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Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study
Øystein Fluge ,
* E-mail: oystein.fluge@gmail.com
Affiliation Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
Ove Bruland,
Affiliations Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway, Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
Kristin Risa,
Anette Storstein,
Affiliation Department of Neurology, Haukeland University Hospital, Bergen, Norway
Einar K. Kristoffersen,
Affiliation Department of Immunology and Transfusion Medicine, Haukeland University Hospital, and The Gade Institute, University of Bergen, Bergen, Norway
Dipak Sapkota,
Halvor Næss,
Olav Dahl,
Affiliations Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway, Institute of Internal Medicine, Section of Oncology, University of Bergen, Bergen, Norway
Harald Nyland,
Olav Mella
Øystein Fluge,
Øystein Fluge Ove Bruland ... Olav Mella
Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.
In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m2 or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients.
The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8–44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6–10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.
The delayed responses starting from 2–7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS.
Trial registration
ClinicalTrials.gov NCT00848692
Citation: Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, et al. (2011) Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. PLoS ONE 6(10): e26358. https://doi.org/10.1371/journal.pone.0026358
Editor: Markus Reindl, Innsbruck Medical University, Austria
Received: June 28, 2011; Accepted: September 25, 2011; Published: October 19, 2011
Copyright: © 2011 Fluge et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The work received financial support from Helse Vest grant no 911557, and also from the legacy of Torstein Hereid. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: Haukeland University Hospital has patents and pending patent applications on the issue of B-cell depletion therapy for chronic fatigue syndrome. Family members of WO2009083602 A1 are pending, as well as granted US 12/348024. The two authors ØF and OM are named as inventors in these applications. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
Chronic fatigue syndrome (CFS)/Myalgic encephalomyelitis (ME) is an illness of unknown aetiology. CFS is characterized by unexplained severe fatigue, excessive post-exercise exhaustion and malaise, sleep disturbances, cognitive impairment, sensory hypersensitivity, muscle and joint pain, headache, bowel symptoms, flu-like episodes and severe impairment of daily functioning. CFS is a major public health problem, with extensive family and public costs for medication, nursing and disability [1], [2]. The prevalence estimates vary up to 1%, but is probably 0.1–0.2% of the population using strict diagnostic criteria [3]. There is at present no established interventional drug treatment for CFS. However, infections frequently precede the outbreak of symptoms and studies point at the immune system being chronically activated [1].
The present line of investigation was initiated after we observed a patient with CFS who experienced unexpected and marked recovery of CFS symptoms lasting for five months during and after cytotoxic chemotherapy for Hodgkin's disease. We recently published the first pilot case series describing clinical activity from B-lymphocyte depletion using the anti-CD20 monoclonal antibody Rituximab in three CFS patients [4]. These observations suggest that B-cells play a significant role in the ongoing clinical features of CFS, and provide clues to possible aetiological mechanisms. To pursue these clues, we performed a randomised, double-blind and placebo-controlled phase II study using Rituximab or saline, in 30 CFS patients.
The study, including amendment, was approved by the Regional Ethical Committee in Norway, no 200800657-9/MRO/400, and by the National Medicines Agency. All patients gave written consent to participate in the study.
Study design, pre-treatment evaluation, and randomisation
This study (KTS-1-2008, EudraCT no. 2007-007973-22, ClinicalTrials.gov NCT00848692) was a single centre, randomised, double-blind, and placebo-controlled phase II trial comprising 30 patients with chronic fatigue syndrome (CFS). The protocol for this trial and supporting CONSORT checklist are available as supporting information (Protocol S1 and Checklist S1). The main aim was to evaluate the use of B-cell depletion with the anti-CD20 monoclonal antibody Rituximab for CFS symptom relief, during 12 months follow-up. The inclusion criteria were: a diagnosis of CFS by a neurologist, according to the Fukuda 1994 criteria [5], age 18–65 years, and written informed consent. Exclusion criteria were: fatigue not fulfilling CFS criteria, previous malignant disease (except basal cell carcinoma and cervical dysplasia), previous long-term immunosuppressive treatment, previous Rituximab treatment, endogenous depression, lack of ability to adhere to protocol, or evidence of on-going infection.
The primary end-point was effect on CFS symptoms (self-reported and physician-assessed) three months after intervention. The secondary endpoints were effects on CFS symptoms (self-reported and physician-assessed) at 2, 4, 6, 8, 10 and 12 months after intervention, and assessment of toxicity during 12 months follow-up. Overall clinical response was also recorded. In November 2008, an amendment was submitted to the Regional Ethical Committee (approved January 2009), with addition to the initial protocol of secondary endpoints at 8 and 10 months after inclusion. This amendment was based on observation of patient 3 in our pilot case series, who had a major clinical response occurring late after Rituximab intervention [4]. The sample size was estimated based on the initial case series [4], showing response in three out of three consecutive patients, presuming an overall response rate (ORR) of at least 60%, and one or two responders among 15 placebo patients.
Most of the participants were recruited from patients referred to Department of Neurology, Haukeland University Hospital, which is a tertiary referral centre. After examining the patient hospital files from approximately 60 patients, 36 patients who after a telephone interview still seemed to fulfil the inclusion criteria were invited to a new thorough assessment at the Department of Oncology, Haukeland University Hospital (ØF and OM). Six out of these 36 patients chose not to participate (Figure 1).
Figure 1. Study flow-diagram.
Approximately 60 patients with CFS diagnosed by a neurologist were identified from the hospital files and contacted by telephone for an interview, and 36 of these were invited for a further thorough assessment. During 12 months follow-up, one out of 15 patients in the placebo group was excluded from further analysis after 28 weeks due to pregnancy, and one after 42 weeks due to study withdrawal and patient's decision to start alternative therapy.
The pre-treatment evaluation included standard laboratory tests (haematological, liver function, renal function), HCG to exclude pregnancy in fertile women, endocrine assessment (thyroid, adrenal, prolactin), serology for virus (EBV, CMV, HSV, VZV, Enterovirus, Parvovirus B19, adenovirus), immunophenotyping of peripheral blood lymphocyte subsets, common autoantibodies, serum immunoglobulins (IgG, IgM, IgA) with IgG subclasses. MRI of the brain had been performed in all patients. Further diagnostic tests were performed if the pre-treatment evaluation including a thorough clinical examination revealed any relevant abnormality that could explain the severe fatigue experienced by the patients.
The 30 patients were randomly allocated to either treatment with Rituximab or placebo using saline. The randomisation was performed prior to study start by the Pharmacy at Haukeland University Hospital, using a simple (unrestricted) method without blocking. The inclusion period was from June 2008 until June 2009, and the follow-up lasted until June 2010.
According to protocol, four months after the last patient entered the study (end of October, 2009), the patient files and code for intervention, Rituximab versus placebo, were inspected by one of the authors (OD, who did not have patient contact). Based upon his assessment, a decision was made to prolong the blinding until the last included patient had finished eight months follow-up (end of February 2010), at which time 19 patients had finished 10 months follow-up, and 13 patients had finished the complete 12 months observation period. The patients were blinded for group allocation until the end of follow-up (at least 12 months, up to 20 months).
Treatment schedule, symptom registration, and follow-up
The patients were in-hospital at the Department of Oncology for one night when given the intervention. The infusion bags had double plastic covers to avoid content identification by nurse or patient. Rituximab 500 mg/m2 (maximum 1000 mg), diluted in saline to a concentration of 2 mg/ml, or an equal volume of saline, were given twice two weeks apart, with nurse surveillance and according to local guidelines used for treating B-cell lymphomas. No additional Rituximab infusions, or other intervention, were given during follow-up. All patients were given oral cetirizine 10 mg, paracetamol 1 g, and dexamethasone 8 mg prior to infusion.
CFS symptom scoring
Before intervention, the patients assessed their CFS disease status the last three months and recorded their symptoms according to a visual analogue scale (1–10, 1: no symptom, 10: very severe symptom) (Figure S1). During follow-up, the patients recorded overall change in each symptom the preceding two weeks, as compared to baseline (Figure S2). The visual analogue scale (0–6) for the follow-up scheme was: 0: Major worsening; 1: Moderate worsening; 2: Slight worsening; 3: No change; 4: Slight improvement; 5: Moderate improvement; 6: Major improvement, similar to a Clinical Global Impression Scale used previously in CFS [6]. The patients were assessed at the outpatient clinic pre-treatment, and at 2, 3, 4, 6, 8, 10, and 12 months follow-up. A separate scheme for physician-assessed symptom change was used, with the same scale (0–6) and recorded at all visits (Figure S3). Pre-treatment, and once every month until 10 months follow-up, the patients recorded the SF-36 short form scheme (Norwegian translation), which is a general health-related quality of life questionnaire also assessing eight subdimensions, such as e.g. physical function, bodily pain, social function and mental health. Before treatment, and at 4 months follow-up, the patients were in addition assessed by a neurologist. Patients still in clinical response were followed also after the study period of 12 months.
Response definitions and statistical analyses
From the self-reported symptoms recorded every second week (Figure S2, scale 0–6), a Fatigue score was calculated as the mean of the four symptoms: Fatigue, Post-exertional exhaustion, Need for rest, Daily functioning. The Pain score was calculated as the mean of the two pain symptoms assessed to be characteristic for the patient (if pre-treatment level ≥5, among Muscle pain, Joint pain, Headache, Cutaneous pain). The Cognitive score was the mean of the three symptoms: Concentration ability, Memory disturbance, Mental tiredness. The "Other symptoms score" was derived from the mean of the two symptoms assessed as characteristic for the patient's CFS disease, among those with the highest self-reported pre-treatment level. Also, the patient's self-reported overall interpretation of their CFS disease was recorded ("CFS overall score"). The Fatigue score, Pain score, Cognitive score, "CFS overall score", and "Other symptoms score", were plotted every second week, for each patient in separate diagrams.
The main response was defined from the Fatigue score. A major response was defined as a Fatigue score ≥4.5 for at least six consecutive weeks, also demanding recordings of some fatigue symptoms as major improvement (value 6) during the response period. A moderate response was recorded as Fatigue score ≥4.5 for at least six consecutive weeks, but without recordings of fatigue symptoms as major improvement during the response period. The ORR included both major and moderate responses. The Chi-square test of proportions was used to compare the ORR between the Rituximab and Placebo groups. Improvements in Fatigue score with duration less than six weeks were not recorded as significant responses, neither were major improvements in Cognitive, Pain or "Other symptoms" score unless followed by a significant improvement in Fatigue score.
The self-reported Fatigue scores with means for each time interval during follow-up (i.e. 16–24 weeks), and physician-assessed Fatigue scores, were plotted. The differences in distribution of Fatigue scores for the consecutive time intervals during follow-up, between the Rituximab and Placebo groups, were compared using General Linear Model (GLM) for repeated measures. Separate analyses for self-reported and physician-assessed Fatigue scores were made. Five time intervals (with mean Fatigue scores in each) were included in the analyses, and Greenhouse-Geisser adjustments were made due to significant Mauchly's tests for sphericity. Main effects for time, for the interaction between time and intervention group, and for the overall difference between groups (Rituximab versus Placebo) were assessed. In addition, the estimates for differences in Fatigue score between groups at the five time intervals during follow-up, each level compared to baseline, were generated from the GLM analyses for the interaction time by intervention group (as tests of within-subjects contrasts).
The response durations were defined as the time interval, during 12 months follow-up, with continuous Fatigue score ≥4.0 and including the periods of major or moderate responses. The analyses of SF-36 short forms, with physical health summary score, mental health summary score, and scores for the eight SF-36 subdimensions, were generated from a standardised syntax file for each patient before treatment and monthly until 10 months follow-up. The changes in SF-36 scores, compared to baseline, were calculated for each patient during follow-up. For the Rituximab and Placebo groups, the mean baseline SF-36 scores, and the mean values for maximum changes in SF-36 scores during follow-up, were compared using t-tests for independent samples. The statistical analyses were performed using SPSS for Macintosh, version 19.
Between June 2008 and June 2009, 30 patients were randomised. The demographic data and CFS disease characteristics are shown in Table 1. The mean age was 37.3 years (80% female) in the Rituximab group, and 31.5 years (60% female) in the Placebo group. The mean CFS disease duration was 5.1 years in the Rituximab group and 8.1 years in the Placebo group, with maximum disease durations of 13 and 18 years, respectively. A clear or possible clinical infection preceding CFS onset could be identified in 73% and 67% of the patients in the Rituximab and Placebo groups, respectively (Table 1). The frequencies of previous autoimmune diseases for patients and first-degree relatives are also shown (Table 1). The baseline symptom scores were derived from the baseline scheme (Figure S1, scale 1–10) as explained, and are shown in Table 2. The levels of baseline self-reported Fatigue score, Cognitive score, Pain score, "Other symptoms" score, and "CFS overall" score, were similar in the Rituximab and Placebo groups. Generally, the patients reported a relatively high level of distress for the different symptom scores, while one patient in the Placebo group reported almost no pain (score 1.3), and one patient in the Placebo group reported only mild cognitive symptoms (score 4.0) (Table 2).
Table 1. Demographic and CFS disease characteristics for patients in the Rituximab and Placebo groups.
Table 2. Baseline self-reported symptom scores, RNase L genotype, and XMRV status, for patients in the Rituximab and Placebo groups.
Lymphocyte subpopulations, including CD19 positive B cells, were determined in EDTA anticoagulated blood samples before treatment, and during all follow-up visits (2, 3, 4, 6, 8, 10 and 12 months). Immunophenotyping of lymphocyte subpopulations was performed using the BD Multitest 6-color TBNK kit with BD Trucount Tubes for relative and absolute concentration determination (BD Biosciences). The samples were prepared according to the manufacturers instructions and immediately analysed on a BD Canto II flowcytometer (BD Biosciences). These data were not made available to the clinical researchers before the end of the study.
Quantitative PCR and PCR for XMRV and MLV, RNase L genotyping
For details of DNA and RNA purification, cDNA synthesis, Quantitative PCR for XMRV detection, XMRV and MLV PCR, Viral amplification, and RNase L genotyping, see Text S1 and Table S1.
Clinical responses
Overall response was recorded from the self-reported Fatigue scores, defined as lasting improvements for at least six consecutive weeks, independent on when the responses occurred during follow-up. A major response was detected in nine patients in the Rituximab group, and in one patient in the Placebo group (p = 0.002). One patient in the each group achieved a moderate response, giving an total ORR of 10 patients in the Rituximab group (67%, 95%CI 41%–85%) and two patients in the Placebo group (13%, 95%CI 4%–38%), p = 0.003 (Table 3).
Table 3. Clinical responses in the Rituximab and Placebo groups, and response durations for patients with significant responses, derived from self-reported Fatigue scores during 12 months follow-up.
The effect of intervention was assessed by studying the interaction effect between time and intervention group, from GLM for repeated measures of self-reported Fatigue score. There was a significant interaction time by intervention group in favour of the Rituximab group (p = 0.018), and an overall difference between groups (p = 0.045) (Figure 2, panels A and B, Table S2). Similarly, in GLM for repeated measures of physician-assessed Fatigue score, the interaction time by intervention group (p = 0.024) and the overall difference between groups (p = 0.021) were both significant in favour of the Rituximab group (Figure 2, panels C and D, Table S2).
Figure 2. Fatigue scores in Rituximab and Placebo groups, self-reported and physician-assessed.
In panel A, the self-reported Fatigue scores were calculated for each patient every second week, from the mean of the four symptoms: Fatigue, Post-exertional exhaustion, Need for rest, Daily functioning. Then the mean values in Fatigue scores for the time intervals during follow-up were plotted. In panel C, the physician-assessed Fatigue scores were calculated from the mean of the same four symptoms, registered by the physician at the visits in the outpatient clinic. In panel B and D, estimated marginal means for self-reported and physician-assessed Fatigue scores during follow-up are shown. The scales on Y-axes were 0–6 (0: Major worsening; 1: Moderate worsening; 2: Slight worsening; 3: No change; 4: Slight improvement; 5: Moderate improvement; 6: Major improvement). The differences in distribution of Fatigue scores during follow-up, between the Rituximab and Placebo groups, were assessed by General Linear Model (GLM) for repeated measures, analysing the effects of time, the interaction time by intervention group, and the overall difference between intervention groups. Below panels C and D, the estimates for differences in mean Fatigue scores between the Rituximab and Placebo groups at the specific time intervals during follow-up, with 95% CI and p-values from the GLM (tests of within-subjects contrasts) are presented. In addition, Holm-Bonferroni step-down adjusted p-values for these time intervals are shown (five comparisons).
From the GLM tests of within-subjects contrasts for the interaction time by intervention group, with estimates for differences in Fatigue score between groups at the specific time intervals, there was no difference in self-reported Fatigue scores between the Rituximab and Placebo groups at the predetermined primary endpoint three months after intervention neither from self-reported nor from physician-assessed symptom scores (Figure 2, panels A–D). The differences in Fatigue scores between intervention groups were most evident between 6–10 months after intervention (Figure 2, panels A–D), i.e. corresponding to secondary endpoints of the study.
The response durations within 12 months follow-up are shown in Table 3, with mean duration 25 weeks (range 8–44) for the 10 responders in the Rituximab group. Interestingly, four patients in the Rituximab group, and one patient in the Placebo group, had response durations beyond the study period of 12 months, i.e. still Fatigue score ≥4 at 12 months. At the time of submission of this manuscript, two patients in the Rituximab group, and one patient in the Placebo group, have lasting major responses for all CFS-related symptoms without signs of relapse, 32, 30, and 23 months after intervention, respectively.
The self-reported symptoms scores were plotted every second week for each patient. These data are shown for the 10 responders in the Rituximab group (Figure 3, panels A–J), and for the two patients with significant improvement in the Placebo group (Figure S4, panels A–B). These charts show that symptoms in all the four main categories tend to follow each other in time. Also included in these plots are the B-cell numbers during follow-up.
Figure 3. CFS symptom changes during follow-up for patients in the Rituximab group with significant responses.
In panels A–J, changes in Fatigue score (black), Cognitive score (red), Pain score (green), "Other symptoms" score (orange), and "CFS overall" score (blue), during 12 months follow-up are shown for the 10 patients in the Rituximab group with significant improvement. The scales on Y-axes were 0–6 (0: Major worsening; 1: Moderate worsening; 2: Slight worsening; 3: No change; 4: Slight improvement; 5: Moderate improvement; 6: Major improvement). Also shown are the B-cell numbers from immunophenotyping of peripheral blood mononuclear cells during follow-up (×106/L).
The SF-36 short form, registering health related quality of life, was filled-in by the patients at baseline and every four weeks during follow-up. Two patients in the Rituximab group did not fill in baseline SF-36 form and were excluded from these analyses, one with a major response and one with no response during follow-up. The patients reported a low baseline "physical health summary score", with a mean value of 24 in the Rituximab and 26 in the Placebo group (scale 0–100, lower value denotes worse symptoms), while the baseline "mental health summary score" was higher with a mean value of 46 in both groups (Table 4). There were no differences in baseline levels for the different SF-36 subdimensions, except for "general health", which was lower in the Rituximab group than in the Placebo group (Table 4). During follow-up, the maximum changes in SF-36 scores (as compared to the baseline level) were significantly different in favour of the Rituximab group, for "physical health summary score" (p = 0.039), and the subdimensions "physical function" (p = 0.014) and "bodily pain" (p = 0.005), while there were trends for difference for "general health" (p = 0.081) and "social function" (p = 0.081). There were no differences in maximum changes (compared to baseline) during follow-up between the Rituximab and Placebo groups, for instance for the subdimensions "role emotional" (p = 0.44) or "mental health" (p = 0.81) (Table 4).
Table 4. SF-36 scores, baseline levels (0–100) and maximum changes (%) during follow-up, for patients in the Rituximab and Placebo groups.
In spite of written and verbal information to avoid pregnancy, one patient was pregnant after 28 weeks follow-up. The randomisation code for this patient was then revealed. She was allocated to the placebo group and was withdrawn from further follow-up registration after 28 weeks. One patient decided to withdraw from the study after 42 weeks follow-up to start alternative therapy. This patient proved also to be allocated to the placebo group.
Infusion-related complaints and side-effects during 12 months follow-up are listed in Table 5. There were no serious adverse events or major toxicity. The complaints during infusion or the following day were mild and also reported by the placebo patients (five in the Rituximab group and four in the Placebo group). Two patients in each group reported slight worsening of CFS the first two months after intervention (Table 5). Two patients in the Rituximab group reported feeling uneasy and sleepless from 2–7 and 6–8 months, respectively, synchronous with a clear clinical response. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening from two months after intervention, in both preceding a clinical response of CFS. One patient in the Rituximab group had a five years history of major CFS symptoms, and reported some lower back pain and episodes of balanitis from 5–7 months, synchronous with improvement of his CFS-related muscle pain and headache and with improving fatigue and cognitive function. His low back pain disappeared, and after the 12 month study period his CFS symptoms have resolved further and he is at present back in full-time work 30 months after intervention.
Table 5. Infusion-related complaints during or the first 24 hours after infusion, and side-effects during 12 months follow-up, in the Rituximab and Placebo groups.
There were some uncomplicated upper airways infections and lower urinary tract infections during follow-up, evenly distributed between the two groups. There were two hospitalisations during the study period within 12 months follow-up, one in the Rituximab group due to abdominal pain where a laparoscopy showed a corpus luteum cyst interpreted as a normal finding, and one in the Placebo group due to a myocardial infarction.
XMRV
In this study, XMRV could not be detected in any of the 30 patients, using four Taqman quantitative PCR setups, and four nested PCR approaches (Text S1 and Table S1), and using both genomic DNA and cDNA from baseline blood samples as templates. When performing coculture of patient lymphocytes with LNCaP prostate cancer cells for biological amplification prior to PCR, XMRV was not detected in any sample. The positive control was readily amplified in all setups, and both sensitivity and specificity of the Taqman assays proved to be high, detecting 5–15 viral copies per vial with dilution series of the plasmid spiked in normal genomic DNA background (data not shown). For details on analyses, see Supporting information.
RNase L
Results from genotyping of the RNase L Q462R variant are shown in Table 2. Two patients in the Placebo group had the 462 R/R genotype. The distribution of the Q/Q, Q/R, and R/R alleles was close to that expected in the general population.
Results from immunophenotyping with B-cell counts, for patients in the Rituximab group (responders and non-responders) and the Placebo group, from baseline and at all visits at 1, 2, 3, 4, 6, 8, 10, and 12 months, are shown in Figure 4. At baseline, three out of 30 patients had a B-cell count below the normal range (110–449×106/L). All patients in the Rituximab group were B-cell depleted at one month after the intervention, except for one patient in which B-cells were not adequately depleted until four months after intervention (Figure 4). During follow-up, there were no differences in B-cell levels between patients in the Rituximab group achieving a response (n = 10), and those with no significant response (n = 5) (Figure 4). Many patients treated with Rituximab were not completely B-cell depleted, with values in the range 0–4 (×106/L) (Figure 4). After two infusions of Rituximab two weeks apart, the B-cell levels started to increase from 4–8 months after intervention, and four out of 15 patients had regained B-cell counts in the normal range at the end of follow-up at 12 months. We also performed Taqman qPCR for the B-cell specific CD19 molecule, normalised according to β-actin mRNA, at baseline and during follow-up at 4, 6 and 8 months. These data confirmed the B-cell depletion in Rituximab-treated patients but could not separate the Rituximab responders and non-responders (data not shown).
Figure 4. B-lymphocytes during follow-up.
B-cell numbers from immunophenotyping of peripheral blood during follow-up are shown, for patients in the Placebo group (black, n = 15), patients in the Rituximab group with significant response (red, n = 10), and patients in the Rituximab group with no response (blue, n = 5). The B-cell value zero was substituted by 0.1 (to be able to plot on the log scale). B-lymphocyte counts ×106/L (normal range 110–449). The error bars denote mean ± SEM.
In this double-blind and placebo-controlled study, treatment with Rituximab (two infusions two weeks apart) was associated with a significant overall clinical response during 12 months follow-up, as compared to placebo using saline. The ORRs were 67% in the Rituximab group and 13% in the Placebo group.
From GLM for repeated measures, there were significant interactions between time and intervention group in favour of the Rituximab group both for self-reported and physician-assessed Fatigue scores. The differences were most evident corresponding to secondary endpoints between 6 and 10 months after intervention. However, at the predetermined primary endpoint, defined as effect on CFS symptoms (Fatigue score) at three months after intervention, there was no difference between the groups.
The change in Fatigue scores was chosen as the main criterion for clinical response because this is a key symptom defining the CFS disease. However, with few exceptions, the different symptoms scores (Fatigue, Cognitive, Pain, "Other symptoms", "CFS overall") followed each other during responses and relapses, indicating that a central mechanism for the symptom maintenance is influenced by the B-cell depletion treatment.
For the 10 Rituximab responders, the response durations varied from 8–44 weeks (within the 12 month study period). These responses were considered to have a significant impact on symptom improvement and quality of life by the patients, by their families, and by the treating physicians. Importantly, four patients in the Rituximab group and one in the Placebo group had response durations beyond 12 months. When submitting this manuscript, two patients in the Rituximab group and one in the Placebo group have lasting major responses with no signs of relapse and are back in full-time work. Two of these patients (one in each group) had the shortest disease durations, 1.0 and 0.7 years, respectively, and in both CFS was preceded by Epstein-Barr infection. These two lasting responses may be examples of spontaneous recovery [7]. The third "long-time responder" with no later relapse had a 5-year history with major CFS symptoms before entering the study.
This study with the primary endpoint at three months after intervention was designed when we had very limited experience with B-cell depletion in CFS, having observed only two pilot patients, both with an early response pattern. In the pilot case series [4] the third patient had major response occurring from 5 ½ until 9 months after intervention, and with an almost identical response and relapse pattern after her second Rituximab treatment. In the present study, only one out of 10 responders in the Rituximab group had an "early" response pattern with the major response starting from 2 months, while the remaining nine responded later, starting to improve from between 3–7 months after treatment.
The SF-36 short form analyses before intervention confirmed a low quality of life particularly for the dimensions related to physical health, while the subdimensions "mental health" and "role emotional" showed higher baseline values. In support for the overall clinical response data, SF-36 analyses during follow-up demonstrated significant differences in favour of the Rituximab group in maximum changes compared to baseline level, for several subdimensions related to physical health, such as "physical health summary score", "physical function" and "bodily pain". There were no significant differences between the groups in maximum changes for in the subdimensions "mental health" or "role emotional". These results support the assumption that CFS is not primarily a mental health disease.
The lack of specific markers of disease and the fact that the CFS diagnosis is controversial imply that the level of diagnostic accuracy and adherence to international criteria are likely to be variable. In this study, patients have been recruited from a tertiary referral centre and were re-evaluated by the researchers, using the Fukuda criteria for inclusion. Retrospectively, we checked the 30 patients according to the Clinical Working Case Definition ("Canadian criteria") [8]. Two patients in the placebo group did not fulfil these criteria, and it could therefore be argued that they might not have CFS. One of these had almost no pain, and one had only slight cognitive symptoms and also reported marked mood disturbances. The latter patient reported major improvement after intervention with saline and was recorded as one of the two responders in the Placebo group. Generally, the patients reported a high level of disease-related symptoms prior to entering the study, with major impact on daily life and ability to participate in family and social activities. Most of the patients had a long CFS disease duration, also with a stable or worsening clinical course the last year before study entry.
A limitation of this study is the lack of predetermined exact definitions of clinical response with respect to duration and extent of improvement. Limited experience with the clinical course of CFS after B-cell depletion when designing the protocol, with erroneous estimation of time frame for the clinical responses, is a main reason why the primary end-point is negative. Therefore, even though this is a randomised, double-blind and placebo-controlled study, there are also exploratory elements with respect to response characterization.
Even when interpreting the results with caution, there are obvious differences between the two groups in favour of the Rituximab group, from the significant interactions time by intervention group and also from difference in ORR. Thus, we have shown that in a subset of CFS patients, Rituximab treatment with subsequent B-cell depletion results in major responses of CFS related symptoms, with responses starting to occur between 2 and 7 months after intervention, and with response durations of 2–15 months and in addition two patients with no relapse. Five patients in the Rituximab group did not achieve a significant response during follow-up. Whether their CFS pathogeneses are unrelated to B-lymphocytes, or whether they could achieve a clinical response through prolonged B-cell depletion with Rituximab maintenance therapy is at present unknown.
The associations between B-cell depletion and clinical responses, and the time frames for clinical responses delayed 2–7 months after the initial and rapid B-cell depletion, indicate that CFS may be an autoimmune disease, often preceded by an infection, and targeting specific parts of the nervous system. We speculate that the responses occurring late after intervention could be explained by the elimination of disease-associated autoantibodies, while the early response pattern could be related to interaction of B-cells with T-cells in antigen presentation, as suggested in systemic lupus erythematosus [9]. Work is in progress in our laboratory to elucidate the localization and nature of a putative target for an autoimmune process.
The high rate of CFS in women compared to men is a suggestion of an underlying autoimmune process. On-going autoimmune phenomena in CFS have been discussed [10] perhaps triggered by infections through molecular mimicry, through structural similarity between a pathogen component and self-structures [11]. Several autoantibodies have been reported in CFS, but their pathogenic roles have not been established, for a review see [10]. In the present study, 23% of the patients had a previous known autoimmune disease, and 40% had first-degree relatives with an autoimmune disease. However, there were low frequencies of positive known common autoantibodies, none had elevated anti-nuclear antibodies, and two had elevated anti-thyroid peroxidase antibodies (data not shown). A possible or established clinical infection before CFS onset was identified in 21 out of 30 patients included (70%).
A recent study of cytokine patterns in CFS showed attenuated Th1 and Th17 immune responses, while there was high Th2 marker expression [12]. A Th2 profile with increase in the numbers of CD4+ and CD8+ T cells secreting IL-4 following polyclonal stimulation, including in resting cells, was demonstrated in CFS patients [13].
There are limited data on the role of B-lymphocytes in CFS. One study of gene expression in peripheral blood mononuclear cells indicated that B cells might be altered in CFS [14]. Our pilot case series [4] suggested that B-cell depletion was associated with clinical improvement in CFS patients. B-cell targeting therapy has been increasingly used for diverse autoimmune diseases in later years [15]. The monoclonal anti-CD20 antibody Rituximab has been the major B-cell depleting agent so far. The B-cells have multiple immune functions, the main ones being antibody production, antigen presentation and regulation of the function and activity of other immune cells, i.e. T-regulatory cells, NK cells and macrophages [16]. Thus, the total effects of B-cell depletion on the immune system are likely to be complex and time-dependent.
In Stiff Person Syndrome, which is a rare autoimmune disease in the central nervous system with autoantibodies targeting glutamic acid decarboxylase (GAD65), the humoral autoimmune response was shown to consist of a Rituximab-sensitive part rapidly cleared after treatment, and a Rituximab-resistant part from long-lived and persistent plasma cells acting as a reservoir for secretion of autoantibodies. This may be one mechanism for lack of effect from B-cell depletion therapy [17].
An alternative explanation for the observed clinical improvement from B-cell depletion could be elimination or reduction of B-lymphotrophic viruses such as cytomegalovirus (CMV) or Epstein-Barr virus (EBV). A recent study [18] showed clinical benefit from long-term valacyclovir or valgancicliovir treatment in a subset of CFS patients with evidence of active on-going herpes virus infections, also shown in a previous small study of 12 patients with elevated antibodies to EBV or human herpes virus 6 (HHV-6) [19]. We find the delayed clinical responses after B-cell depletion, that we observed in the majority of responders, difficult to explain from a viral elimination mechanism. In our opinion, this response pattern is more compatible with the gradual elimination of an autoantibody, perhaps by preferential elimination of short-lived pre-plasma cells. Although poorly understood, immune system alterations seen in stress-related diseases such as post-traumatic stress disorder could also be relevant for the effects of B-cell depletion seen in CFS [20].
In this study there were no serious adverse events. Two hospitalisations (one in each group) during follow-up were not perceived to be caused by the intervention. There were no serious infections. Two patients in the Rituximab group (both responders) had a slight to moderate worsening of pre-existing psoriasis, which could be a direct side-effect from the intervention. Two patients in the Rituximab group (also responders) felt uneasy and sleepless while improving in CFS symptoms. These symptoms are not usual side effects from treatment of B-cell lymphomas and may be related to the effects of B-cell depletion on the underlying CFS disease rather than direct side-effects from Rituximab. The infusion-related complaints were generally mild and reported both from the Rituximab and Placebo groups. Interestingly, no side-effects during follow-up were reported from the five non-responders in the Rituximab group.
Current use of Rituximab in autoimmune diseases has been discussed [21], and a recent review on the safety in rheumatoid arthritis concluded that Rituximab is well tolerated with no increasing rate of serious infections [22]. Even if serious side-effects including reactivation of viral infections such as hepatitis B are very rare, they may appear [23]. A study reviewing progressive multifocal leukoencephalopathy (PML) cases in patients treated with Rituximab, from available databases including the Food and Drug Administration, the manufacturer, physicians, and including a literature review from 1997–2008, identified 52 patients with lymphoproliferative disorders and five patients with autoimmune diseases [24]. All had received either chemotherapy or other immunosuppressive treatment in addition to Rituximab, and to our knowledge PML has not been reported in patients receiving Rituximab monotherapy. The absolute risk of PML is difficult to estimate, but is very low.
Although B-cell depletion has a major impact on the immune system, it can be argued that the persistent and often devastating symptoms of CFS and the very low quality of life in many sufferers justify the use of Rituximab in carefully evaluated CFS patients.
There has been an intense focus on XMRV as a possible causal gammaretroviral infection in CFS patients since the first report in October 2009 [25]. One later study demonstrated presence of closely related MLV in CFS patients [26]. However, several other studies have not been able to reproduce these findings and reported no evidence for XMRV infection in CFS, as examples [27]–[30]. We have not been able to demonstrate XMRV or MLV infection in any of the 30 patients included in this study, despite multiple different approaches including four different highly sensitive Taqman qPCR and four nested PCR approaches, and using both genomic DNA and cDNA as templates. We also performed coculture of patient peripheral blood mononuclear cells with LNCaP prostate cancer cells for biological virus amplification prior to PCR, also with no XMRV positive cases.
In conclusion, we have shown that B-lymphocyte depletion with the monoclonal anti-CD20 antibody Rituximab, two infusions two weeks apart, is associated with significant, though generally transient clinical responses, with CFS symptom improvement in two thirds of the included patients. No major toxicity was observed in 12 months follow-up. Even though this study is small, it is a randomised, double-blind, and placebo-controlled study showing significant differences in favour of the Rituximab group, and with general improvement of all CFS symptoms. Thus, we believe that B-cell depletion targets a central player in the pathogenesis of the CFS disease, directly or indirectly. Whether this mechanism applies to specific subsets of CFS patients or the group as a whole is a subject for further research. While this study can be interpreted as preliminary, being the first to describe the treatment principle in CFS except for our pilot case series [4], we believe the results are best compatible with an autoimmune disease mechanism and that the presented findings may have a major impact on the direction of biomedical research in CFS. Based on new pilot patient experiences, we have now started two new open-label phase-II studies investigating Rituximab treatment with two infusions two weeks apart (as in the present study) followed by maintenance Rituximab infusions at 3, 6, 10 and 15 months, to further explore this treatment principle in CFS (ClinicalTrials.gov, NCT01156909 and NCT01156922). The present study may be interpreted as a "proof of principle". The next studies will indicate to what extent the patients actually over time may recover through B-cell depletion treatment.
Text S1.
Materials and Methods (DNA and RNA purification, and cDNA synthesis. Quantitative PCR for XMRV detection. XMRV and MLV PCR. Viral amplification. RNase L Genotyping).
Scheme for patient's self-reported baseline CFS symptoms. Before intervention, the patients assessed their CFS disease and recorded their symptoms the last three months according to a visual analogue, scale 1–10 (1: no symptom; 5: moderate symptom; 10: very severe symptom).
Scheme for patient's self-reported CFS symptom change during follow-up. During 12 months follow-up, the patients recorded symptom changes the preceding two weeks, as compared to baseline. The visual analogue scale for the follow-up scheme was 0–6 (0: Major worsening; 1: Moderate worsening; 2: Slight worsening; 3: No change; 4: Slight improvement; 5: Moderate improvement; 6: Major improvement).
Scheme for physician-assessed CFS symptoms, at baseline and during follow-up. The patients were assessed at the outpatient clinic before intervention, and at 2, 3, 4, 6, 8, 10, and 12 months follow-up. The physicians assessed the patients CFS disease and recorded the symptoms according to visual analogue scales. Before intervention, the scale was 1–10 (1: no symptom; 5: moderate symptom; 10: very severe symptom). During 12 months follow-up, the physicians assessed patients symptom changes as compared to baseline, scale 0–6 (0: Major worsening; 1: Moderate worsening; 2: Slight worsening; 3: No change; 4: Slight improvement; 5: Moderate improvement; 6: Major improvement).
CFS symptom changes during follow-up, for the two patients in the Placebo group with significant improvement. In panels A and B, changes in Fatigue score (black), Cognitive score (red), Pain score (green), "Other symptoms" score (orange), and "CFS overall" score (blue), during 12 months follow-up are shown for the two patients in the Placebo group with significant improvement. The scales on Y-axes were 0–6 (0: Major worsening; 1: Moderate worsening; 2: Slight worsening; 3: No change; 4: Slight improvement; 5: Moderate improvement; 6: Major improvement). Also shown are the B-cell numbers from immunophenotyping of peripheral blood mononuclear cells during follow-up (×106/L).
Primers and probes for detection of Xenotropic murine leukemia virus-related virus (XMRV) and MLV-related virus.
Effects of intervention group (Rituximab versus Placebo) on Fatigue score during 12 months follow-up, using General Linear Model for repeated measures, with separate analyses for self-reported and physician-assessed symptoms.
(DOC)
Protocol S1.
Trial Protocol.
Checklist S1.
CONSORT Checklist.
The authors thank nurse Helle Øvrebø, the staff at the Lymphoma section, and at the outpatient clinic, Department of Oncology, Haukeland University Hospital. We are grateful to the patients who volunteered for the study.
Conceived and designed the experiments: ØF OM. Performed the experiments: ØF OM OB KR DS AS EK HN. Analyzed the data: ØF OB KR DS EK OM. Contributed reagents/materials/analysis tools: ØF OM OB HN EK OD. Wrote the paper: ØF OM. Revised the manuscript: ØF OB KR DS AS EK H.Næss OD H.Nyland OM.
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Is the Subject Area "B cells" applicable to this article?
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Is the Subject Area "Chronic fatigue syndrome" applicable to this article?
Is the Subject Area "Patients" applicable to this article?
Mental health and psychiatry
Is the Subject Area "Mental health and psychiatry" applicable to this article?
Is the Subject Area "Autoimmune diseases" applicable to this article?
Is the Subject Area "Polymerase chain reaction" applicable to this article?
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TOTD: 'This Town' – Jeremy Loops
Jeremy Loops is an unstoppable musical force following a series of releases that have amassed him over 180 million streams and growing. Now, Jeremy comes full circle to celebrate one of the most significant and influential moments in his life … a collaboration with the legendary Ladysmith Black Mambazo. The new Souvenirs EP features the momentous This Town single with Ladysmith Black Mambazo and unites generations of South Africans through their shared love of music.
"We would like people to get a sense of self-worth from the song and to be encouraged to work towards what they want in life and be patient and know that it will all work out in the end and don't be shy to ask for help if things are tough." – Ladysmith Black Mambazo
As one of the most iconic vocal groups in the world, Ladysmith Black Mambazo formed in the 60's to create traditional world music with energetic, uniquely spirited harmonies. Throughout their celebrated career, the group have won five Grammy awards and seventeen nominations for music that honors their proud heritage. Jeremy Loops' special bond with the group formed from an upbringing that brimmed with musical curiosity and included Graceland, the Paul Simon album that was inspired by and widely features Ladysmith Black Mambazo. His first experience of the astounding vocal power in Ladysmith Black Mambazo ended in tears for the young creative who was left in complete awe.
As a self-taught musician, Jeremy's South African background was filled with sunshine-soaked melodies, a love for surfing and constant Bob Dylan-esque experimentation. When he's not writing or singing, Jeremy finds inspiration in environmentally leaning work such as his co-founded eco-initiative, Greenpop. A much-loved household name in his home country, Jeremy's mountain of successes include collaborations with world-renowned acts like Ed Sheeran, Simone Felice (The Lumineers), Jake Gosling (Shawn Mendes), Tobias Kuhn (Milky Chance), and Carey Willets (Dermot Kennedy).
Despite our crappy graphics (yep, we sure did use Paint. There really is no... Read More+
Husky Loops
Our weekend was way better than yours. And involved far more train delays a... Read More+

redpajama_set_name: RedPajamaCommonCrawl


text:
Training/Onboarding
Supply Chain Education
The Supply Chain Mixes Up Executives
Companies in the supply chain are shuffling executives and offering new promotions.
Brielle Jaekel
Polina Zimmerman from Pexels
Anna Mateu Joins Anderson & Vreeland as Supply Chain Analyst
The appointment of Anna Mateu as supply chain analyst for Anderson & Vreeland, leading manufacturer of flexographic print technologies, equipment and consumables, is announced by Graig Sanderson, purchasing manager for Anderson & Vreeland Inc. Mateu joins Anderson & Vreeland Inc. as a supply chain analyst and will be working from the Irving, Tex. office. Her focus will be on inventory analyzation and, specifically 3M.
Brett Wood Appointed to Senior Executive Officer of Toyota Industries Corporation
Brett Wood, the president & CEO of Toyota Material Handling North America (TMHNA), was recently appointed to Senior Executive Officer of TMHNA's parent company, Toyota Industries Corporation (TICO). Wood becomes the only non-Japanese TICO executive.
Wood, a 31-year veteran of Toyota, will maintain his current responsibilities as TMHNA President & CEO in addition to his new role as an officer of TICO. Wood began his material handling career at Toyota in 1989 as an entry-level engineer and has held many leadership positions within the company in the three-plus decades since then. As president & CEO of TMHNA, Wood oversees two main group companies – Toyota Material Handling (TMH) in Columbus, Indiana, and The Raymond Corporation in Greene, New York.
Dollar Tree Announces Planned Leadership Succession
Dollar Tree, Inc. announced that Michael A. Witynski, 57, enterprise president of Dollar Tree, has been promoted to president and chief executive officer. Gary Philbin, 63, who joined Dollar Tree in 2001 and became CEO in 2017, is retiring after a successful retail career of more than 40 years. To facilitate a smooth transition, Mr. Philbin will remain with the company as an executive and member of the board of directors through Sept. 23, 2020.
Toyota Material Handling U.S.A., Inc.
Software Providers and Companies in Manufacturing, Distribution Have Executive Growth
CPG Supply Chains See New Promotions
Consultants Look for Growth with New Hires
Major Retailers Trade Seasoned Execs
Latest in Professional Development
The Driving Forces Behind Hourly Supply Chain Turnover
Healthcare Supply Chain 2023: Collaboration and Innovation Will Be Key to Transformation
How Smarter Data Management Can Relieve Tech Supply Chain Woes
Investing in the Development of Your Logistics Employees
Out-of-Stock Items Will be Biggest Challenge for Retailers in 2023
39% of respondents claimed that labor and staffing shortages were directly impacting operations at the in-store level, with retail being one of the most impacted sectors to date.
SML RFID
High Salary, Annual Raise Not Enough to Retain Supply Chain Workers: Study
78% of respondents reported a higher turnover rate in the previous 12 months, and 61% expect this to continue or get worse in the year to come.
Bastian Consulting
Supply Chain Network Promotes From Within, Names New Associate Editor
Emry Lloyd was named Associate Editor, succeeding Alexis Mizell-Pleasant, who was named Managing Editor, effective Jan. 3.
5 Ways to Improve the Industrial Industry's Labor Shortage
By taking the necessary steps to address it through harnessing today's digital solutions, companies can empower their existing employees and perhaps attract newer generations to change their point of view to see factories as the workplace of the future.
Fero Labs
Aligning Customer Service with Leadership Priorities
One of the most effective ways to ensure that KPIs align with strategic priorities from leaders is to ask them directly. These responses are helpful for getting a sense of broader goals for your customer service team.
APQC
Need for Job Shops to Modernize U.S. Supply Chains
Results from a Paperless Parts survey indicates a need for job shops and contract manufacturers to modernize.
Paperless Parts
Over Half of Supply Chain Managerial Roles Don't Require Software Experience
Only one-third (30%) of all roles require ERP experience and nearly half (42%) of managerial jobs require no software experience at all, demonstrating a lack of technology adoption across supply chain facilities and operations.
Women in Supply Chain: How to Manage Work-Life Balance
Holly Tran, director of account management for ALOM, and Taylor Houser, account manager for ALOM, both winners of this year's Women in Supply Chain award, talk about the ongoing challenge of balancing work and life.
ALOM Technologies Corp.
5 Trends Affecting Supply Chains in New Year
Adaptability has been key as companies looked to their supply chain teams to overcome a steady stream of disruptive events. Looking ahead to 2023, the end is not yet in sight.
Women in Supply Chain: Not About Being the Loudest in the Room, but the Most Effective
Kathleen Smith, global services operations leader for Converge, an Arrow company, and one of Supply & Demand Chain Executive's 2022 Women in Supply Chain award winners, explains why it's not always about being the loudest voice in the room.
Converge, an Arrow company
Women in Supply Chain: Be Comfortable with the Uncomfortable
Abigail Nawrocki, network GM of specialty fulfillment for Shopify Logistics and one of the winners of this year's Women in Supply Chain award, details the importance of getting comfortable with uncomfortable situations.
Deliverr, division of Shopify Logistics
SCN Summit: Future of Supply Chains Kicks off Today
SCN Summit features industry experts and thought leaders from the supply chain space to talk future of supply chains, what's in store for logistics companies, trends and technologies in logistics and more.
Women in Supply Chain: There's a Place in Supply Chain for Everyone
Paige VanFossen, VP, e-commerce operations, DHL Supply Chain, North America and one of this year's Women in Supply Chain award winners, details why the many layers to the supply chain industry make it so everyone can be involved.
Women in Supply Chain: More Gender-Diverse Workplace Produces Higher Performance
Susan Estes, Senior Supply Chain Consultant, Client Services for Open Sky Group and one of this year's Women in Supply Chain award winners, details how a more gender-diverse workplace environment produces higher performance.
Open Sky Group
3 Personal Insights for Women Breaking Through the Trucking Industry
The demand for drivers and the competitive pay that comes with the job make the trucking industry an untapped resource for women. This is an exciting time to level the playing field and build a revolutionary system that supports startups owned by women.
Davis & Davis Transportation LLC
Suicide Prevention and Mental Wellness in the Workplace
For many companies, safety is often thought of in terms of the physical instead of being seen as both physical and psychological.
Avetta
Women in Supply Chain: Don't Fear Speaking Up
Smitha Raphael, Chief Product and Delivery Officer for SnapFulfil and one of this year's Women in Supply Chain award winners, details why it's easy to question what women know about the supply chain, but that goes away once women speak up.
SnapFulfil
U.S. Drivers Deliver 9 Packages per Hour: Survey
67% of respondents state they now have to complete deliveries to different types of drop-off points, 66% are now expected to work faster, and the same amount (66%) reported an increase in new tasks like identity verification at the door.
5 Lessons Learned from the Stage at This Year's Women in Supply Chain Forum
If I could chat with my 25-year-old self and say, one day, you will help create an event where you will not be the only female in the room, I wonder how my 25-year-old self would respond.
Manifest Celebrates Women in LogisticsTech During Women's Lunch
The Women's Lunch will celebrate women in LogisticsTech in partnership with DHL Supply Chain, Daimler Truck North America, Food Logistics and Supply & Demand Chain Executive.


CLICK TO ENLARGE: In 2015, 105 Emory faculty members wrote or edited 121 books. Here's a closer look at faculty authors and editors for each division of the University.
Emory University faculty wrote or edited 121 books in 2015 — a 20 percent increase from the year before — on topics ranging from literature and philosophy to business and medicine.
To celebrate their achievements, the Center for Faculty Development and Excellence hosted the annual Feast of Words on Feb. 1 at the Emory Barnes & Noble Bookstore. The popular event kicked off Founders Week, Emory's midwinter academic festival, which commemorates the first official meeting of the founders of Emory College on Feb. 6, 1837 — two months after the state of Georgia formally granted a charter to establish the college.
"Emory is very clear: We have a mission statement that says we create, preserve, teach and apply knowledge in the service of humanity," Emory President James Wagner said before leading attendees in a toast to this year's authors. "The Feast of Words is a direct — no proxy required — illustration that Emory is doing its job and that you are doing your jobs."
Before introducing Wagner for the toast, Provost Claire Sterk praised the Feast of Words as "an occasion to really celebrate the intellectual community that we have."
"I think this is amazing: In an era where we talk about university presses having fewer resources to sustain their publishing, where academic publishing overall seems to be changing, and where we are moving to very different ways of getting our knowledge out, here we have gone up 20 percent in terms of the number of books the Emory faculty has put forth."
The 121 books published this year come from 105 faculty authors or editors, including 61 from Emory College of Arts and Sciences, 26 from the School of Medicine, 20 from Emory Law, 12 from Candler School of Theology, three from Oxford College, two each from Goizueta Business School and Rollins School of Public Health, and one from Nell Hodgson Woodruff School of Nursing.
Emeriti faculty are included on the list 11 times, while the year's tally also includes one each from the Center for Ethics and the Center for Digital Scholarship. Fifteen members of the University faculty wrote or edited multiple titles in 2015.
Below is a sample of the diverse books written or edited by Emory faculty this year. For a full list of Emory University books published in 2015, visit here.
For someone who, when he began his MA in anthropology, "could barely place Indonesia on a map," James Bourk Hoesterey has come a long way with the publication of "Rebranding Islam: Piety, Prosperity, and a Self-Help Guru." Now assistant professor of religion, Hoesterey spent two years shadowing the charismatic television preacher known to a nation of admirers as Aa Gym.
With a self-help message of "Manajemen Qolbu" ("Managing the Heart"), Gym transformed himself from a young man without formal religious education into a religious celebrity, national icon and Islamic brand. Viewers by the millions watched his weekly television shows, hundreds of thousands made pilgrimages to his Islamic school, and politicians of all stripes sought photo-ops during campaign season.
The book asks important questions about shifts within the religious culture of Indonesia, the world's largest Muslim-majority country, including: Does Gym's popularity signal a new kind of religious authority? In addition, what does the rise of self-help gurus say about the anxieties and aspirations of middle-class Muslims in Indonesia?
When Gym's devoted public discovered that he embraced polygamy — legal in Indonesia — by taking a second wife, it all came crashing down. Women shredded his picture, the country's president ordered a review of marriage law, and Gym's business empire dissolved.
Surely when praise from Jane Goodall — the United Nations Messenger of Peace —adorns your book's back cover, you have done something right. The book is "Beastly Morality: Animals as Ethical Agents," and the editor is Jonathan Crane, Raymond F. Schinazi Scholar in Bioethics and Jewish Thought at the Center for Ethics.
Jesse Karlsberg, postdoctoral fellow in digital humanities publishing at the Emory Center for Digital Scholarship (ECDS), is the prime mover behind "Original Sacred Harp: Centennial Edition." It is a commemorative, facsimile, reprint edition of the 1911 edition of "Original Sacred Harp," which helped propel Sacred Harp music into the 20th century and affected its practice up to the present. Karlsberg has written an engaging new introduction for the volume that speaks to the book's publication history, social context and reception.
This meticulously digitized and restored copy represents a collaboration between Pitts Theology Library, ECDS, Woodruff Library, and the Sacred Harp Publishing Company.
Karlsberg chose to edit a facsimile reprint rather than re-typeset because, as he says, the original's "quirks, typographical errors, and uneven print quality . . . speak to its historical circumstances." This handsome volume coming back into circulation also marks the beginning of Sounding Spirit, a more sustained effort to publish companion digital annotated and print facsimile editions of a range of significant out-of-print vernacular sacred American music texts.
The book was launched at the annual Emory Sacred Harp event, which last year coincided with a meeting at Emory of the Society for Christian Scholarship in Music. This year's Sacred Harp Sing is set for Saturday, Feb. 13, from 10 a.m. to 3 p.m. in Cannon Chapel; the event is free and open to the public.
"Nothing sparks more thought about thought than encountering a mind different from one's own," writes Laura Otis in "Rethinking Thought: Inside the Minds of Creative Scientists and Artists." From the opening lines of this unique study, Otis puts the limitations of her own mind on full, sometimes comic, view.
Otis is not a visual thinker. Every time she turns the key in her front-door lock, she wiggles it both ways. If she was in a space five minutes before and called upon to describe it, she can't.
Poor Otis? Hardly. With an MA in neuroscience and a PhD in comparative literature, this former MacArthur fellow—now professor of English—has a gem of a mind. The message of her book is that minds must be able to present their strengths variously.
Otis builds a fascinating narrative around, as she calls them, "34 different heads." They include those who work in science or literature or (like Otis) some combination thereof. Some of those she interviewed are well known to the Emory community: Mark Bauerlein, Natasha Trethewey and Salman Rushdie.


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Home	NewsEntertainment	Why You Should Be Watching 'Supernatural'
EntertainmentTV and Movies
Why You Should Be Watching 'Supernatural'
by Vanessa Colantro March 4, 2015
written by Vanessa Colantro March 4, 2015
I know plenty of you have the popular Netflix app or at least watch a couple shows on cable, right? Then you've surely heard about the popular TV show, Supernatural. If the name does not ring a bell, I suggest you immediately go check it out! The show is currently in high demand and on season 10. The series itself has a large fandom because it includes drama, fantasy, and horror at the same time, which are themes that connect with many viewers around the world. Not only that, but sometimes you can catch a little snarky humor from the main characters from time to time. Let's go over all the reasons why you should be watching Supernatural.
Breakdown of What's Happened on Supernatural
Supernatural focuses on two brothers, Dean and Sam Winchester, played by Jensen Ackles and Jared Padalecki, who follow in their father's footsteps as a hunter of evil. Hunters on this series fight off demons, mythical creatures, and gods that roam the earth trying to cause chaos among the human world. The pilot begins with the story line starting 22 years ago when the two brothers were just little boys. The episode gives you a glimpse of the home they grew up in. The camera then switches the attention to their mother who is putting Sam, who is only a couple months old, to sleep. Later, she also puts Dean, who looks to be four, to sleep as well. Later on in the night, the mother hears a nose coming from Sam's bedroom, she instantly goes and checks on Sam making sure he's okay. When she opens the door she is faced with a man with yellow eyes next to the crib.
The demon notices her presence in the room and she is pushed against the wall, making her rise to the ceiling where she is engulfed in flames. Their father realizes something is going on and was able to save Sam and Dean from the fire that was engulfing the entire house. In the wake of the father's grief, he began investigating what actually happened that night in their home. Figuring out that it was a demon that caused the death of his wife, he roamed the states with his two boys, hunting the demon with yellow eyes while also fighting other demons here and there. The episode then skips to present day showing Sam enjoying his night out with a couple of friends. You later find out that Sam left home to pursue a career in law, but that was cut short when his older brother paid him a visit.
Dean shows up in the middle of the night informing Sam that his father has not returned from a mission. However, Sam does not want anything to do with the "family business." Then Sam experiences the same situation as his father, having his girlfriend stuck on the ceiling covered in flames. Now seeking revenge, both the brothers go in search of their father. This search becomes the plot of season one. After the first season, it becomes repetitive since every episode incorporates a new type of demon or monster that they are searching for to find the head demon that is behind the killings of their loved ones.
The Makings of a Hit
The creator of this series, Eric Kripke, had been working on this show for ten years before it was finally picked up by a production company in 2006. Unsuccessfully pitching the topic, the series went through many phases before it became the end product that it is today. The concept shifted ideas, first with an anthology series in mind, and then to tabloid reporters roaming the country fighting demons and bringing you the truth of the world. Finally the time came when they gave Kripke an opportunity to create the first episode to see how the ratings would go. The pilot was watched by an estimated five million viewers and the high ratings convinced the producers to pick up the series for a full season.
A cool fact about the series is that the stories that the Kripke uses in the story line happens to be myths from the actual cities that the brothers investigated on the show. Kripke wanted to bring the spooky stories you hear in your own city to life. Many of the ideas and names he included on the show are inspired by other shows and things like the Winchester Mystery House, Dukes of Hazzard, and the character Han Solo. Other inspirations for Kripke were from movies like Poltergeist, Evil Dead, and An American Werewolf in London. Not only that, but other writers that were a part of this team had to do research about all the supernatural myths and stories that were around the country. There are ten seasons of the show and about twenty episodes in each season. The production company worked very hard to develop these unique stories in each episode while also keeping things entertaining for the viewer.
Dean and SamsupernaturalSupernatural TV show
Vanessa Colantro
Vanessa is a current student at Glendale Community College who will soon be transferring to ASU. Her passion are reading and writing which is obvious why her choice for following a career in journalism. When she isn't reading, writing, and getting the latest jaw dropping scoops she enjoys blogging, watching every show on Netflix, and enjoys spending time with her loved one.
Six Apps To Help You Fall Asleep
2015 Looks Like A Disappointing Year For Horror Movies


SERVER LEASING With professional support.
In this package you will get WP support included. Warranty unlimited. Control your important data with own cloud system by remote administration stored on fully encrypted discs. DMARC signature for communication included. Starting with 100GB of remote storage you can request upgrade of your Private Cloud space.


Planet Aid and Women Empowering Women Host Charity Walk for St. Jude's - Planet Aid, Inc.
Planet Aid and Women Empowering Women hosted a charity walk on October 27 to benefit St. Jude's Children's Research Hospital. A clothing drive was also part of the event, with five cents per pound donated to the hospital. Women Empowering Women founder Treniece Prather spoke about her father who died of Leukemia, explaining that the charity walk was "near and dear to her heart" for this reason. She said her hope is that through the research done at Saint. Jude's Children's Research Hospital, fewer families will lose their loved ones to Leukemia.
Learn more about Women Empowering Women on their Facebook page.
A group of supporters, including local Gastonia police, who participated in the charity walk.


Check of class of star of Beijing tourism bureau 26 restaurant by " pick a bit "
Damaged of facilities facilities stale serious, service is poorer, safe management is non-standard wait for a reason, make this city China the restaurant of 26 stars class such as restaurant of Beijing University hotel, Long Tan by " pick a bit " .
On August 8, beijing tourism bureau released result of check of astral class restaurant, cancelled the astral class qualification of 26 restaurant. Among them, the restaurant of SamSung class includes: Of sunny area China guesthouse of put oneself in another's position of restaurant of pool of Beijing University hotel, dragon, industry; East guesthouse of emerald green Mingzhuang of the city zone 9; Restaurant of 2 stars class includes: Front door is new restaurant of guesthouse of new hotel, restaurant of garden of Hao of the Temple of Heaven, Longshan, brilliance 15; Mountain villa of phoenix of restaurant of two one star and center of drive center conference also were cancelled astral class. Be picked to these restaurant astral reason, when chief is accepting a reporter to interview related city tourism bureau, say, because decorate close down and change to manage property; Damaged of facilities facilities stale is serious; The service is poorer; Safety administration is non-standard wait for a reason, make these restaurant fail to reach astral grade level.
In addition, city tourism bureau is right still the restaurant that 11 management and service respect put in more question gives oral warning. Among them, restaurant of 4 stars class 3, they are: Rich come Gong Wenquan goes vacationing village, medium big public house of abundant century restaurant and Jin Taihai rich. The 8 SamSung restaurant such as house of Yuan Bin of restaurant of Hubei edifice, sea spy, north also amid.
The restaurant with the poorer respect such as 7 management, service, sanitation was offerred notice of criticism yesterday. The restaurant that is criticized is SamSung class restaurant entirely. Include: Found a state a maple garden guesthouse, Ning Yang is big public house, violet restaurant of Jin Moshou palace, Yue is big edifice of center of profit of hotel, great, Zhang Qiu edifice and labor edifice.


Radioactive decay is the process by which the nucleus of an unstable atom loses energy by emitting 'radiation' - which can be in the form of alpha particles, beta particles, gamma rays or conversion electrons.
The emissions are random in the sense that the exact moment that an alpha particle (for example) is emitted cannot be predicted. Neither can its direction of travel. This randomness is an integral part of current quantum theory, and is consistently confirmed by observations. That's to say that no-one can (or ever will be able to) predict when the next decay event will occur.


League of extreme gamers. Bring you two podcasts about wargames and table top games. Mostly our experience and opinions so enjoy it whole it lasts.
After discussing the Bandits last time Kieran and Matt decide to delve into darkness and deceit before the next warband expansion that rules and battle expansion came with.


Our Munich office supports the way we work perfectly. We can quickly and flexibly remodel it for the constantly changing project environment. However, the opportunities offered by the hall as an event site are at least equally valuable as well. Whether for the UBX conference which we organised ourselves or for a development community using the hall for a hackathon.
Even virtual creativity needs physical space. Looking at the photos of Virtual Identity in their Thalkirchen Station office, you may well think that they show nothing more than a typically cool advertising agency and their innovative office space. The aim of the project you will read about below, however, was not to bring a cliché to life: it was the result of a long period of analysis, thorough consultation with the parties involved and a vision, developed closely with the company's management, of how people can work together effectively and harmoniously. The resulting design shows how the outcomes of this sort of close cooperation can be applied coherently and consistently within a structured planning process.
Over the past few years, the advertising agency Virtual Identity has become more and more successful. The agency's growing success was increasingly reflected in its office space, which had also continued to grow organically. In a back building in the heart of Schwabing, Virtual Identity became dispersed over a number of different floors and neighbouring buildings. The agency filled this space to its limits and the structure of their office was dictated by the constraints of the buildings they occupied, increasingly frustrating internal communication and interfering with the development of a shared office culture.
office structure and identity-establishing communication centre that would do justice to Virtual Identity's creative, cross-project work.
Before leasing a property, CSMM and Virtual Identity created a requirements profile that could be used to assess the general feasibility, space efficiency and potential of the new office areas. The development of a space allocation plan and an area plan was a further, crucial step. CSMM therefore undertook an advance assessment of Virtual Identity's internal processes to determine the overall set-up of the new office.
A potential location for the office had also been found: Thalkirchen Station, a listed building which was in the process of being redeveloped into a campus of offices.
The results of CSMM's analysis were ready time for the initial meeting with the building owner to discuss the lease. Since CSMM was involved in the project early on and the property developer had not yet completed the project schedule, this presented a great opportunity for the lessees to influence the development and negotiate relevant terms and responsibilities within the lease.
The landlord's existing concept meant that the requirements set out in Virtual Identity's requirements profile would not be feasible. In the original development, maximum use was to have been made of the leased space, with a gallery installed as a fully-fledged second floor in the hall area. This, however, would have significantly detracted from the loft style of the space and negated the charm of the old repair shop.
Using the results of their initial work and analyses, CSMM then worked closely with Virtual Identity to design a bespoke office concept that would fit the structure of the building and the strict preservation orders set in place.
The workshops moderated by CSMM were important tools in this process and were designed to produce joint responses to questions concerning the optimisation of work processes and on how best to convey the company's values, management culture and communication culture. The far-sighted decision of Virtual Identity's management team to include staff in the design phase encouraged staff buy-in. It also enabled them to work with relevant Key Account staff to develop some "rules" for the future office, with the aim of creating an environment that people would enjoying working, learning and relaxing in.
CSMM created a 1:33 scale model of Thalkirchen Station specially for these workshops so that 3D explanations of important stages in the design process and related concepts could be more easily given. Using this model, work stations, breakout areas, meeting spaces, colour schemes and materials could all be presented clearly for discussion and agreement.
A tight schedule from beginning to completion and Virtual Identity's eventual move-in made separating the responsibilities of landlord and tenant a challenge. Being involved in the early stages of the lease negotiations, however, meant that the tenant's responsibilities could be clearly demarcated. To this end, CSMM prepared the project schedule and the required tender announcement, supervised the construction work and kept Virtual Identity informed of running costs and estimated dates for completion.
A structure split into two clearly defined wings, and detached from the historic building itself, was constructed in the eight-metre high brick hall. The building's two floors draw attention to a centralised space that can be transformed into a stage by the staircase, which offers a fascinating change in perspective and has deep steps for sitting on or doing some casual work from a laptop. The walls of the building have been painted with a blackboard coating to create a giant surface for scribbling down messages, news and creative ideas.
To improve work flows and optimise communication among staff, various meeting spots were created in the form of closed, open and semi-open work spaces. Sliding glass doors and windows in the work zones can also be used to separate the work areas from the central 'piazza' in the middle of the hall. Thanks to CSMM's structured design process, assistance with the lease and consequent advice and planning, the Virtual Identity team were able to move into their office on schedule and on budget for one of their legendary office warming parties.
Thanks to CSMM's structured design process, assistance with the lease and consequent advice and planning, the Virtual Identity team were able to move into their office on schedule and on budget for one of their legendary office warming parties.


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Kremlin: Long-Range weapons for Ukraine will not deter Russia
Türkiye: "US to lose 'neutrality' in NATO if Congress approves F-35 sale to Greece"
Why do the cores of stars spin more slowly than expected?
Report: US Air Force hypersonic Air-Breathing weapon completes final test flight
Italy, industry partners ink Sixth-Gen Jet development for Global Combat Air Program
Rheinmetall in Talks With Lockheed to Produce HIMARS in Germany
France, Australia to supply Ukraine with 155mm shells
US, South Korean defense chiefs vow more drills to counter north
Ukraine says to receive 'Between 120 and 140' heavy western Tanks
Home/Defence News/Report: S. Korea, US to expand anti-submarine drills amid North Korea tension
Report: S. Korea, US to expand anti-submarine drills amid North Korea tension
South Korean and American naval forces have discussed expanding their biennial anti-submarine warfare naval exercise amid North Korea's growing missile threats, a US Navy official confirmed.
The planned expansion of the Silent Shark joint maritime exercise is a response to Pyongyang's evolving submarine-launched ballistic missile (SLBM) technology.
In October, North Korea disclosed it "successfully" test-fired a KN-23 SLBM from a reservoir's underwater launch site.
According to the unnamed navy officer, the 2023 drill is expected to be well-attended, training participants in simulated settings involving Korean diesel-powered submarines and American nuclear-powered vessels.
"Issues including how to bolster interoperability were discussed. But details such as the size and the date of the exercise and which anti-submarine warfare assets will take part in it are still undecided," the official said.
Tensions With North Korea
Pyongyang has stoked tensions across the Korean Peninsula and the South's allied nations over the dozens of missile tests it has launched recently.
In early October, it fired an intermediate-range ballistic missile over Japan for the first time in five years, just one week after it launched two short-range ballistic missiles off the North's east coast.
The consecutive weapons tests followed the bilateral and trilateral maritime drills between South Korea, the US, and Japan, where the nuclear-powered USS Ronald Raegan aircraft carrier provided military support.
North Korea has repeatedly condemned the west's military deployments and joint drills in the Korean Peninsula.
"The exercises are designed to improve their capability to respond to increasing North Korean submarine threats, including its submarine-launched ballistic missiles (SLBM) at a time when it consistently poses nuclear and missile threats with a series of ballistic missile tests," the South Korean navy said.
The US has imposed new sanctions against Pyongyang, including two Singapore-based fuel firms and one in the Marshall Islands for allegedly supporting North Korea's weapons and military programs.
Ukraine to receive Milrem THeMIS UGVs


Discus and support Not able to play Youtube videos in Edge windows10 in Windows 10 Network and Sharing to solve the problem; Dear Team, Unable to play youtube videos in Edge browser... Discussion in 'Windows 10 Network and Sharing' started by JagadishReddy, Sep 9, 2018.
after I applied a windows update my edge browser no longer plays youtube videos; any ides / suggestions?
KB3149135 and KB3163018 causing Youtube (or other videos) unable to play at full screen mode.
Yes, happens on all browsers.
Does the issue occur on playing videos saved in the system drives?
No, only online videos on browsers.
I tried your suggestion twice to uninstall the drivers and reinstalling it again, didnt work.
I also tried installing the update in clean boot, also didnt work.
I went one step further.
play full screen mode again. And I have to go programs feature to uninstall this update everyday! Please help address this issue. Thanks!
As you are unable to access the YouTube website on Windows browsers, we will help you with this issue.
What exactly happens when you try to access the website on the browser?
Were you able to see any error message/ error code on your device?
Let us try the below troubleshooting steps and check if it helps.
Install the latest version of Adobe Flash Player on your device.
For Microsoft Edge: I suggest you to check if the Adobe Flash player is enabled on Microsoft Edge.
Check if the issue persists with accessing the videos.
Hope it helps. Get back to us with an updated status of accessing the videos on Windows browsers for further assistance.


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Date Syrup: A Natural Sweetener That Can Fight Bacterial Infections
NDTV Food | Updated: April 01, 2015 11:21 IST
Date syrup is a dark-coloured and deep-textured natural sweetener that is squeezed out of fresh and fleshy dates. It's most commonly found in the Middle East but also available in health stores around the world.
(Dates Truly Are the Fruit of Paradise)
According to the research presented at the Society for General Microbiology's Annual Conference in Birmingham, UK, date syrup has antibacterial properties and can fight against a number of disease-causing bacteria. This includes bacteria like Staph aureus which is one of the leading causes of skin and soft tissue infections and E coli which is usually found in a person's lower intestine.
Research found that date syrup is able to inhibit the growth of bacteria faster than manuka honey, which has previously been shown to have antibacterial properties and is increasingly used in dressings to improve wound repair.
(Top 5 Things You Can Make with Dates)
Hajer Taleb, a research student from Cardiff Metropolitan University in the UK, identified that the date syrup contains a number of phenolic compounds that form naturally in the date fruit as it matures.
These compounds have previously been shown to have antibacterial activity. Artificial syrup made of the constituent sugars found in natural syrup but lacking the phenolic compounds was not as effective at inhibiting bacterial growth.
(How to Make a Date Shake)
In vitro results showed that date syrup produced traditionally in Basra, Southern Iraq, has antibacterial activity comparable to manuka honey. When the syrup was mixed with a range of disease-causing bacteria like Staphylococcus aureus, Escherichia coli, Enterococcus spp and Pseudomonas aeruginosa, it inhibited their growth. The date syrup was effective in similar amounts to manuka honey but worked more quickly, inhibiting bacterial growth after six hours of treatment, while the manuka honey required longer.
According to Dr Ara Kanekanian, lead researcher from Cardiff Metropolitan University, "While this work is currently in vitro, it suggests that date syrup could exhibit health benefits through its antibacterial activities, similar, or in some cases, better than honey. At this stage, this has mainly been attributed to the presence of phenolic compounds. However, until further research is undertaken, we caution people against using the syrup to treat wounds."
With inputs from PTI
Tags: Dates
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A series of hydroxy 2-aminotetralins, benzhydro[f]quinolines and clonidine were used to determine whether a pharmacological similarity could be demonstrated between presynaptic alpha adrenoceptors which modulate autonomic transmission in the guinea pig. Compounds were assayed on isolated field stimulated guinea-pig ilea (GPI) to determine their inhibitory activities on cholinergic transmission. Inhibition of noradrenergic transmission was determined by assaying compounds on isolated field stimulated guinea-pig atria. 2-Aminotetralins, benzhydro[f]quinolines and clonidine impaired cholinergic and noradrenergic transmission by interacting with presynaptic alpha-2 adrenoceptors. A correlation (r = 0.95; P less than .05) was demonstrated between the activity of a compound on the GPI and guinea-pig atria. IC50 values obtained on GPI were correlated with previously reported IC50 values obtained for binding [3H]clonidine sites in homogenates of calf frontal cortex. A significant correlation was demonstrated (r = 0.99; P less than .05). These data suggest that alpha-2 adrenoceptors localized on guinea-pig atria and GPI are pharmacologically similar. In addition, a similar structure activity relationship was demonstrated for presynaptic alpha-2 adrenoceptors on GPI and binding sites labeled by [3H]clonidine in the calf frontal cortex.


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Sabayon Linux este o distribuție binară bazată pe Linux Gentoo. Are propriile lui repositorii, și propriul manager de pachete binar: Entropy. Pentru a crea pachete, Sabayon folosește managerul bazat pe sursă, Portage de la Gentoo, și folosește intreaga infrastructura si administrație Gentoo.

Referințe

Distribuții bazate pe Gentoo
Distribuții Linux cu eliberare încontinuu
Distribuții Linux x86-64

redpajama_set_name: RedPajamaWikipedia


Shanti Gopal Hospital is a Multi Speciality Clinic in Indirapuram, Ghaziabad. The clinic is visited by psychiatrist like Dr. Rajesh Kumar,Dr. Shipra Nagar and Dr. Kavita Nagpal. The timings of Shanti Gopal Hospital are: Mon-Sun: 00:00-23:55. Some of the services provided by the Clinic are: Cervical Spondylitis Treatment,Artificial Insemination,Parenting Issues & Doubts,Amalgam Removal and Scaling / Polishing etc. Click on map to find directions to reach Shanti Gopal Hospital.
*** ** *** ** *** **** ************* ** ************ I had normal delivery, just because she tries for that. Even other services for various treatment are satisfiable.
I visited the Dr Megha today -19 sep 2016 and I found her very polite, patient. She diagnosed and explain the infection in detail. Prescribed medicine and asked for a visit again.