Due to its relatively slow clinical progression, B cell chronic lymphocytic leukemia (B-CLL) is classically described as a disease of accumulation rather than proliferation. However, evidence for various forms of clonal evolution suggests that B-CLL clones may be more dynamic than previously assumed. We used a nonradioactive, stable isotopic labeling method to measure B-CLL cell kinetics in vivo. Nineteen patients drank an aliquot of deuterated water ( 2 H 2 O) daily for 84 days, and 2 H incorporation into the deoxyribose moiety of DNA of newly divided B-CLL cells was measured by gas chromatography/mass spectrometry, during and after the labeling period. Birth rates were calculated from the kinetic profiles. Death rates were defined as the difference between calculated birth and growth rates. These analyses demonstrated that the leukemic cells of each patient had definable and often substantial birth rates, varying from 0.1% to greater than 1.0% of the entire clone per day. Those patients with birth rates greater than 0.35% per day were much more likely to exhibit active or to develop progressive disease than those with lower birth rates Thus, B-CLL is not a static disease that results simply from accumulation of long-lived lymphocytes. Rather, it is a dynamic process composed also of cells that proliferate and die, often at appreciable levels. The extent to which this turnover occurs has not been previously appreciated. A correlation between birth rates and disease activity and progression appears to exist, which may help identify patients at risk for worsening disease in advance of clinical deterioration.

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), excluding significant dilution by unlabeled ␣-glycerol phosphate. Turnover of plasma TG, modeled from 2 H incorporation over 60 min, was 0.06 min Ϫ1 (half-life 11.5 min). In summary, use of 2 H2O labeling with MIDA of TG-glycerol allows measurement of new ␣-glycerol phosphate-derived TG synthesis and turnover. The hypothesis that mesenteric TG is more lipolytically active than other depots, previously difficult to prove by isotope dilution techniques, was confirmed by this label incorporation approach.triglyceride; mass isotopomer distribution analysis; kinetics; stable isotopes THE SYNTHESIS AND BREAKDOWN RATES of acylglycerides, such as triacylglycerol (TG), play a role in a number of important conditions including obesity, lipodystrophy, and hyperlipidemia as well as processes such as the biogenesis of cellular organelles (3,26). The turnover of TG, the major component of adipose tissue, is of particular interest in view of the increasing prevalence of obesity (23,32). A reliable method for measuring allsource synthesis and turnover of acylglycerides in vivo could provide insights into these and other lipid disorders. To date, however, no such method has been available.One of the methodological barriers to measuring all-source TG turnover has been that the turnover of fatty acid constituents of TG is not synonymous with the turnover of the intact acylglyceride molecule.

Background Large observational implementation studies are needed to triangulate the findings from randomized control trials as they reflect “real‐world” everyday practice. In a pilot study, we attempted to provide additional and complementary insights on the real‐life treatment of allergic rhinitis (AR) using mobile technology. Methods A mobile phone app (Allergy Diary, freely available in Google Play and Apple App stores) collects the data of daily visual analog scales (VAS) for (i) overall allergic symptoms, (ii) nasal, ocular, and asthma symptoms, (iii) work, as well as (iv) medication use using a treatment scroll list including all medications (prescribed and over the counter (OTC)) for rhinitis customized for 15 countries. Results A total of 2871 users filled in 17 091 days of VAS in 2015 and 2016. Medications were reported for 9634 days. The assessment of days appeared to be more informative than the course of the treatment as, in real life, patients do not necessarily use treatment on a daily basis; rather, they appear to increase treatment use with the loss of symptom control. The Allergy Diary allowed differentiation between treatments within or between classes (intranasal corticosteroid use containing medications and oral H1‐antihistamines). The control of days differed between no [best control], single, or multiple treatments (worst control). Conclusions This study confirms the usefulness of the Allergy Diary in accessing and assessing everyday use and practice in AR. This pilot observational study uses a very simple assessment (VAS) on a mobile phone, shows novel findings, and generates new hypotheses.

Due to its relatively slow clinical progression, B cell chronic lymphocytic leukemia (B-CLL) is classically described as a disease of accumulation rather than proliferation. However, evidence for various forms of clonal evolution suggests that B-CLL clones may be more dynamic than previously assumed. We used a nonradioactive, stable isotopic labeling method to measure B-CLL cell kinetics in vivo. Nineteen patients drank an aliquot of deuterated water ( 2 H 2 O) daily for 84 days, and 2 H incorporation into the deoxyribose moiety of DNA of newly divided B-CLL cells was measured by gas chromatography/mass spectrometry, during and after the labeling period. Birth rates were calculated from the kinetic profiles. Death rates were defined as the difference between calculated birth and growth rates. These analyses demonstrated that the leukemic cells of each patient had definable and often substantial birth rates, varying from 0.1% to greater than 1.0% of the entire clone per day. Those patients with birth rates greater than 0.35% per day were much more likely to exhibit active or to develop progressive disease than those with lower birth rates Thus, B-CLL is not a static disease that results simply from accumulation of long-lived lymphocytes. Rather, it is a dynamic process composed also of cells that proliferate and die, often at appreciable levels. The extent to which this turnover occurs has not been previously appreciated. A correlation between birth rates and disease activity and progression appears to exist, which may help identify patients at risk for worsening disease in advance of clinical deterioration.

No abstract

Dietary treatment is important in management of type 2 diabetes or prediabetes, but uncertainty exists about the optimal diet. We randomized adults (n = 34) with glycated hemoglobin (HbA1c) > 6.0% and elevated body weight (BMI > 25) to a very low-carbohydrate ketogenic (LCK) diet (n = 16) or a moderate-carbohydrate, calorie-restricted, low-fat (MCCR) diet (n = 18). All participants were encouraged to be physically active, get sufficient sleep, and practice behavioral adherence strategies based on positive affect and mindful eating. At 12 months, participants in the LCK group had greater reductions in HbA1c levels (estimated marginal mean (EMM) at baseline = 6.6%, at 12 mos = 6.1%) than participants in MCCR group (EMM at baseline = 6.9%, at 12 mos = 6.7%), p = .007. Participants in the LCK group lost more weight (EMM at baseline = 99.9 kg, at 12 mos = 92.0 kg) than participants in the MCCR group (EMM at baseline = 97.5 kg, at 12 mos = 95.8 kg), p < .001. The LCK participants experienced larger reductions in diabetes-related medication use; of participants who took sulfonylureas or dipeptidyl peptidase-4 inhibitors at baseline, 6/10 in the LCK group discontinued these medications compared with 0/6 in the MCCR group (p = .005). In a 12-month trial, adults with elevated HbA1c and body weight assigned to an LCK diet had greater reductions in HbA1c, lost more weight, and reduced more medications than those instructed to follow an MCCR diet.

The failure of chemotherapeutic regimens to eradicate cancers often results from the outgrowth of minor subclones with more dangerous genomic abnormalities or with self-renewing capacity. To explore such intratumor complexities in B-cell chronic lymphocytic leukemia (CLL), we measured B-cell kinetics in vivo by quantifying deuterium ( 2 H)-labeled cells as an indicator of a cell that had divided. Separating CLL clones on the basis of reciprocal densities of chemokine (C-X-C motif) receptor 4 (CXCR4) and cluster designation 5 (CD5) revealed that the CXCR4 dim CD5 bright (proliferative) fraction contained more 2 H-labeled DNA and hence divided cells than the CXCR4 bright CD5 dim (resting) fraction. This enrichment was confirmed by the relative expression of two cell cycle-associated molecules in the same fractions, Ki-67 and minichromosome maintenance protein 6 (MCM6). Comparisons of global gene expression between the CXCR4 dim CD5 bright and CXCR4 bright CD5 dim fractions indicated higher levels of pro-proliferation and antiapoptotic genes and genes involved in oxidative injury in the proliferative fraction. An extended immunophenotype was also defined, providing a wider range of surface molecules characteristic of each fraction. These intraclonal analyses suggest a model of CLL cell biology in which the leukemic clone contains a spectrum of cells from the proliferative fraction, enriched in recently divided robust cells that are lymphoid tissue emigrants, to the resting fraction enriched in older, less vital cells that need to immigrate to lymphoid tissue or die. The model also suggests several targets preferentially expressed in the two populations amenable for therapeutic attack. Finally, the study lays the groundwork for future analyses that might provide a more robust understanding of the development and clonal evolution of this currently incurable disease.