Treatment of secondary hyperparathyroidism in haemodialysis patients: a randomised clinical trial comparing paricalcitol and alfacalcidol

<p>Abstract</p> <p>Background</p> <p>Secondary hyperparathyroidism is a common feature in patients with chronic kidney disease. Its serious clinical consequences include renal osteodystrophy, calcific uremic arteriolopathy, and vascular calcifications that increase morbidity and mortality.</p> <p>Reduced synthesis of active vitamin D contributes to secondary hyperparathyroidism. Therefore, this condition is managed with activated vitamin D. However, hypercalcemia and hyperphosphatemia limit the use of activated vitamin D.</p> <p>In Denmark alfacalcidol is the primary choice of vitamin D analog.</p> <p>A new vitamin D analog, paricalcitol, may be less prone to induce hypercalcemia and hyperphosphatemia.</p> <p>However, a randomised controlled clinical study comparing alfacalcidol and paricalcitol has never been performed.</p> <p>The primary objective of this study is to compare alfacalcidol and paricalcitol. We evaluate the suppression of the secondary hyperparathyroidism and the tendency towards hyperphosphatemia and hypercalcemia.</p> <p>Methods/Design</p> <p>This is an investigator-initiated cross-over study. Nine Danish haemodialysis units will recruit 117 patients with end stage renal failure on maintenance haemodialysis therapy.</p> <p>Patients are randomised into two treatment arms. After a wash out period of 6 weeks they receive increasing doses of alfacalcidol or paricalcitol for a period of 16 weeks and after a further wash out period of 6 weeks they receive the contrary treatment (paricalcitol or alfacalcidol) for 16 weeks.</p> <p>Discussion</p> <p>Hyperparathyroidism, hypercalcemia and hyperphosphatemia are associated with increased cardiovascular mortality in patients with chronic kidney disease.</p> <p>If there is any difference in the ability of these two vitamin D analogs to decrease the secondary hyperparathyroidism without causing hypercalcemia and hyperphosphatemia, there may also be a difference in the risk of cardiovascular mortality depending on which vitamin D analog that are used. This has potential major importance for this group of patients.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT004695</p

Steps in the bacterial flagellar motor

The bacterial flagellar motor is a highly efficient rotary machine used by many bacteria to propel themselves. It has recently been shown that at low speeds its rotation proceeds in steps [Sowa et al. (2005) Nature 437, 916--919]. Here we propose a simple physical model that accounts for this stepping behavior as a random walk in a tilted corrugated potential that combines torque and contact forces. We argue that the absolute angular position of the rotor is crucial for understanding step properties, and show this hypothesis to be consistent with the available data, in particular the observation that backward steps are smaller on average than forward steps. Our model also predicts a sublinear torque-speed relationship at low torque, and a peak in rotor diffusion as a function of torque

Evidence-informed health policy: are we beginning to get there at last

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Lessons learned from EVOLVE for the planning of future global randomized trials in chronic kidney disease

The effect of the calcimimetic cinacalcet on cardiovascular disease in patients undergoing hemodialysis with secondary hyperparathyroidism (sHPT) was evaluated in the EVOLVE trial. This was the largest (in size) and longest (in duration) randomized controlled clinical trial undertaken in this population. During planning, execution, analysis and reporting of the trial many lessons were learned, including those related to the use of a composite cardiovascular primary endpoint, definition of endpoints (particularly heart failure and severe unremitting HPT), importance of age for optimal stratification at randomization, use of unadjusted and adjusted intention-to-treat analysis for the primary outcome, how to respond to a lower than predicted event rate during the trial, development of a pre-specified analytic plan that accounted for non-adherence and for co-interventions that diminished the power of the trial to observe a treatment effect, determination of the credibility of a subgroup effect, use of adverse effects database to investigate rare diseases, collection of blood for biomarker measurement not designated prior to trial initiation, and interpretation of the benefits to harms ratio for individual patients. It is likely that many of these issues will arise in planning of future trials in chronic kidney disease

Chemotaxis When Bacteria Remember: Drift versus Diffusion

{\sl Escherichia coli} ({\sl E. coli}) bacteria govern their trajectories by switching between running and tumbling modes as a function of the nutrient concentration they experienced in the past. At short time one observes a drift of the bacterial population, while at long time one observes accumulation in high-nutrient regions. Recent work has viewed chemotaxis as a compromise between drift toward favorable regions and accumulation in favorable regions. A number of earlier studies assume that a bacterium resets its memory at tumbles -- a fact not borne out by experiment -- and make use of approximate coarse-grained descriptions. Here, we revisit the problem of chemotaxis without resorting to any memory resets. We find that when bacteria respond to the environment in a non-adaptive manner, chemotaxis is generally dominated by diffusion, whereas when bacteria respond in an adaptive manner, chemotaxis is dominated by a bias in the motion. In the adaptive case, favorable drift occurs together with favorable accumulation. We derive our results from detailed simulations and a variety of analytical arguments. In particular, we introduce a new coarse-grained description of chemotaxis as biased diffusion, and we discuss the way it departs from older coarse-grained descriptions.Comment: Revised version, journal reference adde

Activity in perceptual classification networks as a basis for human subjective time perception

Despite being a fundamental dimension of experience, how the human brain generates the perception of time remains unknown. Here, we provide a novel explanation for how human time perception might be accomplished, based on non-temporal perceptual classification processes. To demonstrate this proposal, we build an artificial neural system centred on a feed-forward image classification network, functionally similar to human visual processing. In this system, input videos of natural scenes drive changes in network activation, and accumulation of salient changes in activation are used to estimate duration. Estimates produced by this system match human reports made about the same videos, replicating key qualitative biases, including differentiating between scenes of walking around a busy city or sitting in a cafe or office. Our approach provides a working model of duration perception from stimulus to estimation and presents a new direction for examining the foundations of this central aspect of human experience

Not the Root of the Problem-Hair Cortisol and Cortisone Do Not Mediate the Effect of Child Maltreatment on Body Mass Index.

BACKGROUND: Experiencing maltreatment during childhood exerts substantial stress on the child and increases the risk for overweight and obesity later in life. The current study tests whether hair cortisol-a measure of chronic stress-and its metabolite cortisone mediate the relation between abuse and neglect on the one hand, and body mass index (BMI) on the other. METHOD: The sample consisted of 249 participants aged 8 to 87 years (M = 36.13, SD = 19.33). We collected data on child abuse and neglect using questionnaires, measured cortisol and cortisone concentrations in hair, and BMI. In a structural model, the effects of abuse and neglect on hair cortisol, hair cortisone, and BMI were tested, as well as the covariance between hair cortisol and BMI, and hair cortisone and BMI. RESULTS: Within the sample, 23% were overweight but not obese and 14% were obese. Higher levels of experienced abuse were related to higher cortisone concentrations in hair (β = 0.24, p < .001) and higher BMI (β = 0.17, p =.04). Neglect was not related to hair cortisol, hair cortisone, or BMI. Hair cortisol and cortisone did not mediate the association between maltreatment, and BMI. Sensitivity analyses demonstrate the same pattern of results in a subsample of adult participants currently not living with their parents. However, in younger participants who were still living with their parents, the associations between abuse and cortisone (β = 0.14, p =.35) and abuse and BMI (β = 0.02, p =.92) were no longer significant. CONCLUSION: These findings confirm that experiencing abuse is related to higher BMI but suggest that hair cortisol and cortisone are not the mechanism underlying the association between child maltreatment and BMI. This is the first study to show abuse may be associated to elevated concentrations of hair cortisone-evidence of long-term alterations in chronic stress levels. Future research may benefit from exploring the effects of maltreatment on weight gain in longitudinal designs, including measures of other potential mediators such as eating as a coping mechanism, and more direct indicators of metabolic health

Evaluation of the impact of a school gardening intervention on children's fruit and vegetable intake: a randomised controlled trial.

Background: Current academic literature suggests that school gardening programmes can provide an interactive environment with the potential to change children’s fruit and vegetable intake. This is the first cluster randomised controlled trial (RCT) designed to evaluate whether a school gardening programme can have an effect on children’s fruit and vegetable intake. Methods: The trial included children from 23 schools; these schools were randomised into two groups, one to receive the Royal Horticultural Society (RHS)-led intervention and the other to receive the less involved Teacher-led intervention. A 24-hour food diary (CADET) was used to collect baseline and follow-up dietary intake 18 months apart. Questionnaires were also administered to evaluate the intervention implementation. Results: A total of 641 children completed the trial with a mean age of 8.1 years (95% CI: 8.0, 8.4). The unadjusted results from multilevel regression analysis revealed that for combined daily fruit and vegetable intake the Teacher-led group had a higher daily mean change of 8 g (95% CI: −19, 36) compared to the RHS-led group -32 g (95% CI: −60, −3). However, after adjusting for possible confounders this difference was not significant (intervention effect: −40 g, 95% CI: −88, 1; p = 0.06). The adjusted analysis of process measures identified that if schools improved their gardening score by 3 levels (a measure of school gardening involvement - the scale has 6 levels from 0 ‘no garden’ to 5 ‘community involvement’), irrespective of group allocation, children had, on average, a daily increase of 81 g of fruit and vegetable intake (95% CI: 0, 163; p = 0.05) compared to schools that had no change in gardening score. Conclusions: This study is the first cluster randomised controlled trial designed to evaluate a school gardening intervention. The results have found very little evidence to support the claims that school gardening alone can improve children’s daily fruit and vegetable intake. However, when a gardening intervention is implemented at a high level within the school it may improve children’s daily fruit and vegetable intake by a portion. Improving children’s fruit and vegetable intake remains a challenging task

NS1 Specific CD8(+) T-Cells with Effector Function and TRBV11 Dominance in a Patient with Parvovirus B19 Associated Inflammatory Cardiomyopathy

Background: Parvovirus B19 (B19V) is the most commonly detected virus in endomyocardial biopsies (EMBs) from patients with inflammatory cardiomyopathy (DCMi). Despite the importance of T-cells in antiviral defense, little is known about the role of B19V specific T-cells in this entity. Methodology and Principal Findings: An exceptionally high B19V viral load in EMBs (115,091 viral copies/mg nucleic acids), peripheral blood mononuclear cells (PBMCs) and serum was measured in a DCMi patient at initial presentation, suggesting B19V viremia. The B19V viral load in EMBs had decreased substantially 6 and 12 months afterwards, and was not traceable in PBMCs and the serum at these times. Using pools of overlapping peptides spanning the whole B19V proteome, strong CD8(+) T-cell responses were elicited to the 10-amico-acid peptides SALKLAIYKA (19.7% of all CD8(+) cells) and QSALKLAIYK (10%) and additional weaker responses to GLCPHCINVG (0.71%) and LLHTDFEQVM (0.06%). Real-time RT-PCR of IFN gamma secretion-assay-enriched T-cells responding to the peptides, SALKLAIYKA and GLCPHCINVG, revealed a disproportionately high T-cell receptor Vbeta (TRBV) 11 expression in this population. Furthermore, dominant expression of type-1 (IFN gamma, IL2, IL27 and Tbet) and of cytotoxic T-cell markers (Perforin and Granzyme B) was found, whereas gene expression indicating type-2 (IL4, GATA3) and regulatory T-cells (FoxP3) was low. Conclusions: Our results indicate that B19V Ag-specific CD8(+) T-cells with effector function are involved in B19V associated DCMi. In particular, a dominant role of TRBV11 and type-1/CTL effector cells in the T-cell mediated antiviral immune response is suggested. The persistence of B19V in the endomyocardium is a likely antigen source for the maintenance of CD8(+) T-cell responses to the identified epitopes

A Characterization of Scale Invariant Responses in Enzymatic Networks

An ubiquitous property of biological sensory systems is adaptation: a step increase in stimulus triggers an initial change in a biochemical or physiological response, followed by a more gradual relaxation toward a basal, pre-stimulus level. Adaptation helps maintain essential variables within acceptable bounds and allows organisms to readjust themselves to an optimum and non-saturating sensitivity range when faced with a prolonged change in their environment. Recently, it was shown theoretically and experimentally that many adapting systems, both at the organism and single-cell level, enjoy a remarkable additional feature: scale invariance, meaning that the initial, transient behavior remains (approximately) the same even when the background signal level is scaled. In this work, we set out to investigate under what conditions a broadly used model of biochemical enzymatic networks will exhibit scale-invariant behavior. An exhaustive computational study led us to discover a new property of surprising simplicity and generality, uniform linearizations with fast output (ULFO), whose validity we show is both necessary and sufficient for scale invariance of enzymatic networks. Based on this study, we go on to develop a mathematical explanation of how ULFO results in scale invariance. Our work provides a surprisingly consistent, simple, and general framework for understanding this phenomenon, and results in concrete experimental predictions