GM-CSF Promotes Immune Response and Survival in a Mouse Model of COVID-19.

COVID-19 results in increased expression of inflammatory cytokines, but inflammation-targeting clinical trials have yielded poor to mixed results. Our studies of other disorders with an inflammatory component, including Alzheimer's disease, chemobrain, Down syndrome, normal aging, and West Nile Virus infection, showed that treatment with the 'pro-inflammatory' cytokine granulocyte-macrophage colony stimulating factor (GM-CSF) in humans or mouse models alleviated clinical, behavioral, and pathological features. We proposed that human recombinant GM-CSF (sargramostim) be repurposed to promote both the innate and adaptive immune responses in COVID-19 to reduce viral load and mortality1. Here, we report the results of a placebo-controlled study of GM-CSF in human ACE2 transgenic mice inoculated intranasally with SARS-CoV2 virus, a model of COVID-19. Infection resulted in high viral titers in lungs and brains and over 85% mortality. GM-CSF treatment beginning one day after infection increased anti-viral antibody titers, lowered mean lung viral titers proportionately (p=0.0020) and increased the odds of long-term survival by up to 5.8-fold (p=0.0358), compared to placebo. These findings suggest that, as an activator of both the innate and adaptive immune systems, GM-CSF/sargramostim may be an effective COVID-19 therapy with the potential to protect from re-infection more effectively than treatment with antiviral drugs or monoclonal antibodies.

Quantitative magnetic resonance imaging and histological hoof wall assessment of 3-year-old Quarter Horses.

BACKGROUND: Few noninvasive methods are available for equine hoof wall evaluation. The highly organised wall structures and composition of proteoglycans and collagens may make this region amenable to quantitative MRI (qMRI) techniques of T1ρ and T2 mapping to identify pathology related to proteoglycan content and collagen organisation respectively. OBJECTIVE: To establish normative T1ρ and T2 values of the equine hoof wall of 3-year-old Quarter Horses with histological comparison. STUDY DESIGN: Cadaveric anatomical study. METHODS: Six cadaveric left thoracic feet from 3-year-old racing Quarter Horses with no reported lameness were evaluated using T1ρ and T2 mapping. Mapping was performed at six regions of interest at the toe of each hoof including proximal and distal regions of the inner epidermis, stratum lamellatum and corium. Histology was evaluated for standard hoof morphology and proteoglycan staining. RESULTS: T2 values of the stratum lamellatum and corium were similar (42.9 [95% CI: 41.6-44.2] ms and 44 [95% CI: 42.7-45.3] ms respectively), but both were significantly different to the inner epidermis (35.8 [95% CI: 34.5-37.1] ms, P<0.001). T1ρ values for the inner epidermis, stratum lamellatum and corium were significantly different (25.1 [95% CI: 23.1-27.1] ms, 44.4 [95% CI: 42.4-46.4] ms and 50.1 [95% CI: 48.1-52.1] ms, respectively, P<0.001). Histology demonstrated normal organised morphology. Proteoglycan staining was only visible in the stratum lamellatum and corium. MAIN LIMITATIONS: Cadaveric study with frozen samples used. CONCLUSIONS: Variation of qMRI metrics through the depth of the equine hoof wall was found. Although the highly ordered environment of collagen may contribute to T2 values, there was lack of evidence to support proteoglycan content as a major contributor of T1ρ values. It is possible T1ρ values had a greater dependence on total water content as the lowest values were seen in the epidermis. Additional research using qMRI is needed to determine mapping values in different disease states.

Poly(I:C) source, molecular weight and endotoxin contamination affect dam and prenatal outcomes, implications for models of maternal immune activation.

The viral mimetic polyinosinic:polycytidylic acid (poly(I:C)) is increasingly used to induce maternal immune activation (mIA) to model neurodevelopmental disorders (NDDs). Robust and reproducible phenotypes across studies are essential for the generation of models that will enhance our understanding of NDDs and enable the development of improved therapeutic strategies. However, differences in mIA-induced phenotypes using poly(I:C) have been widely observed, and this has prompted the reporting of useful and much needed methodological guidelines. Here, we perform a detailed investigation of molecular weight and endotoxin variations in poly(I:C) procured from two of the most commonly used suppliers, Sigma and InvivoGen. We demonstrate that endotoxin contamination and molecular weight differences in poly(I:C) composition lead to considerable variability in maternal IL-6 response in rats treated on gestational day (GD)15 and impact on fetal outcomes. Specifically, both endotoxin contamination and molecular weight predicted reductions in litter size on GD21. Further, molecular weight predicted a reduction in placental weight at GD21. While fetal body weight at GD21 was not affected by poly(I:C) treatment, male fetal brain weight was significantly reduced by poly(I:C), dependent on supplier. Our data are in agreement with recent reports of the importance of poly(I:C) molecular weight, and extend this work to demonstrate a key role of endotoxin on relevant phenotypic outcomes. We recommend that the source and batch numbers of poly(I:C) used should always be stated and that molecular weight variability and endotoxin contamination should be minimised for more robust mIA modelling.

Low light intensity in Pekin duck breeder barns has a greater impact on the fertility of drakes than hens.

The Pekin duck is an excellent model for the study of seasonal reproduction. To more completely understand the lighting requirements for maximal fertility in duck breeder houses, we housed adult (45 week old) drakes and hens in the Hope College aviary as 5 drakes and 25 hens. Light conditions in each floor pen were normalized based upon quantal energy and divided into the following categories: (1) to simulate summer, 14.5 h 65 lux with 9.5 h 1 lux; (2) to simulate winter, 8 h 65 lux with 16 h 1 lux; (3) winter augmented, 8 h 65 lux with 16 h at 15 lux. The experiment was repeated with rotation of light treatments among 3 pens until a final N = 6 was obtained. Daily, total number of eggs laid was tallied, and a daily average of eggs laid was calculated throughout the study. Weekly, eggs were weighed and the perivitilline membrane was assayed for the number of sperm holes as an indirect measure of drake fertility. As expected, winter conditions caused a reduction in the percent of eggs laid and a reduction in the number of fertilized eggs compared to the summer light conditions. The augmented winter light conditions prevented the loss in the percent eggs laid and fertilized eggs. Surprisingly, even after 4 wk of the study, the winter conditions did not cause a complete loss of fertility in the Pekin ducks. At the end of the study, no differences in the relative expression in brain deep brain photoreceptors or gonadotropin inhibitory hormone mRNAs were observed among any light treatment. Although a minimum (1 lux) of light can support some fertility, our findings suggest commercial Pekin duck barns may benefit from increasing the augmented light to 15 lux to maintain optimal fertility during winter months. Furthermore, our data suggest that drakes may be more sensitive to environmental light conditions than hens.

Immunolesion of melanopsin neurons causes gonadal regression in Pekin drakes (Anas platyrhynchos domesticus).

Several light sensitive receptors have been described in the avian brain that are thought to regulate the reproductive axis independently from the eyes and pineal gland. Recently, our lab has described the presence of three of these photoneuroendocrine systems in the Pekin duck: opsin, opsin 5, & melanopsin. We set out to test the hypothesis that melanopsin receptive neurons are necessary to maintain seasonal reproductive status along with growth and development in the Pekin drake. To accomplish these goals we first investigated 50-week-old Pekin drakes that were housed in the aviary at Hope College under long day length (18h lights on) conditions in floor pens. To specifically lesion melanopsin-receptive neurons, 3µl of an anti-melanopsin-saporin conjugate (MSAP, 100ng/ul) was injected into the lateral ventricle (n=10). Control drakes were injected with 3µl of equimolar unconjugated anti-melanopsin and saporin (SAP, n=10). Reproductive behaviors were analyzed weekly in a test pen with adult hens and MSAP drakes showed a significant (p<0.01) reduction in reproductive behaviors after week 2. After 5weeks, drakes were euthanized and body weights were measured, and brains, pituitaries, and testes collected and stored for analyses. Mature MSAP-treated drakes had significantly (p<0.001) reduced relative teste weights compared to SAP controls. qRT-PCR analyses of hypothalamus showed a significant reduction (p<0.001) in GnRH and melanopsin mRNA levels, but not opsin 5, vertebrate ancient opsin, or opsin 2 (rhodopsin). Immunocytochemical analyses showed a significant reduction (p<0.01) in tyrosine hydroxylase-immunoreactivity in the PMM. These data suggest that although blue light alone is not able to maintain testicular function, the blue-light sensitive melanopsin activity is critical to maintain gonadal function.

Does collagenase injection disrupt or digest the Dupuytren's cord: a magnetic resonance imaging study.

UNLABELLED: Collagenase clostridium histolyticum has been extensively studied as a treatment modality for Dupuytren's contracture. Its mechanism of action has been documented. It is unknown whether injected collagenase weakens the Dupuytren's cord sufficiently to cause failure during manipulation or if there is digestion and reduction in cord volume. We examined five patients with isolated contractures of the ring or middle metacarpalphalangeal (MP) joint using magnetic resonance imaging (MRI) prior to injection with collagenase and again 1 month following injection. All patients had full correction after manipulation which was maintained at follow-up. The Dupuytren's cord was evaluated with respect to volume, signal intensity, inflammatory changes and continuity. Additionally, signal intensity changes of the flexor tendons and neurovascular structures were recorded. MRI demonstrated cord discontinuity, significant reduction of cord volume and a significant increase in cord signal intensity after treatment with collagenase. There was a slight increase in flexor tendon signal intensity that was not significant. These findings suggest that there may be local chemical dissolution of the cord. Future studies may establish whether or not this will have prognostic implications in terms of correction and recurrence following collagenase injection. LEVEL OF EVIDENCE: IV.

Magnetic resonance imaging of an equine fracture model containing stainless steel metal implants.

REASONS FOR PERFORMING STUDY: Post operative imaging in subjects with orthopaedic implants is challenging across all modalities. Magnetic resonance imaging (MRI) is preferred to assess human post operative musculoskeletal complications, as soft tissue and bones are evaluated without using ionising radiation. However, with conventional MRI pulse sequences, metal creates susceptibility artefact that distorts anatomy. Assessment of the post operative equine patient is arguably more challenging due to the volume of metal present, and MRI is often not performed in horses with implants. Novel pulse sequences such as multiacquisition variable resonance image combination (MAVRIC) now provide improved visibility in the vicinity of surgical-grade implants and offer an option for imaging horses with metal implants. OBJECTIVES: To compare conspicuity of regional anatomy in an equine fracture-repair model using MAVRIC, narrow receiver bandwidth (NBW) fast spin echo (FSE), and wide receiver bandwidth (WBW) FSE sequences. STUDY DESIGN: Nonrandomised in vitro experiment. METHODS: MAVRIC, NBW FSE and WBW FSE were performed on 9 cadaveric distal limbs with fractures and stainless steel implants in the third metacarpal bone and proximal phalanx. Objective measures of artefact reduction were performed by calculating the total artefact area in each transverse image as a percentage of the total anatomic area. The number of transverse images in which fracture lines were visible was tabulated for each sequence. Regional soft tissue conspicuity was assessed subjectively. RESULTS: Overall anatomic delineation was improved using MAVRIC compared with NBW FSE; delineation of structures closest to the metal implants was improved using MAVRIC compared with WBW FSE and NBW FSE. Total artefact area was the highest for NBW FSE and lowest for MAVRIC; the total number of transverse slices with a visible fracture line was highest in MAVRIC and lowest in NBW FSE. CONCLUSION: MAVRIC and WBW FSE are feasible additions to minimise artefact around implants.

OARSI Clinical Trials Recommendations: Hip imaging in clinical trials in osteoarthritis.

Imaging of hip in osteoarthritis (OA) has seen considerable progress in the past decade, with the introduction of new techniques that may be more sensitive to structural disease changes. The purpose of this expert opinion, consensus driven recommendation is to provide detail on how to apply hip imaging in disease modifying clinical trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, artifacts associated with various MRI sequences); quality assurance/control procedures; measurement methods; measurement performance (reliability, responsiveness, and validity); recommendations for trials; and research recommendations.

Correlation of meniscal T2* with multiphoton microscopy, and change of articular cartilage T2 in an ovine model of meniscal repair.

OBJECTIVE: To correlate meniscal T2* relaxation times using ultra-short echo time (UTE) magnetic resonance imaging (MRI) with quantitative microscopic methods, and to determine the effect of meniscal repair on post-operative cartilage T2 values. DESIGN: A medial meniscal tear was created and repaired in the anterior horn of one limb of 28 crossbred mature ewes. MR scans for morphological evaluation, meniscal T2* values, and cartilage T2 values were acquired at 0, 4 and 8 months post-operatively for the Tear and Non-Op limb. Samples of menisci from both limbs were analyzed using multiphoton microscopy (MPM) analysis and biomechanical testing. RESULTS: Significantly prolonged meniscal T2* values were found in repaired limbs than in control limbs, P < 0.0001. No regional differences of T2* were detected for either the repaired or control limbs in the anterior horn. Repaired limbs had prolonged cartilage T2 values, primarily anteriorly, and tended to have lower biomechanical force to failure at 8 months than Non-Op limbs. MPM autofluorescence and second harmonic generation data correlated with T2* values at 8 months (ρ = -0.48, P = 0.06). CONCLUSIONS: T2* mapping is sensitive to detecting temporal and zonal differences of meniscal structure and composition. Meniscal MPM and cartilage T2 values indicate changes in tissue integrity in the presence of meniscal repair.

Mine water geochemistry and metal flux in a major historic Pb-Zn-F orefield, the Yorkshire Pennines, UK.

Recent studies have shown up to 6 % of rivers in England and Wales to be impacted by discharges from abandoned metal mines. Despite the large extent of impacts, there are still many areas where mine water impact assessments are limited by data availability. This study provides an overview of water quality, trace element composition and flux arising from one such area; the Yorkshire Pennine Orefield in the UK. Mine drainage waters across the orefield are characterised by Ca-HCO3-SO4-type waters, with moderate mineralization (specific electrical conductance: 160-525 µS cm(-1)) and enrichment of dissolved Zn (≤2003 µg L(-1)), Ba (≤971 µg L(-1)), Pb (≤183 µg L(-1)) and Cd (≤12 µg L(-1)). The major ion composition of the waters reflects the Carboniferous gritstone and limestone-dominated country rock, the latter of which is heavily karstified in parts of the orefield, while sulphate and trace element enrichment is a product of the oxidation of galena, sphalerite and barite mineralization. Contaminant flux measurements at discharge sites highlight the disproportionate importance of large drainage levels across the region, which generally discharge into first-order headwater streams. Synoptic metal loading surveys undertaken in the Hebden Beck sub-catchment of the river Wharfe highlight the importance of major drainage levels to instream baseflow contamination, with diffuse sources from identifiable expanses of waste rock becoming increasingly prominent as river flows increase.

MRI evaluation of rotational alignment and synovitis in patients with pain after total knee replacement.

Component malalignment can be associated with pain following total knee replacement (TKR). Using MRI, we reviewed 50 patients with painful TKRs and compared them with a group of 16 asymptomatic controls to determine the feasibility of using MRI in evaluating the rotational alignment of the components. Using the additional soft-tissue detail provided by this modality, we also evaluated the extent of synovitis within these two groups. Angular measurements were based on the femoral transepicondylar axis and tibial tubercle. Between two observers, there was very high interobserver agreement in the measurements of all values. Patients with painful TKRs demonstrated statistically significant relative internal rotation of the femoral component (p = 0.030). There was relative internal rotation of the tibial to femoral component and combined excessive internal rotation of the components in symptomatic knees, although these results were significant only with one of the observers (p = 0.031). There was a statistically significant association between the presence and severity of synovitis and painful TKR (p < 0.001). MRI is an effective modality in evaluating component rotational alignment.

Clinical and laboratory features of patients with myophosphorylase deficiency (McArdle disease).

Mutations of PYGM, the gene encoding human myophosphorylase, produce a metabolic myopathy characterised by exercise intolerance and, in some patients, myoglobinuria. To illustrate the clinical and laboratory features of myophosphorylase deficiency, we describe 10 patients diagnosed in Auckland, New Zealand, between 1989 and 2009. We review the clinical, biochemical, and histologic features and the results of mutation analysis. All patients reported exercise intolerance since childhood or the teenage years, starting within minutes of moderate or intense exertion. The "second wind" phenomenon, or myoglobinuria, were each reported in about half the patients. The serum creatine kinase concentration was elevated in all patients where this had been measured. Muscle biopsies revealed subsarcolemmal vacuolation and histochemical absence of myophosphorylase. Analysis of PYGM showed mutations in all alleles, most commonly Arg49Ter or Gly204Ser. One patient harbored a novel mutation, Pro488Arg, predicted to seriously disrupt the tertiary structure of the enzyme. Myophosphorylase deficiency produces a fairly uniform set of symptoms, and consistent elevation of the serum creatine kinase concentration. The diagnosis can be confirmed in most patients by mutation analysis using a blood sample.

Seasonal and spatial variation of diffuse (non-point) source zinc pollution in a historically metal mined river catchment, UK.

Quantifying diffuse sources of pollution is becoming increasingly important when characterising river catchments in entirety - a prerequisite for environmental management. This study examines both low and high flow events, as well as spatial variability, in order to assess point and diffuse components of zinc pollution within the River West Allen catchment, which lies within the northern England lead-zinc Orefield. Zinc levels in the river are elevated under all flow regimes, and are of environmental concern. Diffuse components are of little importance at low flow, with point source mine water discharges dominating instream zinc concentration and load. During higher river flows 90% of the instream zinc load is attributed to diffuse sources, where inputs from resuspension of metal-rich sediments, and groundwater influx are likely to be more dominant. Remediating point mine water discharges should significantly improve water quality at lower flows, but contribution from diffuse sources will continue to elevate zinc flux at higher flows.

Imaging near metal with a MAVRIC-SEMAC hybrid.

The recently developed multi-acquisition with variable resonance image combination (MAVRIC) and slice-encoding metal artifact correction (SEMAC) techniques can significantly reduce image artifacts commonly encountered near embedded metal hardware. These artifact reductions are enabled by applying alternative spectral and spatial-encoding schemes to conventional spin-echo imaging techniques. Here, the MAVRIC and SEMAC concepts are connected and discussed. The development of a hybrid technique that utilizes strengths of both methods is then introduced. The presented technique is shown capable of producing minimal artifact, high-resolution images near total joint replacements in a clinical setting.

Inventory of aquatic contaminant flux arising from historical metal mining in England and Wales.

The impact of discharges from abandoned metal and ironstone mines has been a much studied form of aquatic pollution in recent decades. Few attempts however, have been made to accurately determine the overall contaminant mass flux arising from abandoned mine sites at scales above catchment level. Such assessments are critical to determine the significance of former mining to national, regional and ultimately global trace metal flux. This paper presents the most comprehensive national survey to date across England and Wales of the total pollution burden discharged at source from abandoned non-coal mine sites. 338 discharges have been identified (from 4923 known abandoned metal mines) and while concurrent flow and contaminant concentration records are only available for around 30% of these, significant quantities of metals (and As) have been quantified to be discharged. A minimum of 193 tonnes of Zn, 18.5 tonnes of Pb, 0.64 tonnes Cd, 19.1 tonnes of Cu, 551 tonnes Fe, 72 tonnes Mn and 5.1 tonnes As are released in water discharges from abandoned non-coal mines to the surface water environment of England and Wales each year. Precautionary extrapolation of mass fluxes based on the frequency distribution of measured concentration and flow data, for discharges with absent data, suggests that the actual total mass flux for these contaminants could be up to 41% higher. The mass flux of Pb released from mines exceeds that of all currently permitted discharges (e.g. active industrial sites and wastewater treatment works) to surface waters across England and Wales, while those of As, Cd and Zn are of a similar magnitude. These data put into context the enduring legacy of historic mining on the water environment, highlighting its significance relative to more highly regulated polluting sites. Comparison of the figures with estimates of global trace metal flux suggests that the national total identified here is significant on a global scale.

Helicobacter species in the human colon.

OBJECTIVE: To determine the prevalence, frequency and colonization patterns of Helicobacter species throughout the colon. METHOD: Patients having initial colonoscopy for nonspecific gastrointestinal disturbance had colonic biopsies taken from up to four sites during colonoscopy and examined for evidence of the Helicobacteraceae family using a group-specific PCR. Serum was also collected and examined for IgG reactivity to Helicobacter pylori. RESULTS: 100 patients had colonoscopy of whom 35 were found to have DNA evidence of Helicobacter species throughout the colon, with 22 having H. pylori. Fifteen patients had a demonstrable serum IgG response to H. pylori that was not always associated with molecular evidence of H. pylori DNA in colon biopsies and vice versa. No specific association with colon disease was found in patients with H. pylori infection. CONCLUSION: We found evidence of Helicobacter infection in a significant number of patients presenting for colonoscopy but no specific association between the presence of these bacteria and colon disease. Our finding of disparity between molecular and serological techniques to detect Helicobacter species suggests that future studies should not rely on serology alone to detect these bacteria in the human colon.

Association of white matter hyperintensity measurements on brain MR imaging with cognitive status, medial temporal atrophy, and cardiovascular risk factors.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) are frequently characterized as markers of cerebrovascular disease, whereas medial temporal atrophy (MTA) is a recognized marker of Alzheimer disease (AD). Our purpose was to test the reliability of a visual rating system (VRS) in evaluating WMHs and MTA and in distinguishing healthy from cognitively impaired subjects. MATERIALS AND METHODS: Subjects (n = 192) enrolled in the Florida Alzheimer's Disease Research Center were diagnosed with no cognitive impairment, nonamnestic mild cognitive impairment (na-MCI), amnestic MCI (a-MCI), or probable AD. The severity of WMHs was assessed on T2-weighted fluid-attenuated inversion recovery axial MR images, and the severity of MTA was evaluated on 1.5-mm-thick coronal MR images by using a computer-based visual rating system. Cardiovascular risk factor scores were calculated as the sum of 10 independent cardiovascular risk factors. RESULTS: WMH and MTA scores were greater in subjects with probable AD, relative to those with no cognitive impairment and na-MCI. MTA scores differentiated subjects with a-MCI from those with no cognitive impairment and na-MCI. The total WMH score was significantly related to MTA (r = 0.39; P < .001) but not to cardiovascular risk factor scores (r = 0.07; P = not significant). The overall correct classification rate of probable AD versus no cognitive impairment by using MTA scores was 81.8%, improving to 86.5% when combined with WMH scores. CONCLUSIONS: Both MTA and WMH scores distinguished subjects with no cognitive impairment and probable AD. Combining MTA and WMH scores improved the correct classification rate, whereas WMH scores were significantly related to MTA scores, but not to cardiovascular risk factor scores. This finding suggests that among subjects with a-MCI and probable AD, WMHs on MR images are primarily associated with neurodegenerative disease.

A national strategy for identification, prioritisation and management of pollution from abandoned non-coal mine sites in England and Wales. I. Methodology development and initial results.

In regions affected by historic non-coal (principally metal) mining activity, government agencies are often faced with the challenge of deploying limited remedial resources at abandoned mine sites to achieve maximum improvements in the chemical and ecological quality of impacted ground and surface waters. As such, strategies for the defensible allocation of public funds require comprehensive and systematic frameworks by which to identify and prioritise polluting sites for remediation. This paper describes the development and initial findings of such a national initiative in England and Wales which allies catchment-scale environmental impact assessments using existing public archive data, with recognition of the uncertainty in impact appraisals arising from disparities in data availability between sites and regions. The methodology identifies polluting sites and takes account not only of the chemical and ecological impacts of mine water discharges on receiving watercourses, but also of socio-economic factors such as conservation and heritage concerns, which can both impede or complement efforts to remediate mine sites. Using a Geographic Information System database and a suite of spatial analyses employing Boolean operators, both the extent of the pollution problem from abandoned non-coal mines in England and Wales (6% of 7815 surface water bodies are affected nationally) and the insight that can be gleaned from systematic analyses of existing archive data are highlighted. The results of the nationwide survey can be used as a dynamic database to inform future remedial planning, in terms of prioritising impacted river basins and abandoned non-coal mine sites themselves for either remediation or future monitoring efforts. As the assessment framework is built upon existing water quality and ecological data and mine site/geological data, there is considerable scope for the approach to be applied elsewhere where the legacy of historic mining persists through the widespread pollution of the aquatic environment.

Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease.

OBJECTIVE: Much of what is known about the inflammatory response in the synovial membrane (SM) of patients with osteoarthritis (OA) comes from studies of synovial tissues from end-stage disease. In this study, we sought to better characterize the inflammatory infiltrate in symptomatic patients with early signs of knee OA, and to determine how inflammatory cell populations relate to the pattern of cytokine and degradative enzyme production. METHODS: Study populations comprised patients with degenerative meniscal tears and early cartilage thinning undergoing arthroscopic procedures (early OA) and patients undergoing total knee replacement for end-stage OA. Quantitative real-time polymerase chain reaction (PCR) was used to measure expression of SM cytokines and enzymes implicated in the pathogenesis of inflammatory arthritis and OA, as well as cell lineage-specific markers. We quantified synovial fluid (SF) cytokines and enzymes by enzyme-linked immunosorbent assay (ELISA) and SM cell populations by immunohistochemistry. RESULTS: We found increased levels of SF interleukin-15 (IL-15) protein in the early knee OA patients when compared to end-stage OA. Both SF IL-15 protein and numbers of CD8 cells within SM correlated with matrix metalloproteinase-1 (MMP-1) and three levels. TNF-alpha, IL-6 and IL-21 were also detectable in the SF of the majority of patients, and IL-15 levels were associated with IL-6 levels. CONCLUSION: IL-15 is elevated in early knee OA, suggesting activation of an innate immune response in the SM. The association of IL-15 expression with CD8 transcripts and MMPs implicates this cytokine in OA pathogenesis and as a candidate therapeutic target.

Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease.

BACKGROUND: Despite convenience, accessibility, and strong correlation to severity of Alzheimer disease (AD) pathology, medial temporal lobe atrophy (MTA) has not been used as a criterion in the diagnosis of prodromal and probable AD. METHODS: Using a newly validated visual rating system, mean MTA scores of three bilateral medial temporal lobe structures were compared for subjects with no cognitive impairment (NCI) (n = 117), nonamnestic mild cognitive impairment (MCI) (n = 46), amnestic MCI (n = 45), and probable AD (n = 53). Correlations between MTA scores and neuropsychological test scores at baseline, and predictors of change in diagnosis at 1-year follow-up were evaluated. RESULTS: With NCI as the reference group, a mean MTA cut score of 1.33 yielded an optimal sensitivity/specificity of 85%/82% for probable AD subjects and 80%/82% for amnestic MCI subjects. MTA and Clinical Dementia Rating Sum of Boxes scores at baseline were independent and additive predictors of diagnosis at baseline, and of transition from NCI to MCI or from MCI to dementia at 1-year follow-up. CONCLUSION: Medial temporal lobe atrophy (MTA) scores 1) distinguish probable Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI) subjects from nonamnestic MCI and no cognitive impairment (NCI) subjects, 2) help predict diagnosis at baseline, and 3) predict transition from NCI to MCI and from MCI to probable AD. MTA scores should be used as a criterion in the clinical diagnosis of AD.