hydrocephalus.

UNLABELLED: BACKGOUND/OBJECTIVE: To determine the level of association between uptake of the amyloid positron emission tomography (PET) imaging agent [(18)F]flutemetamol and the level of amyloid-ß measured by immunohistochemical and histochemical staining in a frontal cortical region biopsy site. METHODS: Seventeen patients with probable normal pressure hydrocephalus (NPH) underwent prospective [(18)F]flutemetamol PET and subsequent frontal cortical brain biopsy during ventriculoperitoneal shunting. Tissue amyloid-ß was evaluated using the monoclonal antibody 4G8, thioflavin S and Bielschowsky silver stain. RESULTS: Four of the 17 patients (23.5%) had amyloid-ß pathology based on the overall pathology read and also showed increased [(18)F]flutemetamol uptake. [(18)F]Flutemetamol standardized uptake values from the biopsy site were significantly associated with biopsy specimen amyloid-ß levels (Pearson's r = 0.67; p = 0.006). There was also good correlation between the biopsy specimen amyloid-ß level and uptake of [(18)F]flutemetamol in the region contralateral to the biopsy site (r = 0.67; p = 0.006), as well as with composite cortical [(18)F]flutemetamol uptake (r = 0.65; p = 0.008). The blinded visual read showed a high level of agreement between all readers (κ = 0.88). Two of 3 readers were in full agreement on all images; 1 reader disagreed on 1 of the 17 NPH cases. Blinded visual assessments of PET images by 1 reader were associated with 100% sensitivity to the overall pathology read, and assessments by the 2 others were associated with 75% sensitivity (overall sensitivity by majority read was 75%); specificity of all readers was 100%. CONCLUSIONS: [(18)F]Flutemetamol detects brain amyloid-ß in vivo and shows promise as a valuable tool to study and possibly facilitate diagnosis of Alzheimer's disease both in patients with suspected NPH and among the wider population.

Using the Receptivity model to uncover 'urine blindness': perceptions on the re-use of urine.

Population growth, climatic changes and over-exploitation of natural resources are at the basis of the world's food crisis, which counts almost one million people without sufficient food sustenance. These changes require novel environmental practices which are based on nutrient recovery and management in agriculture. This contribution analyses and discusses users' perceptions on re-use of urine as fertilizer through the lenses of the Receptivity model. A search was performed on Scopus (as well as other web search engines) using the keywords: urine, nutrient recovery and sanitation. Results shows how questions related to awareness, association, acquisition and application of the environmental change can represent hurdles to novel models of nutrient recovery and the use of urine in agriculture. Examples of hurdles identified from the literature relate to poor understanding of potential for urine reuse, social stigma attached to using dry sanitation and applying urine in agriculture and poor operational knowledge of application of urine in agriculture. Conclusion relates to the illustration of implications of such challenges on the design of environmental interventions.

An in vivo evaluation of cerebral cortical amyloid with [18F]flutemetamol using positron emission tomography compared with parietal biopsy samples in living normal pressure hydrocephalus patients.

PURPOSE: The primary objectives of this study were to assess the safety of [(18)F]flutemetamol injection and determine the level of association between the quantitative estimates of brain uptake of [(18)F]flutemetamol and the quantitative immunohistochemical (IHC) estimates of amyloid levels in cerebral cortex biopsies obtained during shunt placement in patients with normal pressure hydrocephalus (NPH). PROCEDURES: Parietal lobe biopsies were obtained from 12 subjects (mean (SD), 71 (8.1) years), during shunt placement for NPH. Shunt procedures and biopsies were performed within 8 weeks after the positron emission tomography (PET) imaging, and followed by a computed tomography scan. The quantitative estimates of the brain uptake of [(18)F]flutemetamol (standard uptake value ratios (SUVRs)) from the biopsy site, contralateral to the biopsy site, and composite were made from the analysis of PET images. The quantitative IHC levels of amyloid load were estimated using a monoclonal antiamyloid ß antibody, 4 G8 (in percent area), as the standard of truth (N = 8, of which 5 had full histopathology staining). The primary analysis determined the level of association between the SUVR (with cerebellum as the reference region) from the biopsy site, and the level of amyloid was determined from IHC estimates of amyloid in the biopsy sample. RESULTS: [(18)F]Flutemetamol injection was found to be well tolerated. The biopsied area well represented the amyloid deposition throughout the cortex in this small sample. The biopsy site SUVR was significantly correlated with the biopsy specimen amyloid ß level (expressed as percent of biopsy specimen area staining with 4 G8). The full model was significant (p = 0.0174). In the secondary efficacy analyses, contralateral (to biopsy site) and composite SUVR values correlated significantly with the percent of biopsy specimen staining for amyloid ß based on 4 G8. Blinded visual [(18)F]flutemetamol image interpretations showed a sensitivity of 100 % and a specificity of 100 % with pathology reads staining for amyloid plaque with Bielschowsky and thioflavin S and overall pathology read. The results of the blinded reader agreement for [(18)F]flutemetamol PET showed full agreement among three readers. CONCLUSIONS: PET imaging of NPH patients following the administration of [(18)F]flutemetamol injection was highly correlated with the presence of fibrillar amyloid ß in subsequent cortical biopsy samples in this small sample. Administration of [(18)F]flutemetamol injection was well tolerated.

[(18)F]Flutemetamol PET imaging and cortical biopsy histopathology for fibrillar amyloid ß detection in living subjects with normal pressure hydrocephalus: pooled analysis of four studies.

Molecular imaging techniques developed to 'visualize' amyloid in vivo represent a major achievement in Alzheimer's disease (AD) research. This pooled analysis of four studies determined the level of association between uptake of the fibrillar amyloid ß positron emission tomography (PET) imaging agent [(18)F]flutemetamol (Pittsburgh Compound B analog with a 5.5 times longer half-life to enable it to be used in the clinical setting) and neuritic plaques and fibrillar amyloid ß measured by pathologic staining of cortical region biopsy samples. Fifty-two patients with suspected normal pressure hydrocephalus underwent prospective (n = 30) or retrospective (n = 22) [(18)F]flutemetamol PET imaging for detection of cerebral cortical fibrillar amyloid ß and cortical brain biopsy during intracranial pressure measurement or ventriculo-peritoneal shunting. [(18)F]Flutemetamol uptake was quantified using standardized uptake value ratio (SUVR) with cerebellar cortex as the reference region. Tissue fibrillar amyloid ß was evaluated using immunohistochemical monoclonal antibody 4G8 and histochemical agents Thioflavin S and Bielschowsky silver stain, and an overall pathology result based on all available immunohistochemical and histochemical results. Biopsy site and contralateral [(18)F]flutemetamol SUVRs were significantly associated with neuritic plaque burden assessed with Bielschowsky silver stain (r (spearman's) = 0.61, p = 0.0001 for both), as was the composite SUVR with biopsy pathology (r (spearman's) = 0.74, p < 0.0001). SUVR and immunohistochemical results with 4G8 for detecting fibrillar amyloid ß were similar. Blinded image evaluation showed strong agreement between readers (κ = 0.86). Overall sensitivity and specificity by majority read were 93 and 100 %. Noninvasive in vivo [(18)F]flutemetamol PET imaging demonstrates strong concordance with histopathology for brain fibrillar amyloid ß, supporting its promise as a tool to assist physicians with earlier detection of the disease process and making diagnostic decisions about concomitant AD and other diseases associated with brain amyloidosis.

Tissue stroma as a regulator of leukocyte recruitment in inflammation.

The stromal milieu (cellular and matrix components) helps establish tissue "address-codes" that direct leukocyte behavior in inflamed tissue. Coordinated interactions among the stroma, leukocytes, and ECs dictate which leukocytes are recruited, whether they are retained within the inflamed site, and how long they survive. Herein, we discuss how the stromal milieu influences the leukocyte recruitment cascade. Moreover, we explore how corruption of the stromal phenotype in chronic inflammatory diseases contributes to undesired, continuous recruitment of leukocytes. Emerging complex, multicellular, multilayered (co-)culture models are now addressing the molecular circuitry involved in regulating stromal organization during inflammation. Understanding context-specific changes in pro- or anti-inflammatory agents derived from the stroma, such as IL-6 (and its cofactors), is important for the generation of therapeutic strategies that restore the balance between recruitment and clearance of the inflammatory infiltrate in chronic disease.

The role of non-hematopoietic stromal cells in the persistence of inflammation.

Inflammation results from the complex interaction between hematopoietic and stromal cells and growing evidence supports a key role for the stroma in driving the switch from acute resolving to persistence in chronic inflammatory diseases. Stromal cells have also been shown to play a critical role in cancer biology, being involved in cancer growth, dissemination, and inhibition of the autologous immune response, ultimately favoring persistence and metastatic spread. Similarly, blood and lymphatic endothelial cells contribute to tissue homeostasis during physiological inflammation but also lead to discorded leukocyte and tumor cell accumulation in pathological inflammation and cancer. This review aims to summarize the role that pathogenic stroma plays in the pathogenesis of diseases such as cancer and chronic inflammation.