Common and dissociable regional cerebral blood flow differences associate with dimensions of psychopathology across categorical diagnoses.

The high comorbidity among neuropsychiatric disorders suggests a possible common neurobiological phenotype. Resting-state regional cerebral blood flow (CBF) can be measured noninvasively with magnetic resonance imaging (MRI) and abnormalities in regional CBF are present in many neuropsychiatric disorders. Regional CBF may also provide a useful biological marker across different types of psychopathology. To investigate CBF changes common across psychiatric disorders, we capitalized upon a sample of 1042 youths (ages 11-23 years) who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. CBF at rest was quantified on a voxelwise basis using arterial spin labeled perfusion MRI at 3T. A dimensional measure of psychopathology was constructed using a bifactor model of item-level data from a psychiatric screening interview, which delineated four factors (fear, anxious-misery, psychosis and behavioral symptoms) plus a general factor: overall psychopathology. Overall psychopathology was associated with elevated perfusion in several regions including the right dorsal anterior cingulate cortex (ACC) and left rostral ACC. Furthermore, several clusters were associated with specific dimensions of psychopathology. Psychosis symptoms were related to reduced perfusion in the left frontal operculum and insula, whereas fear symptoms were associated with less perfusion in the right occipital/fusiform gyrus and left subgenual ACC. Follow-up functional connectivity analyses using resting-state functional MRI collected in the same participants revealed that overall psychopathology was associated with decreased connectivity between the dorsal ACC and bilateral caudate. Together, the results of this study demonstrate common and dissociable CBF abnormalities across neuropsychiatric disorders in youth.

Glutamate imaging (GluCEST) reveals lower brain GluCEST contrast in patients on the psychosis spectrum.

Psychosis commonly develops in adolescence or early adulthood. Youths at clinical high risk (CHR) for psychosis exhibit similar, subtle symptoms to those with schizophrenia (SZ). Malfunctioning neurotransmitter systems, such as glutamate, are implicated in the disease progression of psychosis. Yet, in vivo imaging techniques for measuring glutamate across the cortex are limited. Here, we use a novel 7 Tesla MRI glutamate imaging technique (GluCEST) to estimate changes in glutamate levels across cortical and subcortical regions in young healthy individuals and ones on the psychosis spectrum. Individuals on the psychosis spectrum (PS; n=19) and healthy young individuals (HC; n=17) underwent MRI imaging at 3 and 7 T. At 7 T, a single slice GluCEST technique was used to estimate in vivo glutamate. GluCEST contrast was compared within and across the subcortex, frontal, parietal and occipital lobes. Subcortical (χ2 (1)=4.65, P=0.031) and lobular (χ2 (1)=5.17, P=0.023) GluCEST contrast levels were lower in PS compared with HC. Abnormal GluCEST contrast levels were evident in both CHR (n=14) and SZ (n=5) subjects, and correlated differentially, across regions, with clinical symptoms. Our findings describe a pattern of abnormal brain neurochemistry early in the course of psychosis. Specifically, CHR and young SZ exhibit diffuse abnormalities in GluCEST contrast attributable to a major contribution from glutamate. We suggest that neurochemical profiles of GluCEST contrast across cortex and subcortex may be considered markers of early psychosis. GluCEST methodology thus shows promise to further elucidate the progression of the psychosis disease state.

Comparison of In Vivo and Ex Vivo MRI of the Human Hippocampal Formation in the Same Subjects.

Multiple techniques for quantification of hippocampal subfields from in vivo MRI have been proposed. Linking in vivo MRI to the underlying histology can help validate and improve these techniques. High-resolution ex vivo MRI can provide an intermediate modality to map information between these very different imaging modalities. This article evaluates the ability to match information between in vivo and ex vivo MRI in the same subjects. We perform rigid and deformable registration on 10 pairs of in vivo (3 T, 0.4 × 0.4 × 2.6 mm3) and ex vivo (9.4 T, 0.2 × 0.2 × 0.2 mm3) scans, and describe differences in MRI appearance between these modalities qualitatively and quantitatively. The feasibility of using this dataset to validate in vivo segmentation is evaluated by applying an automatic hippocampal subfield segmentation technique (ASHS) to in vivo scans and comparing SRLM (stratum/radiatum/lacunosum/moleculare) surface to manual tracing on corresponding ex vivo scans (and in 2 cases, histology). Regional increases in thickness are detected in ex vivo scans adjacent to the ventricles and were not related to scanner, resolution differences, or susceptibility artefacts. Satisfactory in vivo/ex vivo registration and subvoxel accuracy of ASHS segmentation of hippocampal SRLM demonstrate the feasibility of using this dataset for validation, and potentially, improvement of in vivo segmentation methods.

European LeukemiaNet-defined primary refractory acute myeloid leukemia: the value of allogeneic hematopoietic stem cell transplant and overall response.

We sought to appraise the value of overall response and salvage chemotherapy, inclusive of allogeneic hematopoietic stem cell transplant (AHSCT), in primary refractory acute myeloid leukemia (prAML). For establishing consistency in clinical practice, the 2017 European LeukemiaNet (ELN) defines prAML as failure to attain CR after at least 2 courses of intensive induction chemotherapy. Among 60 consecutive patients (median age 63 years) correspondent with ELN-criteria for prAML, salvage was documented in 48 cases, 30/48 (63%) being administered intensive chemotherapy regimens and 2/48 consolidated with AHSCT as first line salvage. 13/48 (27%) attained response: CR, 7/13 (54%), CRi, 2/13 (15%), MLFS, 4/13 (31%). The CR/CRi rate was 9/48 (19%), with CR rate of 7/48 (15%). On univariate analysis, intermediate-risk karyotype was the only predictor of response (44% vs 17% in unfavorable karyotype; P = 0.04). Administration of any higher-dose (>1 g/m2) cytarabine intensive induction (P = 0.50), intensive salvage chemotherapy (P = 0.72), targeted salvage (FLT3 or IDH inhibitors) (P = 0.42), greater than 1 salvage regimen (P = 0.89), age < 60 years (P = 0.30), and de novo AML (P = 0.10) did not enhance response achievement, nor a survival advantage. AHSCT was performed in 12 patients with (n = 8) or without (n = 4) CR/CRi/MLFS. 1/2/5-year overall survival (OS) rates were 63%/38%/33% in patients who received AHSCT (n = 12) vs 27%/0%/0% in those who achieved CR/CRi/MLFS but were not transplanted (n = 5), vs 14%/0%/0% who were neither transplanted nor achieved CR/CRi/MLFS (n = 43; P < 0.001); the median OS was 18.6, 12.6 and 5.6 months, respectively. Although CR/CRi/MLFS bridged to AHSCT (n = 8), appeared to manifest a longer median OS (20 months), vs (13.4 months) for those with no response consolidated with AHSCT (n = 4), the difference was not significant P = 0.47. We conclude AHSCT as indispensable for securing long-term survival in prAML (p = 0.03 on multivariate analysis), irrespective of response achievement.

Maintaining a frozen shipping environment for Phase I clinical trial distribution.

The need for stringent temperature control provides significant challenges to pharmaceutical distributors operating in all sectors of the industry. Products with a frozen storage label requirement can be significantly problematic. This study aimed to provide evidence of robust and reproducible frozen shipment arrangements to be operated by a Phase I clinical trial unit. Dry ice was used to achieve a deep frozen internal parcel environment and was tested in a laboratory setting using ultra low temperature loggers within dummy product packs within the test parcels. The laboratory dry ice packing configuration was then repeatedly tested in real time transits using a Glasgow to London delivery schedule. An internal temperature specification was set to not exceed -10 degrees C during the transport. During each delivery, external temperature monitoring measured the temperature stress experienced by the box in transit. Results demonstrated the ability of the chosen system to not exceed -13.6 degrees C on average (-10 degrees C maximum) when exposed to external temperatures of up to +20.1 degrees C (mean kinetic temperature). The effect was maintained for at least 52.5h.

Reductions of E. coli, echovirus type 12 and bacteriophages in an intermittently operated household-scale slow sand filter.

Point-of-use (POU) drinking water treatment technology enables those without access to safe water sources to improve the quality of their water by treating it in the home. One of the most promising emerging POU technologies is the biosand filter (BSF), a household-scale, intermittently operated slow sand filter. Over 500,000 people in developing countries currently use the filters to treat their drinking water. However, despite this successful implementation, there has been almost no systematic, process engineering research to substantiate the effectiveness of the BSF or to optimize its design and operation. The major objectives of this research were to: (1) gain an understanding of the hydraulic flow condition within the filter (2) characterize the ability of the BSF to reduce the concentration of enteric bacteria and viruses in water and (3) gain insight into the key parameters of filter operation and their effects on filter performance. Three 6-8 week microbial challenge experiments are reported herein in which local surface water was seeded with E. coli, echovirus type 12 and bacteriophages (MS2 and PRD-1) and charged to the filter daily. Tracer tests indicate that the BSF operated at hydraulic conditions closely resembling plug flow. The performance of the filter in reducing microbial concentrations was highly dependent upon (1) filter ripening over weeks of operation and (2) the daily volume charged to the filter. BSF performance was best when less than one pore volume (18.3-L in the filter design studied) was charged to the filter per day and this has important implications for filter design and operation. Enhanced filter performance due to ripening was generally observed after roughly 30 days. Reductions of E. coli B ranged from 0.3 log10 (50%) to 4 log10, with geometric mean reductions after at least 30 days of operation of 1.9 log10. Echovirus 12 reductions were comparable to those for E. coli B with a range of 1 log10 to >3 log10 and mean reductions after 30 days of 2.1 log10. Bacteriophage reductions were much lower, ranging from zero to 1.3 log10 (95%) with mean reductions of only 0.5 log10 (70%). These data indicate that virus reduction by BSF may differ substantially depending upon the specific viral agent.

Monocytosis is an adverse prognostic factor for survival in younger patients with primary myelofibrosis.

We recently developed a modified Dupriez prognostic scoring system (PSS) that effectively discriminated between high-, intermediate-, and low-risk young patients (age < or =60 years) with primary myelofibrosis (PMF) based on the respective presence of none, one, or two or more of the following parameters: hemoglobin <10 g/dL, leukocyte count <4 or >30 x 10(9)L(-1), and platelet count <100 x 10(9)L(-1). The current study (n=129; median age, 52 years; 69 males) reveals, on multivariable analysis, that an absolute monocyte count of > or =1 x 10(9)L(-1) carries an independent predictive value (p=0.02), for an inferior survival, in addition to that provided by hemoglobin level (p=0.002), platelet count (0.02), and leukocyte count (p=0.16). The inclusion of the monocyte count as a fourth risk factor enabled the construction of a new and improved Mayo PSS; median survival was 173, 61, and 26 months in the absence of all four (low-risk), three (intermediate-risk), or two or less (high-risk) adverse features, respectively (p<0.0001). The independent prognostic value of monocytosis was validated in a separate database of 97 patients with PMF from another institution.

Low time resolution in schizophrenia Lengthened windows of simultaneity for visual, auditory and bimodal stimuli.

The guarantee of perceptual coherence for events through everyday life situations depends upon the capacity to correctly integrate series of multi-sensory experiences. Patients with schizophrenia have been shown to reveal a deficit in integrating, i.e., "binding", perceptual information together. However, results in the literature have also suggested the reverse effect. Indeed, in certain paradigms patients have revealed more binding phenomenon than healthy controls and reported experiencing two distinct events as occurring "together". This finding suggests that patients may require longer time intervals between two distinct events before being able to perceive them as "one-after-the-other". The question here was to test whether this perceptual binding abnormality in schizophrenia is confined to events within the same modality or whether it is also present across sensory modalities. Thirty patients with schizophrenia were compared with 33 normal controls using a simultaneity judgement paradigm. There were two uni-modal conditions in which stimuli were presented in the same modality (visual or auditory) and one bimodal condition (audio-visual). Participants were presented with stimuli varying across a range of inter-stimulus intervals (ISI). They were required to judge whether they experienced two stimuli as occurring "together" or "one-after-the-other". Compared to controls and in all conditions, patients needed larger ISI to experience two stimuli as "one-after-the-other" (all ISI x Group interactions p<5 x 10(-5)). These abnormalities correlated with the disorganization dimension but not with the dosage of chlorpromazine equivalent. The increase of the time interval needed to perceive two stimuli as "one-after-the-other", reflect an abnormally low time resolution in patients with schizophrenia. We discuss the possible involvement of anatomical disconnectivity in schizophrenia which would specifically affect the time integration properties of neural assemblies.

Characteristics and outcome of patients with therapy-related acute promyelocytic leukemia front-line treated with or without arsenic trioxide.

Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n=7) or in combination with ATO (n=24), CTX (n=53), or both (n=19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82-99%) as compared to CTX/ATRA (78%, 95% CI, 64-87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80-93%) without difference according to treatment (P=0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.

FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature.

We previously studied clinico-pathologic features of 89 consecutive adult patients with moderate-to-severe eosinophilia, and reported a FIP1L1-PDGFRA prevalence of 12%. In that series, all 11 FIP1L1-PDGFRA+ patients receiving imatinib achieved a complete response. We now extend our observations through a study of 741 unselected patients with eosinophilia for FIP1L1-PDGFRA, and present longer term follow up data for the imatinib-treated cohort. We also include data for three previously unreported FIP1L1-PDGFRA+ patients. Among the 741 requests, only 21 (3%) were found to carry the FIP1L1-PDGFRA mutation. While all 14 FIP1L1-PDGFRA+ patients receiving imatinib achieved a complete response, the 4 patients who attempted to discontinue imatinib all relapsed. We also find that it is possible to maintain patients in clinical remission with an empirically derived schedule of low-dose (50-100 mg), intermittent (once daily to once weekly) imatinib. Lastly, we present a comprehensive review of the literature pertaining to FIP1L1-PDGFRA in order to address several key aspects of this mutation from a clinical standpoint.

Allogeneic stem cell transplantation and donor lymphocyte infusions for chronic myelomonocytic leukemia.

Prognosis in chronic myelomonocytic leukemia (CMML) is unfavorable and the optimal therapy remains uncertain. Currently, allogeneic stem cell transplantation is the only known curative therapeutic option. However, the data available are limited and restricted to small retrospective series. There is even less information on the use of donor lymphocyte infusions (DLI) for this disease. We reviewed our experience of allogeneic stem cell transplantation and DLI for adults with CMML. Seventeen consecutive adults underwent allogeneic stem cell transplantation from related (n=14) or unrelated (n=3) donors. Median age was 50 years (range 26-60). Seven patients (41%) demonstrated relapse or persistent disease at a median of 6 months (range 3-55.5). Five patients underwent DLI for morphologic relapse and one for mixed donor chimerism. Two patients achieved durable complete remissions of 15 months each. The overall transplant-related mortality was 41% (n=7). With a median follow-up of 34.5 months, three patients (18%) currently remain alive and in continuous CR. The current study demonstrates a graft-versus-leukemia effect in CMML, both for allogeneic stem cell transplantation and for DLI. Nevertheless, consistent with reported experience of others, overall outcomes remain less than optimal and unpredictable.

Magnocellular and parvocellular visual pathways have different blood oxygen level-dependent signal time courses in human primary visual cortex.

PURPOSE: The magnocellular and parvocellular pathways (M and P pathways) are the major pathways of the visual system, with distinct histologic and physiologic properties that may also have different metabolic characteristics. We hypothesize that the differences of the 2 visual pathways would also manifest as differences in the signal time course of blood oxygen level-dependent functional MR imaging (BOLD fMRI). The differences in BOLD signal time course may provide insight into the metabolic requirements of the 2 pathways. METHODS: Eleven fMRI sessions on 6 subjects were performed using stimuli that preferentially activated the 2 pathways. Regions commonly activated by both the M and P stimuli in the primary visual cortex (V1) were determined, and the contrast elicited by the stimulus, time-to-peak (TTP), and the full width at half maximum (FWHM) of the BOLD signal time course were measured. RESULTS: The functional stimuli activated cortical regions described previously in the literature, such as V1, V4, and V5. Within V1, the TTP of the signal time course of the 2 stimuli were statistically different, with the P stimulus generating TTPs that were on average 12% faster than the M stimulus (P = .0037). CONCLUSION: We have demonstrated the ability to functionally differentiate the M and P stimuli in a commonly activated anatomic region. Because the BOLD response is dependent on the ratio of oxyhemoglobin and deoxyhemoglobin in the blood, the difference in the BOLD time course between the 2 stimuli suggests that the oxygen demand of the 2 pathways may be different.

Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro.

Recent studies indicate that a rare population of primitive quiescent BCR-ABL(+) cells are innately insensitive to imatinib mesylate (IM) and persist after IM therapy of patients with chronic myeloid leukemia (CML). New approaches to the eradication of these cells are therefore likely to be crucial to the development of curative therapies for CML. We have now found that Ara-C, LY294002 (a PI-3 (phosphatidylinositol-3' kinase) kinase inhibitor), 17AAG (a heat-shock protein (HSP)-90 antagonist) and lonafarnib (a farnesyltransfease inhibitor) all enhance the toxicity of IM on K562 cells and on the total CD34(+) leukemic cell population from chronic phase CML patients. However, for quiescent CD34(+) leukemic cells, this was achieved only by concomitant exposure of the cells to lonafarnib. Ara-C or LY294002 alone blocked the proliferation of these cells but did not kill them, and Ara-C, LY294002 or 17AAG in combination with IM enhanced the cytostatic effect of IM but did not prevent the subsequent regrowth of the surviving leukemic cells. These studies demonstrate the importance of in vitro testing of novel agents on the subset of primary leukemic cells most likely to determine long-term treatment outcomes in vivo.

A phase I study of 153Sm-EDTMP with fixed high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma.

Despite response rates of 30% after high-dose chemotherapy with autologous hematopoietic stem cell transplant, patients with multiple myeloma are not cured. 153Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP; Quadramet) is a short-range, beta-emitting therapeutic radiopharmaceutical with avid skeletal uptake. In total, 12 patients were treated with escalating doses of 153Sm-EDTMP (N=3/group; 6, 12, 19.8, and 30 mCi/kg) and a fixed dose of melphalan (200 mg/m(2)). No dose limiting toxicity was seen. To better standardize the marrow compartment radiation dose, the study was modified such that an additional six patients were treated at a targeted absorbed radiation dose to the red marrow of 40 Gy based on a trace labeled infusion 1 week prior to the therapy. Despite rapid elimination of unbound radiopharmaceutical via kidneys and bladder, no episodes of nephrotoxicity, hemorrhagic cystitis, or delayed radiation nephritis were observed with a median follow-up of 31 months (range 8.5-44). Median times to ANC>0.5 and platelet >20 x 10(6)/l were 12 and 11 days, respectively, with no graft failures. Overall response rate was 94% including seven very good partial responses and five complete responses. Addition of 153Sm EDTMP to melphalan conditioning appears to be safe, well-tolerated and worthy of further study.

Characterisation of the biosand filter for E. coli reductions from household drinking water under controlled laboratory and field use conditions.

More than a billion people in the developing world lack access to safe and reliable sources of drinking water. Point of use (POU) household water treatment technology allows people to improve the quality of their water by treating it in the home. One emerging POU technology is the biosand filter (BSF), a household-scale, intermittently operated slow sand filter. Laboratory and field studies examined Escherichia coli reductions achieved by the BSF. During two laboratory studies, mean E. coli reductions were 94% and they improved over the period of filter use, reaching a maximum of 99%. Field analysis conducted on 55 household filters near Bonao, Dominican Republic averaged E. coli reductions of 93%. E. coli reductions by the BSF in laboratory and field studies were less than those typically observed for traditional slow sand filters (SSFs), although as for SSFs microbial reductions improved over the period of filter use. Further study is needed to determine the factors contributing to microbial reductions in BSFs and why reductions are lower than those of conventional SSFs.

Chronic neutrophilic leukemia (CNL): a clinical, pathologic and cytogenetic study.

This report describes a single institution's recent experience with six patients fulfilling the diagnostic criteria of chronic neutrophilic leukemia. No patient had the Philadelphia chromosome or the BCR/ABL fusion gene. None of the common cytogenetic abnormalities characteristic of myeloid disorders were detected. Two patients demonstrated clonal evolution during the course of the disease. All responded initially to therapy with hydroxyurea with control of leukocytosis and reduction in splenomegaly. Three patients eventually became refractory to hydroxyurea, manifesting progressive neutrophilia without blastic transformation. Aggressive chemotherapy to control progressive leukocytosis resulted in death due to cytopenias in two of these patients. The third patient received less intensive chemotherapy and died of progressive disease. One patient died after transformation of the disease into undifferentiated acute myeloid leukemia. Two patients remain alive with stable disease on hydroxyurea therapy, 12 and 54 months after initial diagnosis. Chronic neutrophilic leukemia is a rare clinicopathologic entity that can be distinguished from chronic myelogenous leukemia, the recently described neutrophilic-chronic myelogenous leukemia, and myelodysplastic syndrome. The clinical course is heterogeneous, with a definite risk of death from either blastic transformation or progressive neutrophilic leukocytosis. Continued study and reporting of these cases must be encouraged.

Maintaining the cold chain shipping environment for Phase I clinical trial distribution.

The study aimed to demonstrate satisfactory inter-UK transit of cold storage clinical trial material. The product environment had to be maintained between 0 and 8 degrees C throughout transit until delivery. Straightforward, low cost and simplified shipping arrangements were sought that would be appropriate for small-scale Phase I clinical trial activities. A laboratory test defined an optimal three frozen gel pack configuration to maintain refrigerated environmental conditions for dummy product packs in a single type and size of insulated shipper. The internal environment was temperature monitored at 30-min intervals in all tests. Twelve Glasgow to London transits were then studied over 2 years to include all seasonal temperature variations. A configuration using three frozen gel packs and 4 h pre-chill of the transit container maintained the internal environment at 0-8 degrees C for up to 48 h during autumn, winter and spring. A modified four frozen gel pack configuration was suitable for summer transit. Thus cold shipment verification was successfully carried out for a small-scale distribution operation. It was proven that refrigerated shipping conditions could be maintained using a straightforward and cost effective 'passive' type system consisting of frozen gel packs and insulated transit containers.

Drug- not carrier-dependent haematological and biochemical changes in a repeated dose study of cyclosporine encapsulated polyester nano- and micro-particles: size does not matter.

Biodegradable nanoparticles are being considered more often as drug carriers to address pharmacokinetic/pharmacodynamic issues, yet nano-product safety has not been systematically proven. In this study, haematological, biochemical and histological parameters were examined on 28 day daily dosing of rats with nano- or micro-particle encapsulated cyclosporine (CsA) to confirm if any changes observed were drug or carrier dependent. CsA encapsulated poly(lactide-co-glycolide) [PLGA] nano- (nCsA) and micro-particles (mCsA) were prepared by emulsion techniques. CsA (15, 30, 45 mg/kg) were administered by oral gavage to Sprague Dawley (SD) rats over 28 days. Haematological and biochemical metrics were followed with tissue histology performed on sacrifice. Whether presented as nCsA or mCsA, 45 mg/kg dose caused significant loss of body weight and lowered food consumption compared to untreated control. Across the doses, both nCsA and mCsA produce significant decreases in lymphocyte numbers compared to controls, commensurate with the proprietary product, Neoral(®) 15. Dosing with nCsA showed higher serum drug levels than mCsA presumably owing to the smaller particle size facilitating absorption. The treatment had no noticeable effects on inflammatory/oxidative stress markers or antioxidant enzyme levels, except an increase in ceruloplasmin (CP) levels for high dose nCsA/mCsA group. Further, only subtle, sub-lethal changes were observed in histology of nCsA/mCsA treated rat organs. Blank (drug-free) particles did not induce changes in the parameters studied. Therefore, it is extremely important that the encapsulated drug in the nano-products is considered when safety of the overall product is assessed rather than relying on just the particle size. This study has addressed some concerns surrounding particulate drug delivery, demonstrating safe delivery of CsA whilst achieving augmented serum concentrations.