“
“Neither randomized controlled trials nor efforts to identify genetic markers have been helpful with regard to the goal of individualizing diuretic therapy in the treatment of hypertension, a goal that receives little clinical or research attention. This review will examine, and bring attention to, the considerable yet overlooked information relevant to individualizing diuretic therapy.

It will bring attention to clinical, biochemical, and pharmacological clues that can be helpful in identifying who is likely to respond to a diuretic, who needs a stronger diuretic regimen, selleck chemicals which diuretic to prescribe, and how to minimize adverse effects. New directions for clinical research aimed at individualizing use in hypertension will be explored. Research and clinical attention to the goal of individualizing diuretic treatment in hypertension need to be renewed, to help us achieve greater hypertension control with

fewer adverse effects and lower costs.”
“A series of 1-aminotetralin scaffolds was synthesized via metal-catalyzed ring-opening reactions of heterobicyclic alkenes. Small libraries of amides and amines were made using the amino group of each scaffold as a handle. Screening of these libraries against human opioid receptors led to the identification of (S)-(S)-5.2a as a high-affinity selective mu BAY 73-4506 order ligand (IC(50) mu = 5 nM, kappa = 707 nM, delta = 3,795 nM) displaying mu-agonist/antagonist properties due to its selleck kinase inhibitor partial agonism (EC(50) = 2.6 mu M; E(max) = 18%). Crown Copyright (C) 2008 Published by Elsevier Ltd. All rights reserved.”
“B cells are efficient APCs when they internalize antigen via BCR-mediated uptake. Adoptively transferred antigen-presenting B cells can induce T-cell tolerance to foreign and self antigens; however, it is unknown whether endogenous B cells presenting self-peptides interact with naive T cells and contribute to peripheral T-cell self-tolerance. Moreover, the relative abilities of mature B-cell subsets to induce T-cell tolerance have not been examined. To address these questions, we created a new mouse model wherein a very small fraction of B cells expresses an antigen transgene that cannot be transferred

to other APCs. We limited antigen expression to follicular, marginal zone, or B-1 B-cell subsets and found that small numbers of each subset interacted with naive antigen-specific T cells. Although antigen expressed by B-1 B cells induced the most T-cell division, divided T cells subsequently disappeared from secondary lymphoid tissues. Independent of which B-cell subset presented antigen, the remaining T cells were rendered hypo-responsive, and this effect was not associated with Foxp3 expression. Our data show that physiologically relevant proportions of B cells can mediate peripheral T-cell tolerance, and suggest that the mechanisms of tolerance induction might differ among follicular, marginal zone, and B-1 B-cell subsets.

[Conclusion] Detailed and diverse investigations should be performed considering the number and characteristics of subjects. and the limitations influencing the NFB training period.”
“P>Aim\n\nThe goal of this study is to characterize the changes in 33 biomarkers within the gingival crevicular fluid during the 3-week induction and 4-week resolution of stent-induced, biofilm overgrowth mediated, experimental gingivitis in humans.\n\nMethods\n\nExperimental gingivitis was induced in 25 subjects for 21 days followed by treatment with a sonic powered toothbrush for 28 days. Clinical indices and gingival crevicular fluids were collected weekly during induction and biweekly during resolution. Samples

were analysed using a bead-based multiplexing analysis for the simultaneous selleck chemicals llc measurements of 33 biomarkers within

each sample including cytokines, matrix-metalloproteinases (MMPs) and adipokines. Prostaglandin-E(2) was measured by enzyme-linked immunoadsorbant assay. Statistical testing using general linear models with structured covariance matrices were performed to compare stent to contralateral (non-stent) changes in clinical signs and in biomarker levels over time.\n\nResults\n\nGingivitis induction was associated with a significant 2.6-fold increase in interleukin 1-beta (IL-beta), a 3.1-fold increase in IL-1 alpha and a significant decrease in multiple chemokines as well as MMPs-1, -3 and 13. All changes in www.selleckchem.com/products/apr-246-prima-1met.html clinical signs and mediators rebounded to baseline in response to treatment in the resolution phase.\n\nConclusions\n\nStent-induced gingivitis is associated with marked, but reversible increases in IL-alpha a and IL-1 beta with suppression of multiple

chemokines as well as selected MMPs.”
“How supplementary eye field (SEF) contributes to visual search is unknown. Inputs from cortical and subcortical structures known to represent visual salience suggest that SEF may Selleck Trichostatin A serve as an additional node in this network. This hypothesis was tested by recording action potentials and local field potentials (LFPs) in two monkeys performing an efficient pop-out visual search task. Target selection modulation, tuning width, and response magnitude of spikes and LFP in SEF were compared with those in frontal eye field. Surprisingly, only similar to 2% of SEF neurons and similar to 8% of SEF LFP sites selected the location of the search target. The absence of salience in SEF may be due to an absence of appropriate visual afferents, which suggests that these inputs are a necessary anatomical feature of areas representing salience. We also tested whether SEF contributes to overcoming the automatic tendency to respond to a primed color when the target identity switches during priming of pop-out. Very few SEF neurons or LFP sites modulated in association with performance deficits following target switches. However, a subset of SEF neurons and LFPs exhibited strong modulation following erroneous saccades to a distractor.

AWLD showed reduced numbers of immature and naive B cells (vs. controls), but higher PB counts of plasmablasts (vs. the other 2 groups). Although PB memory B cells were reduced among the patients, the percentage of surface (s)IgA(+) cells (particularly CD27(-)/sIgA(+) cells) was increased in AH, whereas both sIgG(+) and sIgA(+) memory B cells were GS-1101 cost significantly overrepresented in AWLD versus healthy donors. Regarding circulating plasmablasts, patients with AH only showed significantly reduced counts of sIgG(+) cells versus controls. In contrast, the proportion of both sIgA(+) and sIgG(+) plasmablastsfrom all plasmablastswas reduced in AH and increased in AWLD (vs. the other 2 groups). ConclusionsAH

and AWLD patients display a significantly reduced PB B-cell count, at the expense of decreased numbers of recently produced immature/regulatory B cells and naive B cells, together with an increase in Ig-switched memory B lymphocytes and plasmablasts, Selleckchem 3-deazaneplanocin A particularly of IgA(+) cells.”
“The cAMP/PKA signalling pathway and transcription factor cAMP response

element-binding protein (CREB) play key roles in long-term memory (LTM) formation. We used two closely related parasitic wasp species, Cotesia glomerata and Cotesia rubecula, which were previously shown to be different in LTM formation, and sequenced at least nine different CREB transcripts in both wasp species. The splicing patterns, functional domains and amino acid sequences were similar Selleckchem PHA-739358 to those found in the CREB genes of other organisms. The predicted amino acid sequences of the CREB isoforms were identical in both wasp species. Using real-time quantitative PCR we found that two low abundant CREB transcripts are differentially expressed in the two wasps, whereas the expression levels of high abundant transcripts

are similar.”
“T-cell large granular lymphocytic (LGL) leukemia is a complex diagnosis, requiring persistent clonal expansions of LGLs, and cytopenias. Often the diagnosis is unclear as non-clonal expansions of LGLs commonly occur in reactive conditions. To better understand T-LGL leukemia, we performed a comprehensive clinicopathologic analysis of 85 patients with LGL expansions. Interestingly, distinct CD8 + (dim)/CD57 + populations, seen by flow cytometry, were significantly associated with clonal T-LGL leukemia (P<0.001) as well as neutropenia (median absolute neutrophil count (ANC) 1.45 vs 3.19 x 10(9)/l; P=0.0017). Furthermore, cases with distinct CD8+(dim)/ CD57 + populations and monoclonal T cells had even lower ANCs (median ANC 1.41 x 10(9)/l; P=0.001) compared with cases without these dual criteria. Additionally, complete or partial loss of CD5 expression was independently associated with clonal T-LGL leukemia (P<0.001) and neutropenia (median ANC 1.41 vs 2.70 x 10(9)/l; P=0.002).

The other 90 kDa protein, which was unstable and produced in low yields, was posited as NapA from the napDAGHB-type operon. Two napA genes have been sequenced from the napEDABC-type and napDAGHB-type Belnacasan cell line operons of S. gelidimarina.

Native NAP from S. putrefaciens was resolved as one NapA monomer and one NapAB heterodimer. Two amino acid substitutions in NapA correlated with the isolation of NAP as a NapA monomer or a NapAB heterodimer. The resolution of native, redox-active NapA isoforms in Shewanella provides new insight into the respiratory versatility of this genus, which has implications in bioremediation and the assembly of microbial fuel cells. (C) 2010 Elsevier Inc. All rights reserved.”
“BACKGROUND: Isolated limb infusion (ILI) is an effective and minimally invasive treatment

option for delivering regional chemotherapy in patients with metastatic melanoma confined to a limb. Recurrent or progressive disease after an ILI, however, presents a challenge for further treatment. The value of repeat ILI in this situation has not been well documented. METHODS: Forty-eight patients were identified who had been treated with a repeat ILI. In all patients, a cytotoxic combination of melphalan and actinomycin D was used. RESULTS: The median time between the 2 procedures was 11 months. The complete response (CR) rate after repeat ILI was 23%, compared with 31% after the initial ILI (P=.36). The overall response was 83%, compared with 75% after the first procedure (P=32). The selleck products median duration of response was 11 months (10 months for patients with CR; P=.80), and median survival was 38 months. In those patients achieving a CR, the median survival was 68 months (P=.003). Toxicity after repeat ILI was increased, with 20 patients experiencing Wieberdink grade III limb toxicity (considerable erythema and edema with blistering) and 5 patients experiencing

grade IV toxicity (threatened or actual Etomoxir Metabolism inhibitor compartment syndrome), whereas after the initial ILI these toxicity grades occurred in 14 patients and 1 patient, respectively (P=.03). No patient experienced grade V toxicity (requiring amputation). CONCLUSIONS: Repeat ILI is an attractive treatment option to achieve limb salvage in patients with inoperable recurrent or progressive melanoma after a previous ILI. It can be associated with significant short-term regional toxicity, but is well tolerated by most patients, with satisfactory response rates. Cancer 2009;115:1932-40. (C) 2009 American Cancer Society.”
“A deficiency in the early components of complement is associated with an increased susceptibility to pyrogenic infections and multiple autoimmune diseases. We previously reported a Japanese case of selective C1s deficiency resulting from a compound heterozygosity for a 4-bp deletion in exon X and a nonsense mutation Glu597X in exon XII of the C1s gene.

NRG-1 beta obviously reduced and delayed the cerebral damage. With the duration of ischemia, the expression of MMP-9 gradually Screening Library cell line increased in the control group. NRG-1 beta decreased the level of MMP-9 compared with that in the control group (P < 0.01). NSE immunoreaction transiently elevated at the early stage of cerebral ischemia insult, and then gradually decreased in the control group. The administration of NRG-1 beta significantly increased the level of NSE, and thus delayed the time and the degree of neuron damage. There were statistical differences in contrast to the control group (P < 0.01). There was no relationship between the expressions of the

two proteins. MMP-9 might aim at various target cells at different stages and contribute to the inflammatory reaction after cerebral ischemia-reperfusion insult. NRG-1 PFTα purchase beta inhibits the activation of MMP-9 and development of inflammation, enhances the activity of NSE, improves the microenvironment of neuron survivals, and delays the phase of irreversible neuron necrosis. Therefore, NRG-1 beta

may play a neuroprotective role in cerebral ischemia/reperfusion.”
“Context: Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar is implicated in dyslipidemia, fatty liver, and insulin resistance.\n\nObjective: The aim of the study was to develop a simple outpatient tolerance test for lipogenic sensitivity to dietary sugar.\n\nDesign and Setting: In inpatients given repeated doses of fructose, protocol 1 compared the acute increase in DNL determined from the percentage of palmitate (“new palmitate”) and the percentage of isotopically labeled palmitate (“% DNL”)in very low-density lipoprotein triglyceride (TG). Protocol 2 compared the increase in new palmitate in outpatients given three different sugar beverages in a randomized

crossover design.\n\nParticipants: There were 15 lean and overweight volunteers in protocol 1 and 15 overweight JNJ-26481585 manufacturer volunteers in protocol 2.\n\nInterventions: In protocol 1, subjects received 1.4 g/kg fructose in divided oral doses over 6 h; in protocol 2, subjects received 0.5 g/kg fructose, 0.5 g/kg fructose plus 0.5g/kg glucose, or 1 g/kg fructose plus 1g/kg glucose each as a single oral bolus.\n\nMain Outcome Measures: We measured the increase in DNL by two methods. Results: After repeated doses of fructose, new palmitate was significantly correlated with the increase in %DNL (Delta, r = 0.814; P < 0.001) and with fasting insulin levels (area under the curve, r = 0.754; P = 0.001). After a single sugar dose, new palmitate showed a dose effect and was greater after fructose plus glucose. Very low-density lipoprotein TG and total TG significantly increased in both protocols.

Collectively, these results provide evidence that 7HF-mediated inhibition of pro-inflammatory cytokines functionally results in marked protection in experimental

models of acute and chronic inflammation. (C) 2010 Elsevier B.V. All rights reserved.”
“Identification of dietary and lifestyle variables associated with the development of Parkinson’s disease (PD) may offer pathogenetic clues and prevention opportunities. In a population-based prospective cohort study, 26,173 participants in the EPIC-Greece cohort had sociodemographic, anthropometric, medical, dietary and lifestyle variables ascertained at enrolment and periodically reassessed with follow-up contacts. Based on these data, subjects were screened as GSK2126458 possible PD cases if they Quizartinib (1) reported either a medical diagnosis of PD or use of anti-PD drugs and (2) did not report preceding causes of secondary parkinsonism. For diagnostic validation, possible incident PD cases were assessed by a focused 3-item telephone questionnaire. Cox proportional hazards regression was used to evaluate associations between potential predictors

and incident PD. The main multivariate model included gender, age, marital status, schooling years, farming occupation, smoking status, caffeinated coffee, body mass index, physical activity and energy intake. Additional models included all above variables plus one dietary item at a time. Incidence rate adjusted to the European population was 16.9 per 100,000 person-years. In multivariate models, incident PD exhibited strong positive association with consumption of milk, but not cheese or yoghurt. This finding may help narrow down the search for potential dairy product components with a facilitatory role in PD. Concerning other dietary components, inverse association was found between polyunsaturated fat intake and incident PD. Also, inverse association was found with tobacco smoking, in line with previous studies, but not with caffeine.”
“Coronary artery disease (CAD) and stroke are the major health problems

in many countries because of their increasing prevalence and high mortality. It is well known that CAD and stroke are based on atherosclerosis and shared environmental and www.selleckchem.com/products/ldk378.html genetic risk factors. Recently, an association of a functional sequence variation -154G>A in the angiotensin receptor-like 1 (AGTRL1) with a susceptibility to stroke was reported. In this study, we investigated a total of 1479 CAD cases and 2062 controls from the Japanese and Korean populations to validate the association of AGTRL1 with CAD. However, we obtained no evidence of the association in both the Japanese (odds ratio (OR)=0.95, 95% confidence interval (CI); 0.82-1.10, P=0.47, allele count model) and Korean (OR 0.90, 95% CI; 0.77-1.05, P=0.18, allele count model) populations.

\n\nResults: After hormonal treatment 9 (82%) patients showed an objective response (4 complete response; 5 partial response), one showed stable disease (26+ months) and one progressive disease. Response duration was from 4+ to 252+ months (median 48+ months).\n\nConclusion: Hormonal treatment for measurable residual or recurrent low-grade ESS has a high response rate and should be considered as the treatment ABT-263 price of choice for patients in which recurrent disease cannot easily be resected. (C) 2009 Elsevier Ireland Ltd. All rights reserved.”
“Data from the longitudinal

West of Scotland Twenty-07 Study: Health in the Community was used to examine whether, over a 20 year period, the self-reported health of people living in deprived areas became poorer faster compared to those living in more affluent

areas. Three cohorts (born in the 3-MA order early 1930s, 1950s and 1970s) are included, covering 60 years of the life span. Using multilevel growth curve models, a 40% probability of reporting poor health was predicted among residents of more deprived areas at an earlier age (66) compared to those living in more affluent areas (83). Wider area differences were seen for men than for women. Our findings indicate that attempts to reduce area differences in health should start young but also continue throughout the lifespan. (C) 2011 Elsevier Ltd. All rights reserved.”
“The Ecosystem Management Decision Support (EMDS) CAL-101 concentration system has been used by the US Department of Agriculture, Forest Service and Bureaus of the Department of the Interior since 2006 to evaluate wildfire potential across all administrative units in the continental US, and to establish priorities for allocating fuel-treatment budgets. This article discusses an EMDS

fuels-treatment decision-support application, agency experiences with the application, and the extent to which it addressed concerns in Congress, and those of the General Accountability Office. EMDS aids the budget allocation process by providing a rational, transparent, and reproducible process that can be clearly communicated to Congressional staff and oversight personnel. However, practical application of this decision-support process was not without challenges, which included missing or suboptimal data, clearly articulated fuels management objectives, and improved understanding (via re-assessing decision logic from prior years) of trade-offs in decision-making. Published by Elsevier B.V”
“Cytomegalovirus (CMV) is one of the most significant viral pathogens during pregnancy and in immunocompromised patients. Antiviral prophylactic strategies are limited by toxicities, drug-drug interactions and development of antiviral resistance.

The functional DNA markers for lcyE were associated with lutein, and with the ratio of carotenoids in the alpha and beta branches, but not with provitamin A levels. However, the combined effects of the two genes were stronger than their individual effects on all carotenoids.\n\nConclusions: Tropical maize inbred lines harbouring the favourable alleles of the crtRB1-5′TE and 3′TE functional markers produce higher levels of provitamin A. AC220 Such maize lines can be used

as donor parents to speed up the development of provitamin A biofortified tropical maize varieties adapted to growing conditions and consumer preferences, providing a route towards mitigation of vitamin A malnutrition in Sub-Saharan Africa.”
“Introduction: Maximal

oxygen uptake VO(2max) has an important place in the assessment of cardiopulmonary fitness. Currently there is insufficient normative data for Iranian adolescents. With this preliminary study, we aimed to set up the first normative data for our laboratory which may also serve as a basis for future large population-based studies in Iran.\n\nMaterial and methods: We assessed the peak oxygen consumption of 95 healthy Iranian adolescents, aged 13-17 years, and examined the cardiopulmonary responses to exercise test in relation to their age, sex and body size. Between June and September 2007, the level of aerobic capacity was evaluated by maximal oxygen consumption VO(2max)), which was calculated Mocetinostat using the exercise test on a bicycle ergometer.\n\nResults: During a four-month period, the cardiopulmonary exercise test was conducted on a population-based sample of 95 adolescents (44 boys and 51 girls). The mean age and body mass index were 15.59 +/- 1.85 years and 23.46 +/- 5.05 kg/m(2), respectively. The VO(2max) of boys was significantly higher in boys than in girls (16.71 +/- 8.72/12.48 +/- 6.25 ml/kg/min respectively, p = 0.001).\n\nConclusions: The current study presents normal data for a small representative sample of healthy Iranian adolescents. VO(2max) in our study was in the poor to average range when compared to the standard values of other populations. This information should prompt policy makers and medical

educators to address this problem, and to consider promoting exercise and integrating physical fitness into the school MEK inhibitor side effects curriculum.”
“Numerous members of the Brassicaceae possess non-photoconvertible water-soluble chlorophyll (Chl)-binding proteins (Class II WSCPs), which function as Chl scavengers during cell disruption caused by wounding, pest/pathogen attacks, and/or environmental stress. Class II WSCPs have two extension peptides, one at the N-terminus and one at the C-terminus. The N-terminal peptide acts as a signal peptide, targeting the protein to the endoplasmic reticulum body, a unique defensive organelle found only in the Brassicaceae. However, the physiological and biochemical functions of the C-terminal extension peptide had not been characterized previously.

“
“Introduction: We have previously reported that bacterial toxins, especially endotoxins such as lipopolysaccharides (LPS), might be important causative agents in the pathogenesis of rheumatoid arthritis (RA) in an in vitro model that simulates the potential effects of residing in damp buildings. Since numerous inflammatory processes are linked with the nuclear factor-kappa B (NF-kappa B), we investigated in detail the effects of LPS on the NF-kappa B pathway and the postulated formation of procollagen-endotoxin complexes.\n\nMethods: An in vitro model of human chondrocytes was used to investigate LPS-mediated inflammatory signaling.\n\nResults: Immunoelectron microscopy revealed that

LPS physically interact with collagen type II in the extracellular selleck compound matrix (ECM) and anti-collagen type II significantly reduced this interaction. BMS-345541 (a specific inhibitor of I kappa B kinase (IKK)) or wortmannin (a specific inhibitor of phosphatidylinositol 3-kinase (PI-3K)) inhibited the LPS-induced degradation of the ECM and apoptosis in chondrocytes. This effect was completely inhibited by combining BMS345541 and wortmannin. Furthermore, BMS-345541 and/or wortmannin suppressed the LPS-induced upregulation of catabolic enzymes that mediate ECM degradation (matrix

metalloproteinases-9, -13), cyclooxygenase-2 and apoptosis (activated caspase-3). These proteins are regulated by NF-kappa find more B, suggesting that the NF-kappa B and PI-3K pathways are involved in LPS-induced cartilage degradation. The induction of NF-kappa B correlated with activation of I kappa B alpha kinase, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation and p65 nuclear translocation. Further upstream, LPS induced the expression of

Toll-like receptor 4 (TLR4) and bound with TLR4, indicating that LPS acts through TLR4.\n\nConclusion: These results suggest that molecular associations BAY 63-2521 between LPS/TLR4/collagen type II in chondrocytes upregulate the NF-kappa B and PI-3K signaling pathways and activate proinflammatory activity.”
“P>Purpose:\n\nTo determine the prevalence of epilepsy and seizures in the Navajo.\n\nMethods:\n\nWe studied 226,496 Navajo residing in the Navajo Reservation who had at least one medical encounter between October 1, 1998 and September 30, 2002. We ascertained and confirmed cases in two phases. First, we identified patients with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes signifying epilepsy or seizures using Indian Health Service (IHS) administrative data. Second, we reviewed medical charts of a geographic subpopulation of identified patients to confirm diagnoses and assess the positive predictive value of the ICD-9-CM codes in identifying patients with active epilepsy.

This study connects neuronal coding of the auditory space with natural stimulus statistics and generates new experimental predictions. Moreover, results presented here suggest that cortical regions with seemingly different functions may implement the same computational strategy-efficient coding.”
“HIV-1 infection and antiretroviral therapy are associated with a dyslipidemia marked by low levels of high-density lipoprotein

and increased cardiovascular disease, but it is unclear whether virion replication plays a causative role in these changes. The HIV-1 Nef protein can impair ATP cassette binding transporter A1 (ABCA1) cholesterol efflux from macrophages, a potentially pro-atherosclerotic effect. This viral inhibition of efflux was correlated with a direct interaction between ABCA1 and Nef. Here, we defined the ABCA1 www.selleckchem.com/products/Tipifarnib(R115777).html domain required for the Nef-ABCA1 protein-protein interaction Quizartinib mouse and determined whether this interaction mediates the ability of Nef to downregulate ABCA1. Nef expressed in HEK 293 cells strongly inhibited ABCA1 efflux and protein levels but did not alter levels of cMIR, another transmembrane protein. Analysis of a panel of ABCA1 C-terminal mutants

showed Nef binding required the ABCA1 C-terminal amino acids between positions 2225 and 2231. However, the binding of Nef to ABCA1 was not required for inhibition because the C-terminal ABCA1 mutants that did not bind Nef were still downregulated by Nef. selleck inhibitor Given this discordance, the mechanism of downregulation was investigated and was found to involve the acceleration of ABCA1 protein degradation but did not to depend upon the ABCA1 PEST sequence, which mediates the calpain

proteolysis of ABCA1. Furthermore, it did not associate with a Nef-dependent induction of signaling through the unfolded protein response but was significantly dependent upon proteasomal function and could act on an ABCA1 mutant that fails to exit the endoplasmic reticulum. In summary, we show that Nef downregulates ABCA1 function by a post-translational mechanism that stimulates ABCA1 degradation but does not require the ability of Nef to bind ABCA1.”
“Synthetic gene regulatory networks show significant stochastic fluctuations in expression levels due to the low copy number of transcription factors. When a synthetic gene network is allowed to regulate a downstream network, the response time of the regulating transcription factors increases. This effect has been termed “retroactivity”. In this article, we describe a method for estimating the retroactivity of a given system by measuring the stochastic noise in the transcription factor expression. We show that the noise in the output signal of the network can be affected significantly when the output is connected to a downstream module. More specifically, the output signal noise can show significantly longer correlations. We define retroactivity by the change in the correlation time.