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Objective The aim of this study was to characterize the safety and efficacy of filgotinib, lanraplenib and tirabrutinib in patients with active SS. Methods This multicentre, double-blind study randomized patients with active primary or secondary SS [EULAR SS disease activity index (ESSDAI) ≥5) to receive filgotinib 200 mg (Janus kinase-1 inhibitor), lanraplenib 30 mg (spleen tyrosine kinase inhibitor), tirabrutinib 40 mg (Bruton’s tyrosine kinase inhibitor), or placebo. The composite primary end point was the week-12 proportion of patients fulfilling protocol-specified improvement criteria (based on CRP and SS-related symptoms). The EULAR SS patient-reported index (ESSPRI) and the ESSDAI change from baseline (CFB) were secondary end points. Exploratory end points included disease-related biomarkers. Treatment-emergent adverse events (AEs) represented safety outcomes. Results The mean of the baseline ESSDAI was 10.1, and of ESSPRI was 6.2 in the 150 patients who were treated; 125 completed the 24-week placebo-controlled treatment period. At week 12, 43.3% of the filgotinib group achieved the primary end point (P = 0.17 vs placebo) vs 42.3% (P = 0.16), 34.7% (P = 0.33), and 26.7% of lanraplenib, tirabrutinib, and placebo groups, respectively. Neither secondary end point was met. Biomarker reductions included immunoglobulins classically associated with SS disease activity. Filgotinib ESSDAI CFB appeared more pronounced in subgroups with baseline ESSDAI ≥14 or without DMARDs/CSs. Most AEs were Grade 1 or 2. Conclusion Three drugs with disparate mechanisms were tested, but no significant differences vs placebo in primary or secondary end points were observed. These results may be considered hypothesis-generating, given the drug tolerability, subgroup analysis, and biomarker findings. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT03100942.

The Covid-19 pandemic has revealed myriad social, economic, and health inequities that disproportionately burden populations that have been made medically or socially vulnerable. Inspired by state and local governments that declared racism a public health crisis or emergency, the Anti-Racism in Public Health Act of 2020 reflects a shifting paradigm in which racism is considered a social determinant of health. Indeed, health inequities fundamentally rooted in structural racism have been exacerbated by the Covid-19 pandemic, which calls for the integration of antiracist praxis to promote ethical public health research processes. This commentary describes ways in which antiracist praxis-which emphasizes empowerment of traditionally marginalized populations-offers strategies to explicitly address power imbalance, stigmatization, and other consequences of structural racism in public health research.

As a field, bioethics has failed to adequately change in a direction that pursues and addresses continually shifting contemporary social problems, in particular, anti-Black racism. In this essay, we draw from interviews with four senior Black scholars-Anita L. Allen, Claretta Y. Dupree, Patricia A. King, and Lawrence J. Prograis, Jr.-to learn from their experiences in this field dominated by White-majority thought and to consider thematically how best to recalibrate bioethics to imagine a braver, broader, and better bioethics, one that centers social justice and is equipped to work against anti-Black racism.

Background: Essential tremor (ET) is among the most prevalent neurological diseases. Its environmental determinants are poorly understood. Harmane (1-methyl-9H-pyrido[3, 4-b]indole), a dietary tremor-producing neurotoxin, has been linked to ET in a few studies in New York and Madrid. Mercury, also a tremor-producing neurotoxin, has not been studied in ET. The Faroe Islands have been the focus of epidemiological investigations of numerous neurological disorders. Objective: In this population-based, case-control study, we directly measured blood harmane concentrations (HA) and blood mercury concentrations (Hg) in ET cases and controls. Methods: In total, 1,328 Faroese adults were screened; 26 ET cases were identified whose (HA) and (Hg) were compared to 197 controls. Results: Although there were no statistically significant differences between diagnostic groups, median (HA) was 2.7× higher in definite ET (4.13 g–10/mL) and 1.5× higher in probable ET (2.28 g–10/mL) than controls (1.53 g–10/mL). Small sample size was a limitation. For definite ET versus controls, p = 0.126. (Hg) were similar between groups. Conclusions: We demonstrated marginally elevated (HA) in definite and probable ET. These data are similar to those previously published and possibly extend etiological links between this neurotoxin and ET to a third locale. The study did not support a link between mercury and ET.

Research in the field of Chinese second/foreign language (L2) acquisition, at present, does not match the increasing demand to learn Chinese as an L2, given that Chinese is the fastest growing foreign language (FL) in countries such as Japan, South Korea, the United States, Canada and Australia. There is a significant gap between Chinese L2 acquisition research and the large body of literature in second language acquisition (SLA), which mainly focuses on English L2. The need for more research in Chinese SLA is compelling.Particularly, research in Chinese L2 word order acquisition requires more attention because word order plays a more complex role in Chinese than in English. Chinese relies heavily on word order for information structuring of a sentence because this language lacks other means, such as verb endings indicating tense and aspect, to accomplish this function. Due to the different roles word order plays in Chinese and English, adult English-speaking learners find Chinese word order acquisition very challenging. Chinese L2 word order errors frequently occur in learners' L2 production. However, Chinese L2 researchers and teachers are left with no means to adequately describe and explain these errors for instruction purposes. This dissertation develops such a means -- a comprehensive taxonomy of Chinese L2 word order errors. This taxonomy organizes these errors into a logical system of classification. Through the classification, explicit description of various Chinese L2 word order errors is achieved, and specific sources of these errors are traced.Data was collected from 116 native-English-speaking learners of Chinese at a large university in Australia. The Chinese L2 learners were divided into three proficiency levels based on their institutional status. Four hundred and eight word order errors were extracted by qualitatively analyzing the learners’ written samples. Among the 408 word order errors, 404 (99%) are successfully classified into different categories according to a new criterion proposed in this dissertation.The new taxonomy provides a principle-based description and explanation of various Chinese L2 word order errors. A word order error is deemed to constitute an error when it violates a relevant word order principle (or sub-principle). These principles not only explain why an error is an error but also provide a means for correcting the error. In a pedagogical sense, the directness and explicitness in explaining word order errors achieved by employing this taxonomy cannot be achieved by relying on any other sources of errors available in the literature.The new taxonomy overcomes the limitations of existing taxonomies in the literature that are either superficial, or unsystematic, or not empirically testable. For example, it draws on the Cognitive Functionalist Approach of L2 acquisition. Both its description and explanation of Chinese L2 word errors go beyond superficiality. The approach maintains that adult L2 learners' conceptualization of the world is initially based on their L1. Their conceptualization of the world imposes constraints on the linguistic structures of their L2. Therefore, errors may occur when English learners of Chinese impose their conceptualization based on the English language onto the Chinese structures. The new taxonomy is systematic because it categorizes word order errors using one criterion. New categories emerging from the data and the existing categories from the literature are incorporated into one system. Finally, the new taxonomy is empirically testable because many new categories emerged from the data. It is an open-ended rather than a closed system. New categories can be added as necessary.The dissertation finds that violation of relevant word order principles has a high explanatory value for the various word order errors encountered in the data. This has clear pedagogical implications. Chinese L2 learners generally lack awareness of the word order principles (and sub-principles) on which the new taxonomy is based. These principles and sub-principles are seen to be of considerable importance to the acquisition of Chinese L2 word order. In order to improve learners' word order performance, the results of this study indicate that it is imperative for the basic Chinese word order principles be included in a CFL curriculum.

Background Elevated tissue levels of the tremor-producing neurotoxin, harmane, have been detected in patients with essential tremor (ET) in the USA and Spain. Recently, a study in the Faroe Islands similarly noted an elevation in blood harmane concentrations in probable and definite ET cases. The underlying mechanism is not understood. Possible mechanisms include increased dietary consumption (esp. through cooked meats), impaired metabolism, or increased endogenous production of harmane. To investigate this issue further, we conducted a population-based study in the Faroe Islands to examine meat consumption and meat cooking practices in ET cases and controls. Methods 1,328 Faroese adults were screened for tremor and 27 ET cases were identified. Meat consumption and meat cooking practices were compared to 200 controls. Detailed data were collected via questionnaires regarding current meat consumption for 14 meat types and meat cooking doneness for 8 meat types. Data were also available on blood harmane concentrations. Results Current meat consumption was similar in ET cases and controls in 12 out of 14 meat types, with no differences observed after a Bonferroni correction in any meat type; no difference was observed when stratified by gender. No difference was observed in meat doneness between ET cases and controls. Blood harmane concentrations were not correlated with dietary data. Discussion This is the first population-based study of harmane-linked dietary factors in ET. The study suggests the observed difference in blood harmane in ET is not driven by dietary differences and is likely due to other mechanisms (e.g., impaired metabolism).

Adult neurogenesis takes place in the brain subventricular zone (SVZ) in the lateral walls of lateral ventricles and subgranular zone (SGZ) in the hippocampal dentate gyrus (HDG), and functions to supply newborn neurons for normal brain functionality. Subchronic Mn exposure is known to disrupt adult neurogenesis in the SVZ. This study was designed to determine whether Mn exposure disturbed neurogenesis within the adult HDG. Adult rats (10 weeks old) received a single dose of bromodeoxyuridine (BrdU) at the end of 4-week Mn exposure to label the proliferating cells. Immunostaining and cell counting data showed that BrdU(+) cells in Mn-exposed HDG were about 37% lower than that in the control (p

Oxygen-ozone (O3) therapy serves as an alternative medical technique that increases the oxygen in the body along with the introduction of O3. O3 therapy has finally reached a level where the biological mechanisms of action have been understood, showing that they are in the domain of physiology, biochemistry, and pharmacology. Few clinical applications have been reviewed here as well as exemplifying that O3 therapy is particularly useful in musculoskeletal disorders. In the therapeutic range, O3 can be used as a more effective and safe substitute of standard medications. O3 therapy has been used for many years for its ability to inactivate various viruses, cancer, and acquired immune deficiency syndrome but is now making strides in the treatment of musculoskeletal disorders such as rheumatoid arthritis, lumbar facet joint syndrome, subacromial bursitis, carpal tunnel syndrome, osteoarthritis, hip bursitis, shoulder adhesive capsulitis, herniated disc, and temporomandibular joint disorder.

Porphyrias are inherited disorders of the heme biosynthetic pathway, usually characterized by dermatological changes due to the accumulation of byproducts in the pathway. Select porphyrias also affect the nervous system, namely hereditary coproporphyria, acute intermittent porphyria and variegate porphyria. Complications include paralysis, hyponatremia which can risk central pontine myelinolysis, seizures and coma. Neurological complications usually result from severe episodes of acute attacks. Acute attacks may also elicit neuropsychiatric symptoms such as confusion, hallucinations, anxiety and psychosis. However, these manifestations are generally self-limiting. Due to the generally low incidence of porphyria and full knowledge the associated neurological and psychiatric manifestations, we review the relevant porphyrias along with their clinical manifestations, evaluation, and management to raise its awareness in the clinical picture and to prevent misdiagnosis. Porphyria should be considered within the differential diagnosis for unexplained neurological symptoms.

Background PsA is a chronic inflammatory musculoskeletal disease characterized by joint and skin inflammation, enthesitis, dactylitis, and nail lesions. In the recent EQUATOR study, filgotinib (FIL), an oral, selective Janus kinase 1 (JAK1) inhibitor, produced significant and sustained improvements on the signs and symptoms of PsA compared to placebo (PBO).1 As targeted JAK1 inhibition by FIL has potential to simultaneously block multiple inflammatory pathways, we analyzed biomarker samples from EQUATOR using exploratory multiplex biomarker panels. Objectives To evaluate the impact of targeted JAK1 inhibition on the circulating biomarkers in patients with active PsA. Methods Design and results of the EQUATOR study—a 16-week, double-blind, multicenter, phase 2 study in subjects with active PsA (NCT03101670)—have been published.1 Subjects were randomized 1:1 to 200 mg FIL (n=65) or PBO (n=66) once daily. Serum samples (FIL n=60 and PBO n=61) were collected at baseline (BL), week 1, week 4, and week 16, and analyzed using 135 multiplex biomarker screening panels. Biomarker changes from BL were analyzed on all time-paired subject data and reported for weeks 1, 4, and 16. Results FIL treatment produced significant reductions serum concentration of multiple biomarkers associated with PsA disease activity. We identified 4 clusters of biomarker response based on the kinetics and magnitude of changes from BL (Figure); Cluster 1: rapid, substantial and sustained reduction (>25% from BL by week 1); Cluster 2: rapid and moderate reduction (5%–15% from BL by week 1); Cluster 3: delayed reduction (significant reduction by week 4); and Cluster 4: moderate increase (5%–10% from BL). Although initial grouping was based on the speed and magnitude of biomarker response, a number of biomarkers formed subclusters representing discrete biological functions. Cluster 1 included 2 acute phase reactants (CRP, SAA) while Cluster 2 included inflammatory mediators (TNFR1, CXCL10, IL-12/-23; CXCL10 and IL-12/-23 reached full reduction by week 1). Cluster 3 was the largest group and represented biomarkers of matrix remodeling (MMP1, TIMP1), cell adhesion (ICAM-1, E-selectin), and angiogenesis (VEGF-A). Cluster 4 had biomarkers related to diverse functions (Eotaxin, CEA, adiponectin). Conclusion In patients with active PsA, FIL treatment significantly decreased levels of circulating biomarkers, including acute-phase reactants, proinflammatory cytokines and chemokines, and various adhesion molecules. These data support the idea that FIL treatment results in rapid and sustained reduction of the inflammatory milieu present in autoimmune inflammatory diseases, consistent with efficacy previously reported for this study.1 Reference [1] Mease PJ, et al. Lancet. 2018;392:2367-2377. Disclosure of Interests Dafna D Gladman Grant/research support from: AbbVie, Amgen, Celgene, Lilly, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB, Rene Galien Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Corrine Jamoul Employee of: Galapagos NV, Mona Trivedi Shareholder of: Amgen and Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Neelufar Mozaffarian Shareholder of: Gilead, Employee of: Gilead, OhKyu Yoon Shareholder of: Gilead Sciences, Inc., Amgen, Employee of: Gilead Sciences, Inc., Amgen, Wendy Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., JiYun Kim Shareholder of: Gilead Sciences, Inc., Employee of: Bayer Healthcare, LLC, Gilead Sciences, Inc.

Background Spleen tyrosine kinase (SYK) mediates immunoreceptor signaling and is essential in activation of cells including B lymphocytes, monocytes, macrophages, dendritic cells, and osteoclasts. SYK may play an important role in the initiation and progression of autoimmune diseases, including rheumatoid arthritis (RA) and lupus. GS-9876 is a novel, potent, highly selective oral inhibitor of SYK in phase 2 trials for autoimmune diseases. Objectives To evaluate the efficacy, safety, and pharmacokinetics of GS-9876, and its impact on biomarkers relevant to RA as well as the SYK and JAK pathways. Methods Patients with active RA with prior inadequate response to methotrexate (MTX) or a biologic antirheumatic drug were randomized 1:1:1:1 to receive GS-9876 30 mg, GS-9876 10 mg, selective JAK1 inhibitor filgotinib (FIL) 200 mg, or matching placebo (PBO) once daily for 12 weeks on a stable background of oral MTX. The primary endpoint for GS-9876 was the change in DAS28(CRP) at week 12. Pharmacokinetics and various biomarkers were evaluated at several time points, including VectraDA and stimulation of whole blood in TruCulture (MyriadRBM) tubes. Results A total of 83 patients received the study drug and 79 completed the study. Fourteen patients (16.9%) were male and 69 (83.1%) were female. The majority were white (77, 92.8%). The mean (SD) age at baseline (BL) was 55 (11.5) years (range 18 to 73). The primary and secondary endpoints are reported in Table 1. For DAS28(CRP), the mean (SD) at BL was 5.75 (0.961) with a median of 5.69; a statistically significant reduction at week 12 was observed only in patients receiving FIL as compared to PBO (Table 1). Adverse events (AEs) were reported across all groups (37.5% in the combined GS-9876 arms, 38.1% in FIL, 40.9% in PBO). No deaths or serious AEs were reported. Plasma exposures of all study drugs were comparable to those observed in healthy subjects and historical data. Ex vivo stimulated whole blood identified differential responses between GS-9876 and PBO. Conclusion Clinical efficacy of GS-9876 in RA was not observed, but GS-9876 was safe and well-tolerated over a 12-week period in patients with RA on MTX. FIL showed favorable safety and clinical efficacy consistent with prior data, validating the study concept and design. Additionally, biomarker changes with GS-9876 support the continuation of studies in lupus-related diseases. References [1] Kivitz AJ, et al. ACR 2018. Abstract 2518. Disclosure of Interests Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Speakers bureau: Celgene, Horizon, Merck and Genetech, Flexion, Daksha Mehta: None declared, Franziska Matzkies Shareholder of: Gilead, Employee of: Gilead, Afsaneh Mozaffarian Employee of: Gilead Sciences, Inc., Rebecca Kunder Shareholder of: Gilead Sciences, Inc., Julie A. Di Paolo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Neelufar Mozaffarian Shareholder of: Gilead, Employee of: Gilead, Sean Hsueh Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., JiYun Kim Shareholder of: Gilead Sciences, Inc., Employee of: Bayer Healthcare, LLC, Gilead Sciences, Inc., Wendy Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lin Liu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., John Sundy Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Mark C. Genovese Grant/research support from: Sanofi/Genzyme, Genentech/Roche, RPharm, Consultant for: Sanofi/Genzyme, Genentech/Roche, RPharm

The Open Circuit Voltage (OCV) is a measure of the electromotive force of the battery, which has a monotonic relationship with the State of Charge (SOC). This relationship is widely used inSOCestimation. However, Li-ionbatteries have different capacities available at different temperatures, leading to the great variation of the SOC definition. In addition,the OCV-SOC curve of the battery varies greatly at different temperatures.And it isthusnecessary to store multiple OCV-SOC curves or OCV-Temperature fitting curves at different SOC in hardware while using this method.Thereforeit comes with great challenge to accurately estimate SOC of batteries at different temperatures.In this paper, wepropose a method to normalize battery capacity by top SOC alignment, which is adopted to estimate SOC at -20 °C~+55 °C only by the OCV-SOC curve at room temperaturefor Li-ionbatteries (LiNi1/3Co1/3Mn1/3O2, NCM). The normalized OCV-SOC curves are very similar, and the curve at room temperaturecan be used to represent the curves at other temperatures. Experimental results indicate that this proposed method exhibits a high accuracy and can reduce the data volume dramatically for SOC estimation. It delivers a good engineering solution for battery management system in electric vehicles and power grid energy storage.

Due to environmental concerns, operators are often required to dispose their produced saltwater into disposals, i.e., SWD wells. The key challenge is that the saltwater contains varieties of damaging species with compositions varying batch-wise. In addition, the compelled turbulence during pumping worsens the situation further. As the results of constant formation damage and lack of turbulence-taming measure, SWD wells frequently experience rapid pressure escalation during operation, which is a major hurdle holding back this industry. In this report, we walk through the identification of key issues facing SWD, followed by the proposal of a prospective solution. The solution consists of primarily a real-time well stimulation via turbulence control with a non-damaging friction reducer that works essentially in all common oilfield brines. The qualification and screening of this friction reducer, as a technique to fight against formation damage via turbulence control, is described, followed by the corroboration with field results.

The brain subventricular zone (SVZ) is a source of neural precursor cells; these cells travel along the rostral migratory stream (RMS) to destination areas in the process of adult neurogenesis. Recent x-ray fluorescence (XRF) studies reveal an extensive accumulation of copper (Cu) in the SVZ. Earlier human and animal studies also suggest an altered Cu homeostasis after manganese (Mn) exposure. This study was designed to test the hypothesis that Mn exposure by acting on the divalent metal transporter-1 (DMT1) altered Cu levels in SVZ and RMS, thereby affecting adult neurogenesis. Adult rats received intraperitoneal (i.p.) injections of 6 mg Mn/kg as MnCl2 once daily for 4 weeks with concomitant injections of bromodeoxyuridine (BrdU) for 5 days in the last week. In control rats, Cu levels were significantly higher in the SVZ than other brain regions examined. Mn exposure significantly reduced Cu concentrations in the SVZ (P < 0.01). Immunohistochemical data showed that in vivo Mn exposure significantly increased numbers of BrdU(þ) cells, which were accompanied with increased GFAP(þ) astrocytic stem cells and DCX(þ) neuroblasts in SVZ and RMS. Quantitative RT-PCR and Western blot confirmed the increased expression of DMT1 in SVZ following in vivo Mn exposure, which contributed to Mn accumulation in the neurogenesis pathway. Taken together, these results indicate a clear disruptive effect of Mn on adult neurogenesis; the effect appears due partly to Mn induction of DMT1 and its interference with cellular Cu regulation in SVZ and RMS. The future research directions based on these observations are also discussed.

Regulation of cellular copper (Cu) homeostasis involves Cu-transporting ATPases (Cu-ATPases), i.e., ATP7A and ATP7B. The question as to how these Cu-ATPases in brain barrier systems transport Cu, i.e., toward brain parenchyma, cerebrospinal fluid (CSF), or blood, remained unanswered. This study was designed to characterize roles of Cu-ATPases in regulating Cu transport at the blood-brain barrier (BBB) and blood-CSF barrier (BCB) and to investigate how exposure to toxic manganese (Mn) altered the function of Cu-ATPases, thereby contributing to the etiology of Mn-induced parkinsonian disorder. Studies by quantitative real-time RT-PCR (qPCR), Western blot, and immunocytochemistry revealed that both Cu-ATPases expressed abundantly in BBB and BCB. Transport kinetic studies by in situ brain infusion and ventriculo-cisternal (VC) perfusion in Sprague Dawley rat suggested that the BBB was a major site for Cu entry into brain, whereas the BCB was a predominant route for Cu efflux from the CSF to blood. Confocal evidence showed that the presence of excess Cu or Mn in the choroid plexus cells led to ATP7A relocating toward the apical microvilli facing the CSF, but ATP7B toward the basolateral membrane facing blood. Mn exposure inhibited the production of both Cu-ATPases. Collectively, these data suggest that Cu is transported by the BBB from the blood to brain, which is mediated by ATP7A in brain capillary. By diffusion, Cu ions move from the interstitial fluid into the CSF, where they are taken up by the BCB. Within the choroidal epithelial cells, Cu ions are transported by ATP7B back to the blood. Mn exposure alters these processes, leading to Cu dyshomeostasis-associated neuronal injury.

Parkinson's disease (PD) is a late-life neurodegenerative disease. Genetic and environmental factors play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin that shows structural resemblance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).In 2002 and 2007, we demonstrated elevated blood harmane concentrations [HA] in essential tremor (ET) cases. We now assessed whether blood [HA] were elevated in Parkinson's disease (PD) as well.Blood [HA] were quantified by high performance liquid chromatography. Subjects comprised 113 PD cases and 101 controls.Mean log blood [HA] in PD cases was double that of controls (0.59±0.63 g(-10)/ml vs. 0.27±0.63 g(-10)/ml, p0.001). A non-parametric test on non-transformed data (median blood [HA]=3.31 g(-10)/ml in cases and 1.44 g(-10)/ml in controls) also showed this difference (p0.001). In unadjusted and then adjusted logistic regression analyses, log blood [HA] was associated with PD (odds ratio [OR]unadjusted 2.31, 95% confidence interval [CI] 1.46-3.67, p0.001; OR(adjusted) 2.54, 95% CI 1.55-4.16, p0.001). In PD, log blood [HA] co-varied with family history, being lowest in PD cases with no family history (0.54±0.60 g(-10)/ml) and highest in PD cases with a family history of both ET and PD (0.84±0.68 g(-10)/ml) (p=0.06).Blood harmane appears to be elevated in PD. The finding needs to be reproduced in additional cohorts to assess its generalizability. The higher concentration in familial PD suggests that the mechanism may involve genetic factors.

Background Environmental correlates for essential tremor (ET) are largely unexplored. The search for such environmental factors has involved the study of a number of neurotoxins. Harmane (1-methyl-9H-pyrido[3,4- b ]indole) is a potent tremor-producing toxin. In two prior case–control studies in New York, we demonstrated that blood harmane concentration was elevated in ET patients vs. controls, and especially in familial ET cases. These findings, however, have been derived from a study of cases ascertained through a single tertiary referral center in New York. Objective Our objective was to determine whether blood harmane concentrations are elevated in familial and sporadic ET cases, ascertained from central Spain, compared to controls without ET. Methods Blood harmane concentrations were quantified by a well-established high performance liquid chromatography method. Results The median harmane concentrations were: 2.09 g −10 /ml (138 controls), 2.41 g −10 /ml (68 sporadic ET), and 2.90 g −10 /ml (62 familial ET). In an unadjusted logistic regression analysis, log blood harmane concentration was not significantly associated with diagnosis (familial ET vs. control): odds ratio = 1.56, p = 0.26. In a logistic regression analysis that adjusted for evaluation start time, which was an important confounding variable, the odds ratio increased to 2.35, p = 0.049. Conclusions Blood harmane levels were slightly elevated in a group of familial ET cases compared to a group of controls in Spain. These data seem to further extend our observations from New York to a second cohort of ET cases in Spain. This neurotoxin continues to be a source of interest for future confirmatory research.

para-aminosalicylic acid (PAS; 4-amino-2-hydroxybenzoic acid), an antituberculosis drug in use since the 1950s, has recently been suggested to be an effective agent for treatment of manganese-induced parkinsonian disorders. However, the neuropharmacokinetics of PAS and its metabolite N-acetyl-para-aminosalicylic acid (AcPAS; N-acetyl-4-amino-2-hydroxybenzoic acid) are unknown. This study was designed to investigate the pharmacokinetics of PAS and its distribution in brain to help better design the dosing regimen for clinical trials. Male Sprague-Dawley rats received single femoral artery injections of PAS (200 mg/kg). Plasma, cerebrospinal fluid, and brain tissues were collected, and PAS and AcPAS concentrations were quantified by high-performance liquid chromatography. After administration, the concentrations of PAS declined rapidly in plasma with an elimination t(½) of 34 min; the metabolite AcPAS was detected in plasma and eliminated with a t(½) of 147 min. PAS and AcPAS were detected in brain tissues; AcPAS had a much higher tissue concentration and a longer t(½) than the parent PAS in most tissues examined. Although both were present in blood or tissues as free, unbound molecules, AcPAS appeared to have a higher tissue affinity than PAS. Taken together, our results suggest that a dosing regimen with continuous intravenous infusion of PAS is necessary to achieve therapeutic levels in targeted brain regions. Furthermore, PAS and AcPAS seem to be effective in reducing manganese levels in brain.

Tremor is a widespread phenomenon in human populations. Environmental factors are likely to play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-β]indole) is a potent tremor-producing β-carboline alkaloid. Lead is another tremor-producing neurotoxicant. The effects of harmane and lead with respect to tremor have been studied in isolation.We tested the hypothesis that tremor would be particularly severe among individuals who had high blood concentrations of both of these toxicants.Blood concentrations of harmane and lead were each quantified in 257 individuals (106 essential tremor cases and 151 controls) enrolled in an environmental epidemiological study. Total tremor score (range = 0-36) was a clinical measure of tremor severity.The total tremor score ranged from 0 to 36, indicating that a full spectrum of tremor severities was captured in our sample. Blood harmane concentration correlated with total tremor score (p = 0.007), as did blood lead concentration (p = 0.045). The total tremor score was lowest in participants with both low blood harmane and lead concentrations (8.4 ± 8.2), intermediate in participants with high concentrations of either toxicant (10.5 ± 9.8), and highest in participants with high concentrations of both toxicants (13.7 ± 10.4) (p=0.01).Blood harmane and lead concentrations separately correlated with total tremor scores. Participants with high blood concentrations of both toxicants had the highest tremor scores, suggesting an additive effect of these toxicants on tremor severity. Given the very high population prevalence of tremor disorders, identifying environmental determinants is important for primary disease prevention.

Diabetic foot ulcers (DFU) are a burden to the diabetic community. With increasing medical bills, to unsuccessful treatment, those suffering from DFUs can use alternative therapeutics. First seen in the mid-1800s, ozone (O3) is thought to be unstable, due to inherent molecular nature. With the help of pharmaceutical science, various O3 treatments have flourished in the medical community to help those suffering from DFUs. Promising results are seen through numerous studies. Usually, a mixture of both O2 and O3 is seen in pressurized machines as administered to the foot ulcer. Foot ulcers, specifically DFUs, need to be assessed, cleaned, and treated as fast as possible for the fastest results. Results such as amputation can be seen if the foot is not attended to as soon as possible. With fast growing clinical trials in O3 therapy and quick administration of the O3, O3 therapy may be on the rise to be at the forefront of treating DFUs. Compelling evidence is seen in clinical trials, but more must be done to fully understand the role of O3 in DFUs.

Para-aminosalicylic acid (PAS), an FDA-approved anti-tuberculosis drug, has been used successfully in the treatment of severe manganese (Mn)-induced Parkinsonism in humans [Jiang Y-M, Mo X-A, Du FQ, Fu X, Zhu X-Y, Gao H-Y, et al. Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study. J Occup Environ Med 2006;48:644-9]. This study was conducted to explore the capability of PAS in reducing Mn concentrations in body fluids and tissues of Mn-exposed animals. Sprague-Dawley rats received daily intraperitoneally (i.p.) injections of 6mg Mn/kg, 5 days/week for 4 weeks, followed by a daily subcutaneously (s.c.) dose of PAS (100 and 200mg/kg as the PAS-L and PAS-H group, respectively) for another 2, 3 or 6 weeks. Mn exposure significantly increased the concentrations of Mn in plasma, red blood cells (RBC), cerebrospinal fluid (CSF), brain and soft tissues. Following PAS-H treatment for 3 weeks, Mn levels in liver, heart, spleen and pancreas were significantly reduced by 25-33%, while 3 weeks of PAS-L treatment did not show any effect. Further therapy with PAS-H for 6 weeks reduced Mn levels in striatum, thalamus, choroid plexus, hippocampus and frontal cortex by 16-29% (p

Harmane, one of the heterocyclic amines (HCAs), is a potent neurotoxin linked to human diseases. Dietary exposure, especially in cooked meats, is the major source of exogenous exposure for humans. However, knowledge of harmane concentrations in cooked meat samples is limited. Our goals were to (1) quantify the concentration of harmane in different types of cooked meat samples, (2) compare its concentration to that of other more well-understood HCAs, and (3) examine the relationship between harmane concentration and level of doneness. Thirty barbecued/grilled meat samples (8 beef steak, 12 hamburger, 10 chicken) were analyzed for harmane and four other HCAs (2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine [PhIP], amino-3,8-dimethylimidazo[4,5-f]quinoxaline [MeIQx], 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline [DiMeIQx], and 2-amino-1,6-dimethylfuro[3,2-e]imidazo[4,5-b]pyridine [IFP]). Mean (+/- SD) harmane concentration was 5.63 (+/- 6.63) ng/g; harmane concentration was highest in chicken (8.48 +/- 9.86 ng/g) and lowest in beef steak (3.80 +/- 3.6 ng/g). Harmane concentration was higher than that of the other HCAs and significantly correlated with PhIP concentration. Harmane concentration was associated with meat doneness in samples of cooked beef steak and hamburger, although the correlation between meat doneness and concentration was greater for PhIP than for harmane. Evidence indicates that harmane was detectable in nanograms per gram quantities in cooked meat (especially chicken) and, moreover, was more abundant than other HCAs. There was some correlation between meat doneness and harmane concentration, although this correlation was less robust than that observed for PhIP. Data such as these may be used to improve estimation of human dietary exposure to this neurotoxin.

Our recent data suggest a high accumulation of copper (Cu) in the subventricular zone (SVZ) along the wall of brain ventricles. Anatomically, SVZ is in direct contact with cerebrospinal fluid (CSF), which is secreted by a neighboring tissue choroid plexus (CP). Changes in Cu regulatory gene expressions in the SVZ and CP as the function of aging may determine Cu levels in the CSF and SVZ. This study was designed to investigate the associations between age, Cu levels, and Cu regulatory genes in SVZ and plexus. The SVZ and CP were dissected from brains of 3-week, 10-week, or 9-month old male rats. Analyses by atomic absorption spectroscopy revealed that the SVZ of adult and old animals contained the highest Cu level compared with other tested brain regions. Significantly positive correlations between age and Cu levels in SVZ and plexus were observed; the SVZ Cu level of old animals was 7.5- and 5.8-fold higher than those of young and adult rats (p < 0.01), respectively. Quantitation by qPCR of the transcriptional expressions of Cu regulatory proteins showed that the SVZ expressed the highest level of Cu storage protein metallothioneins (MTs), while the CP expressed the high level of Cu transporter protein Ctr1. Noticeably, Cu levels in the SVZ were positively associated with type B slow proliferating cell marker Gfap (p < 0.05), but inversely associated with type A proliferating neuroblast marker Dcx (p < 0.05) and type C transit amplifying progenitor marker Nestin (p < 0.01). Dmt1 had significant positive correlations with age and Cu levels in the plexus (p < 0.01). These findings suggest that Cu levels in all tested brain regions are increased as the function of age. The SVZ shows a different expression pattern of Cu-regulatory genes from the CP. The age-related increase of MTs and decrease of Ctr1 may contribute to the high Cu level in this neurogenesis active brain region.

Literature data indicate that bone is a major storage organ for manganese (Mn), accounting for 43% of total body Mn. However, the kinetic nature of Mn in bone, especially the half-life (t(1/2)), remained unknown. This study was designed to understand the time-dependence of Mn distribution in rat bone after chronic oral exposure. Adult male rats received 50 mg Mn/kg (as MnCl2) by oral gavage, 5 days per week, for up to 10 weeks. Animals were sacrificed every 2 weeks during Mn administration for the uptake study, and on day 1, week 2, 4, 8, or 12 after the cessation at 6-week Mn exposure for the t(1/2) study. Mn concentrations in bone (MnBn) were determined by AAS analysis. By the end of 6-week's treatment, MnBn appeared to reach the steady state (T(ss)) level, about 2-3.2 fold higher than MnBn at day 0. Kinetic calculation revealed t(1/2)s of Mn in femur, tibia, and humerus bone of 77 (r=0.978), 263 (r=0.988), and 429 (r=0.994) days, respectively; the average t(1/2) in rat skeleton was about 143 days, equivalent to 8.5 years in human bone. Moreover, MnBn were correlated with Mn levels in striatum, hippocampus, and CSF. These data support MnBn to be a useful biomarker of Mn exposure.

Background Harmane (1-methyl-9H-pyrido[3,4- b ]indole) (HA) is a potent neurotoxin that has been linked to two neurological diseases, essential tremor and Parkinson's disease. Blood harmane concentrations [HA] are elevated in patients with both diseases. An important question is whether HA is specifically linked with these diseases or alternatively, is a non-specific marker of neurological illness. Objectives We assessed whether blood [HA] was elevated in patients with a third neurological disease, dystonia, comparing them to controls. Methods Blood [HA] was quantified by high performance liquid chromatography. Subjects comprised 104 dystonia cases and 107 controls. Results Mean log blood [HA] in dystonia cases was similar to that of controls (0.41 ± 0.51 g −10 /ml vs. 0.38 ± 0.61 g −10 /ml, t = 0.42, p = 0.68). In unadjusted and adjusted logistic regression analyses, log blood [HA] was not associated with the outcome (diagnosis of dystonia vs. control): odds ratio (OR) unadjusted = 1.11, 95% confidence interval (CI) = 0.69–1.79, p = 0.68; OR adjusted = 1.07, 95% CI = 0.58–1.97, p = 0.84. Conclusions In contrast to the elevated blood [HA] that has been reported in patients with essential tremor and Parkinson's disease, our data demonstrate that blood [HA] was similar in patients with dystonia and controls. These findings provide the first support for the notion that an elevated blood [HA] is not a broad feature of neurological disease, and may be a specific feature of certain tremor disorders.

Analysis of rodent brains with X-ray fluorescence (XRF) microscopy combined with immunohistochemistry allowed us to demonstrate that local Cu concentrations are thousands of times higher in the glia of the subventricular zone (SVZ) than in other cells. Using XRF microscopy with subcellular resolution and intracellular X-ray absorption spectroscopy we determined the copper (I) oxidation state and the sulfur ligand environment. Cu K-edge X-ray absorption near edge spectroscopy is consistent with Cu being bound as a multimetallic Cu-S cluster similar to one present in Cu-metallothionein. Analysis of age-related changes show that Cu content in astrocytes of the SVZ increases fourfold from 3 weeks to 9 months, while Cu concentration in other brain areas remain essentially constant. This increase in Cu correlates with a decrease in adult neurogenesis assessed using the Ki67 marker (both, however, can be age-related effects). We demonstrate that the Cu distribution and age-related concentration changes in the brain are highly cell specific.

Background Harmane (1-methyl-9H-pyrido[3,4-β]indole), a potent neurotoxin that has tremor-producing properties in animal models, is present in many foods; although we have demonstrated a difference in tissue harmane concentrations in ET cases vs. controls, all work to date has involved blood samples. Objectives We quantified harmane concentrations in human cerebellum, a brain region of particular pathogenic interest in essential tremor (ET), comparing ET to control brains. Methods Cerebellar cortex was snap frozen and stored at −80 °C in aliquots for biochemical analyses. Harmane concentration was assessed using high performance liquid chromatography. Results Geometric mean brain harmane concentrations (adjusted for postmortem interval [PMI] and freezer time) were higher in ET cases than controls: 1.0824 (95% confidence interval = 0.9405–1.2457) vs. 0.8037 (0.6967–0.9272), p = 0.004. Geometric mean of brain harmane concentrations (adjusting for PMI and freezer time) was highest in ET cases who reported other relatives with tremor (1.2005 [0.8712–1.6541]), intermediate in ET cases without family history (1.0312 ([0.8879–1.1976]), and both were significantly higher than controls (p = 0.02). Conclusions This study provides additional evidence of a possible etiological importance of this toxin in some cases of the human disease ET.

Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors are likely to play important etiological roles. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. Previously, elevated blood harmane concentrations were demonstrated in ET cases compared to controls, but these observations have all been cross-sectional, assessing each subject at only one time point. Thus, no one has ever repeat-assayed blood harmane in the same subjects twice. Whether the observed case-control difference persists at a second time point, years later, is unknown. The current goal was to reassess a sample of our ET cases and controls to determine whether blood harmane concentration remained elevated in ET at a second time point. Blood harmane concentrations were quantified by a well-established high-performance liquid chromatography method in 63 ET cases and 70 controls. A mean of approximately 6 yr elapsed between the initial and this subsequent blood harmane determination. The mean log blood harmane concentration was significantly higher in cases than controls (0.30 ± 0.61 g(-10)/ml versus 0.08 ± 0.55 g(-10)/ml), and the median value in cases was double that of controls: 0.22 g(-10)/ml versus 0.11 g(-10)/ml. The log blood harmane concentration was highest in cases with a family history of ET. Blood harmane concentration was elevated in ET cases compared to controls when reassessed at a second time point several years later, indicating what seems to be a stable association between this environmental toxin and ET.

The neurotoxic effect of manganese (Mn) establishes itself in a condition known as manganism or Mn induced parkinsonism. While this condition was first diagnosed about 170 years ago, the mechanism of the neurotoxic action of Mn remains unknown. Moreover, the possibility that Mn exposure combined with other genetic and environmental factors can contribute to the development of Parkinson's disease has been discussed in the literature and several epidemiological studies have demonstrated a correlation between Mn exposure and an elevated risk of Parkinson's disease. Here, we introduce X-ray fluorescence imaging as a new quantitative tool for analysis of the Mn distribution in the brain with high spatial resolution. The animal model employed mimics deficits observed in affected human subjects. The obtained maps of Mn distribution in the brain demonstrate the highest Mn content in the globus pallidus, the thalamus, and the substantia nigra pars compacta. To test the hypothesis that Mn transport into/distribution within brain cells mimics that of other biologically relevant metal ions, such as iron, copper, or zinc, their distributions were compared. It was demonstrated that the Mn distribution does not follow the distributions of any of these metals in the brain. The majority of Mn in the brain was shown to occur in the mobile state, confirming the relevance of the chelation therapy currently used to treat Mn intoxication. In cells with accumulated Mn, it can cause neurotoxic action by affecting the mitochondrial respiratory chain. This can result in increased susceptibility of the neurons of the globus pallidus, thalamus, and substantia nigra pars compacta to various environmental or genetic insults. The obtained data is the first demonstration of Mn accumulation in the substantia nigra pars compacta, and thus, can represent a link between Mn exposure and its potential effects for development of Parkinson's disease.

Para-aminosalicylic acid (PAS), an approved drug for treatment of tuberculosis, is a promising therapeutic agent for treatment of manganese (Mn)-induced parkinsonian syndromes. Lack of a quantifying method, however, has hindered the clinical evaluation of its efficacy and there upon new drug development. This study was aimed at developing a simple and effective method to quantify PAS and its major metabolite, N-acetyl-para-aminosalicylic acid (AcPAS), in plasma, cerebrospinal fluid (CSF) and tissues. Biological samples underwent one-step protein precipitation. The supernatant was fractionated on a reversed-phase C18 column with a gradient mobile system, followed by on-line fluorescence detection. The lower limits of quantification for both PAS and AcPAS were 50 ng/ml of plasma and 17 ng/g of tissues. The intra-day and inter-day precision values did not exceed 5% and 8%, respectively, in all three matrices. The method was used to quantify PAS and AcPAS in rat plasma and brain following a single iv injection of PAS. Data showed a greater amount of PAS than AcPAS in plasma, while a greater amount of AcPAS than PAS was found in brain tissues. The method has been proven to be sensitive, reproducible, and practically useful for laboratory and clinical investigations of PAS in treatment of Mn Parkinsonism.

The choroid plexus, a barrier between the blood and cerebrospinal fluid (CSF), is known to accumulate lead (Pb) and also possibly function to maintain brain's homeostasis of Abeta, an important peptide in the etiology of Alzheimer's disease. This study was designed to investigate if Pb exposure altered Abeta levels at the blood-CSF barrier in the choroid plexus. Rats received ip injection of 27 mg Pb/kg. Twenty-four hours later, a FAM-labeled Abeta (200 pmol) was infused into the lateral ventricle and the plexus tissues were removed to quantify Abeta accumulation. Results revealed a significant increase in intracellular Abeta accumulation in the Pb-exposed animals compared to controls (p

Dear Editor: Gunter et al. may have mixed the concepts of the subcellular distribution with the end point of cellular toxicity. In our discussion, we have explicitly pointed out that “a relatively small amount of Mn in the mitochondrial fraction as demonstrated by this and Morello’s work should not rule out the importance of mitochondria in Mn-induced cytotoxicity, as the structural and functional integrity of mitochondria is pivotal to the cell survival.” In fact, our own studies have found that Mn exposure inhibits mitochondrial [Fe-S] containing enzymes including aconitase and Complex-I (Zheng et al., 1998; Chen at al., 2001). Detrimental effect of Mn on mitochondria notwithstanding, our finding on less than 0.5% of cellular 54Mn recovered from the mitochondrial fraction is indeed surprising, yet reflecting the experimental outcomes. As to the “high concentration” of Mn (100 μM) used in our study, we had read, prior to our experimentation, the comment made by Gunter et al., 2006, quoted as “Based on published data from tissue Mn measurements and observation of symptoms in monkeys, taken after weekly injections of Mn at a range of doses over a period of months, the threshold for clinical signs of toxicity was around 100 μM in globus pallidus and stratum and increase in both severity and frequency with concentration above that level” (page 1824). The Mn concentration in our report was so justified as taking into consideration this and other reports. We wish to point out that the presence of suggested “redistribution of Mn2+” in the fractionation study bespeaks the fact that Mn ions may in fact loosely bind to the mitochondrial components. Hence, the minuscule amount of Mn in mitochondria is deemed to be insignificant with regards to the overall subcellular storage of Mn. Respectfully, Kiran Kalia, Ph.D. Sardar Patel University, Vallabh Vidyanagar, Gujarat, India Wendy Jiang, M.D., Ph.D. Purdue University, West Lafayette, Indiana, USA Wei Zheng, Ph.D. Purdue University, West Lafayette, Indiana, USA

Manganese (Mn) is known to pass across the blood–brain barrier and interact with dopaminergic neurons. However, the knowledge on the subcellular distribution of Mn in these cell types upon exposure to Mn remained incomplete. This study was designed to investigate the subcellular distribution of Mn in blood–brain barrier endothelial RBE4 cells, blood–cerebrospinal fluid barrier choroidal epithelial Z310 cells, mesencephalic dopaminergic neuronal N27 cells, and pheochromocytoma dopaminergic PC12 cells. The cells were incubated with 100 μM MnCl2 with radioactive tracer 54Mn in the culture media for 24 h. The subcellular organelles, i.e., nuclei, mitochondria, microsomes, and cytoplasm, were isolated by centrifugation and verified for their authenticity by determining the markers specific to cellular organelles. Data indicated that maximum Mn accumulation was observed in PC12 cells, which was 2.8, 5.2- and 5.9-fold higher than that in N27, Z310 and RBE4 cells, respectively. Within cells, about 92%, 72%, and 52% of intracellular 54Mn were found to be present in nuclei of RBE4, Z310, and N27 cells, respectively. The recovery of 54Mn in nuclei and cytoplasm of PC12 cells were 27% and 69%, respectively. Surprisingly, less than 0.5% and 2.5% of cellular 54Mn was found in mitochondrial and microsomal fractions, respectively. This study suggests that the nuclei may serve as the primary pool for intracellular Mn; mitochondria and microsomes may play an insignificant role in Mn subcellular distribution.

Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors likely play an etiological role. Harmane (1-methyl-9H-pyrido[3,4- b ]indole) is a potent tremor-producing neurotoxin. In 2002, we demonstrated elevated blood harmane concentrations in an initial sample of 100 ET cases compared to 100 controls. Between 2002 and 2007, we assembled a new and larger sample of ET cases and controls. We now attempt to replicate our previous findings. Cases and controls were frequency-matched on age, gender, and race. Blood harmane concentrations were quantified by high-performance liquid chromatography. Subjects comprised 150 ET cases and 135 controls (mean age 65.3 ± 15.5 vs. 65.5 ± 14.2 years, p = 0.94). Mean log blood harmane concentration was ∼50% higher in cases than controls (0.50 ± 0.54 g −10 /ml vs. 0.35 ± 0.62 g −10 /ml, p = 0.038). In a logistic regression analysis, log blood harmane concentration was associated with ET (OR adjusted 1.56, 95% CI 1.01–2.42, p = 0.04), and odds of ET was 1.90 (95% CI 1.07–3.39, p = 0.029) in the highest versus lowest log blood harmane tertile. Log blood harmane was highest in ET cases with familial ET (0.53 ± 0.57 g −10 /ml), intermediate in cases with sporadic ET (0.43 ± 0.45 g −10 /ml) and lowest in controls (0.35 ± 0.62 g −10 /ml) (test for trend, p = 0.026). Blood harmane appears to be elevated in ET. The higher concentrations in familial ET suggests that the mechanism may involve genetic factors.

BACKGROUND: There is high unmet need in frail pts with relapsed CLL, particularly in those characterized by adverse prognostic factors such as presence of del(17p) and/or TP53 mutations. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kd recently approved for the treatment of relapsed CLL in combination with R. This report describes results from the 2nd interim analysis (IA) of a Phase 3 study evaluating IDELA in combination with R in relapsed CLL with focus on various risk subgroups of pts. METHODS: A Phase 3 study evaluated IDELA+R vs placebo (PBO)+R in pts with CLL requiring therapy after progression RESULTS: 220 pts (110/group) with median age of 71 yrs (78% ≥65 yrs), median time since diagnosis of 8.5 yrs, and median number of 3 prior therapies (range: 1-12) were randomized. 43% had del(17p)/TP53 mutation and 84% had unmutated IGHV. At the time of data cut-off, the median (range) exposure was 5 (0-17) mos on IDELA+R and 4 (0-15) mos on PBO+R. 76% of pts on IDELA+R and 46% of pts on PBO+R were continuing on study. Median PFS was not reached for pts on IDELA+R and was 5.5 mos for pts on the comparator arm. At 12 months, the PFS rates for pts on IDELA treatment was 66% compared to 13% for pts on PBO+R. PFS strongly favored IDELA+R in all risk-subgroups, including those with genetic risk factors such as del(17p)/TP53 mutations, del(11q) (FIGURE 1) or unmutated IGHV as well as with disease-related risk factors like advance Rai stage or high levels of β2-microglobulin. Adverse events (any Gr/Gr ≥3) occurring in ≥20% of pts on IDELA treatment were: pyrexia (IDELA+R 35%/3%; PBO+R 17%/1%), fatigue (IDELA+R 28%/3%; PBO+R 27%/2%), nausea (IDELA+R 26%/0%; PBO+R 21/0%), chills (IDELA+R 21%/2%; PBO+R 16%/0%), diarrhea/colitis (IDELA+R 21%/5%; PBO+R 15%/0%). ALT/AST elevation (any Gr/Gr ≥3) occurred in 40%/8% of pts on IDELA+R and in 20%/1% of pts on PBO+R. At the time of this analysis, 19 total deaths had occurred on the primary study: 6 on IDELA+R and 13 on PBO+R. TABLE 1: Summary of efficacy in various risk subgroups, and safety. TABLE 1:. Summary of efficacy in various risk subgroups, and safety. a) Number of patients on both arms evaluable at the time of analysis b) Number of patients on both arms with respective test result. Note: Distribution of risk features on both arms was balanced. c) Includes 16 preferred terms FIGURE 1: KM estimates of PFS in pts with del(17p) or TP53mutation or del(11q) vs pts without any of these factors. IDELA+R without these risk factors: median PFS 12.1 mos (74% at 12 mos); IDELA+R with these risk factors: median PFS not reached (62% at 12 mos); PBO+R without these risk factors: median PFS 8.2 mos (19% at 12 mos); and PBO+R with these risk factors: median PFS 4 mos (8% at 12 mos). Curve comparison: Pts with these risk factors: HR = 0.16 (95% CI: 0.08, 0.32); Pts without these risk factors: HR = 0.24 (95% CI: 0.09, 0.66). FIGURE 1:. KM estimates of PFS in pts with del(17p) or TP53mutation or del(11q) vs pts without any of these factors. IDELA+R without these risk factors: median PFS 12.1 mos (74% at 12 mos); IDELA+R with these risk factors: median PFS not reached (62% at 12 mos); PBO+R without these risk factors: median PFS 8.2 mos (19% at 12 mos); and PBO+R with these risk factors: median PFS 4 mos (8% at 12 mos). Curve comparison: Pts with these risk factors: HR = 0.16 (95% CI: 0.08, 0.32); Pts without these risk factors: HR = 0.24 (95% CI: 0.09, 0.66). CONCLUSIONS: IDELA+R demonstrated statistically significant improvement over PBO+R in PFS, ORR, and OS with an acceptable safety profile in these frail pts with relapsed CLL. These results confirm the 1st interim analysis of comparable efficacy of IDELA+R across all risk groups, including those with high-risk genomic markers like del(17p), TP53 mutations, and del(11q). Disclosures Sharman: Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. Furman:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. O'Brien:Gilead Sciences: Research Funding. Tausch:Gilead Sciences: Research Funding. Kreuzer:Gilead Sciences: Research Funding. Jiang:Gilead Sciences: Employment, Equity Ownership. Lazarov:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Science: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Stilgenbauer:Gilead Sciences: Research Funding.

7011^ Background: Idelalisib (IDELA) is a potent and selective inhibitor of PI3Kδ, which is critical for activation, proliferation and survival of B cells and their homing and retention in lymphoid...

Manganese (Mn) intoxication results in neurological conditions similar, but not identical, to idiopathic Parkinson’s disease. While the mechanism(s) by which Mn exposure leads to neurotoxic effects remains unclear, studies by magnetic resonance imaging demonstrate a high Mn accumulation in the hippocampal formation (HPCf) of the brain. Metal quantification using this method is not possible. Using x-ray fluorescence imaging, we measured the distribution of Mn in the HPCf for a rodent model of chronic Mn exposure and quantitatively compared it with distributions of other biologically relevant metals. We found considerable increases in average Mn concentrations in all analyzed areas and we identified the dentate gyrus (DG) and the cornus ammonis 3 (CA3) layer as areas accumulating the highest Mn content (~1.2 µg Mn/g tissue). The DG is significantly enriched with iron (Fe), while the CA3 layer has high zinc (Zn) content. Additionally, significant spatial correlations were found for Mn/Zn concentrations across the identified substructures of the HPCf and for Mn/Fe concentrations in the DG. Combined results support that at least two mechanisms may be responsible for Mn transport and/or storage in the brain, associated with either Fe or Zn. Subcellular resolution images of metal distribution in cells of the CA3 show diffuse Mn distributions consistent with Mn localization in both the cytoplasm and nucleus. Mn was not increased in localized intracellular Fe or copper accumulations. A consistent Mn/Zn correlation both at the tissue (40 µm × 40 µm) and cellular (0.3 µm × 0.3 µm) levels suggests that a Zn transport/storage mechanism in the HPCf is likely associated with Mn accumulation.