Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)Lymphocyte subpopulation imbalances, bone marrow hematopoiesis and histopathology in rituximab-treated lymphoma patients with late-onset neutropenia Leukemia (2008) Several observations implicate the administration of rituximab in the development of severe late-onset neutropenia (LON) in some patients with lymphoma treated with rituximab±chemo-therapy. [1][2][3][4][5] The incidence of LON varies between series; this might be explained, at least in part, by the failure to detect some neutropenic episodes due to their short duration, the relatively long time to onset and the usually uncomplicated course. However, there is a gradual increase in the frequency of rituximab-related LON probably due to the widespread use of rituximab in the standard treatment of lymphomas and also due to the ongoing awareness for this event.Several groups, including ours, have provided indirect evidence to implicate an immune-mediated mechanism in the pathogenesis of rituximab-associated LON. [1][2][3]6 However, published data are mainly based on small series and are often contradictory, perhaps due to the selective evaluation of isolated parameters. Our previous studies suggesting that LON in rituximab-treated lymphoma patients may be associated with T-cell large granular lymphocytic (T-LGL) proliferation 1-2 alluded to the possibility of altered T-cell responses associated with B-cell depletion induced by rituximab. To probe this hypothesis further, in the present study, we performed a detailed immunological and immunohistological study looking for quantitative changes and/or an activated profile of lymphocytes in rituximab-treated patients with LON, focusing on the possibility of T-cell-mediated suppression of bone marrow (BM) hematopoiesis.The study included 12 patients (10 men and 2 women) with a median age of 48 years (range, 26-67 years) who developed unexplained LON after treatment with rituximab±chemother-apy for diffuse large B-cell lymphoma (DLCL; n ¼ 4), chronic lymphocytic leukemia (CLL; n ¼ 4), mantle-cell lymphoma (MCL; n ¼ 3) or splenic marginal-zone lymphoma (SMZL; n ¼ 1). LON was defined as the unexplained reduction in neutrophil counts p1.0 Â 10 9 l À1 (grade 3 according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC)) following neutrophil recovery after completion of the intended treatment with rituximab±chemotherapy, without evidence of disease progression and before addition of chemotherapy. One DLCL patient developed neutropenia while on maintenance monotherapy with rituximab. The remainder (n ¼ 11) received rituximab in combination with CHOP (DLCL, MCL, SMZL) or fludarabine-cyclophosphamide (CLL). LON occurred at a median of 95 (range, 67-420) days after the last administration of rituximab. Neutrophil nadir during neutropenia episodes in each patient ranged from 0.01 Â 10 9 to 0.85 Â 10 9 l À1 (median 0.52 Â 10 9 l À1 ). The recovery from neutropenia was observed at a median of 56 (range, 28-...
Quercetin (Que) is a flavonoid associated with high oxygen radical scavenging activity and potential neuroprotective activity against Alzheimer's disease. Que's oral bioavailability is limited by its low water solubility and extended peripheral metabolism; thus, nasal administration may be a promising alternative to achieve effective Que concentrations in the brain. The formation of Que−2-hydroxypropylated−β-cyclodextrin (Que/HP-β-CD) complexes was previously found to increase the molecule's solubility and stability in aqueous media. Que−methyl−β-cyclodextrin (Que/Me-β-CD) inclusion complexes were prepared, characterized, and compared with the Que/HP-β-CD complex using biophysical and computational methods (phase solubility, fluorescence and NMR spectroscopy, differential scanning calorimetry (DSC), and molecular dynamics simulations (MDS)) as candidates for the preparation of nose-to-brain Que's delivery systems. DSC thermograms, NMR, fluorescence spectroscopy, and MDS confirmed the inclusion complex formation of Que with both CDs. Differences between the two preparations were observed regarding their thermodynamic stability and inclusion mode governing the details of molecular interactions. Que's solubility in aqueous media at pH 1.2 and 4.5 was similar and linearly increased with both CD concentrations. At pH 6.8, Que's solubility was higher and positively deviated from linearity in the presence of HP-β-CD more than with Me-β-CD, possibly revealing the presence of more than one HP-β-CD molecule involved in the complex. Overall, water solubility of lyophilized Que/Me-β-CD and Que/HP-β-CD products was approximately 7−40 times and 14−50 times as high as for pure Que at pH 1.2−6.8. In addition, the proof of concept experiment on ex vivo permeation across rabbit nasal mucosa revealed measurable and similar Que permeability profiles with both CDs and negligible permeation of pure Que. These results are quite encouraging for further ex vivo and in vivo evaluation toward nasal administration and nose-to-brain delivery of Que.
The population based Steroid Profile (SP) ratio of testosterone (T) and epitestosterone (E) has been considered as a biomarker approach to detect testosterone abuse in '80s. The contemporary Antidoping Laboratories apply the World Antidoping Agency (WADA) Technical Document (TD) for Endogenous Androgenic Anabolic Steroids (EAAS) in the analysis of SP during their screening. The SP Athlete Biological Passport (ABP) adaptive model uses the concentrations of the total of free and glucuronide conjugated forms of six EAASs concentrations and ratios measured by GC/MS. In the Antidoping Lab Qatar (ADLQ), the routine LC/MS screening method was used to quantitatively estimate the sulfate conjugated EAAS in the same analytical run as for the rest qualitative analytes. Seven sulfate EAAS were quantified for a number of routine antidoping male and female urine samples during screening. Concentrations, statistical parameters and selected ratios for the 6 EAAS, the 6 sulfate EAAS and 29 proposed ratios of concentrations from both EAAS and sulfate EAAS, which potentially used as SP ABP biomarkers, population reference limits and distributions have been estimated after the GC/MSMS analysis for EAAS and LC/Orbitrap/MS analysis for sulfate EAAS.
The urinary 'steroid profile' in doping control analysis is a powerful tool aimed at detecting intra-individual deviations related to the abuse of endogenous steroids. Factors altering the steroid profile include, among others, the excessive fluid intake leading to low endogenous steroids concentrations compared to an individual's normal values. Cases report the use of hyperhydration by athletes as a masking method during anti-doping urine sample collection. Seven healthy physically active non-smoking Caucasian males were examined for a 72-hour period using water and a commercial sports drink as hyperhydration agents (20 mL/kg body weight). Urine samples were collected and analyzed according to World Anti-Doping Agency (WADA) technical documents. Although, significant differences were observed on the endogenous steroid concentrations under the studied hyperhydration conditions, specific gravity adjustment based on a reference value of 1.020 can eliminate the dilution induced effect. Adjustment methods based on creatinine and urinary flow rate were also examined; however, specific gravity was the optimum method in terms of effectiveness to adjust concentrations close to the baseline steroid profile and practicability. No significant effect on the urinary steroid ratios was observed with variability values within 30% of the mean for the majority of data. Furthermore, no masking on the detection ability of endogenous steroids was observed due to hyperhydration. It can be concluded that any deviation on the endogenous steroid concentrations due to excessive fluid intake can be compensated by the specific gravity adjustment and therefore, hyperhydration is not effective as a masking method on the detection of the abuse of endogenous steroids.
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