Sympathetic Activation and Baroreflex Function during Intradialytic Hypertensive Episodes

BACKGROUND: The mechanisms of intradialytic increases in blood pressure are not well defined. The present study was undertaken to assess the role of autonomic nervous system activation during intradialytic hypertensive episodes. METHODOLOGY/PRINCIPAL FINDINGS: Continuous interbeat intervals (IBI) and systolic blood pressure (SBP) were monitored during hemodialysis in 108 chronic patients. Intradialytic hypertensive episodes defined as a period of at least 10 mmHg increase in SBP between the beginning and the end of a dialysis session or hypertension resistant to ultrafiltration occurring during or immediately after the dialysis procedure, were detected in 62 out of 113 hemodialysis sessions. SBP variability, IBI variability and baroreceptor sensitivity (BRS) in the low (LF) and high (HF) frequency ranges were assessed using the complex demodulation technique (CDM). Intradialytic hypertensive episodes were associated with an increased (n = 45) or decreased (n = 17) heart rate. The maximal blood pressure was similar in both groups. In patients with increased heart rate the increase in blood pressure was associated with marked increases in SBP and IBI variability, with suppressed BRS indices and enhanced sympatho-vagal balance. In contrast, in those with decreased heart rate, there were no significant changes in the above parameters. End-of-dialysis blood pressure in all sessions associated with hypertensive episode was significantly higher than in those without such episodes. In logistic regression analysis, predialysis BRS in the low frequency range was found to be the main predictor of intradialytic hypertension. CONCLUSION/SIGNIFICANCE: Our data point to sympathetic overactivity with feed-forward blood pressure enhancement as an important mechanism of intradialytic hypertension in a significant proportion of patients. The triggers of increased sympathetic activity during hemodialysis remain to be determined. Intradialytic hypertensive episodes are associated with higher end-of-dialysis blood pressure, suggesting that intradialytic hypertension may play a role in generation of interdialytic hypertension

Genome-Wide Screen for Mycobacterium tuberculosis Genes That Regulate Host Immunity

In spite of its highly immunogenic properties, Mycobacterium tuberculosis (Mtb) establishes persistent infection in otherwise healthy individuals, making it one of the most widespread and deadly human pathogens. Mtb's prolonged survival may reflect production of microbial factors that prevent even more vigorous immunity (quantitative effect) or that divert the immune response to a non-sterilizing mode (qualitative effect). Disruption of Mtb genes has produced a list of several dozen candidate immunomodulatory factors. Here we used robotic fluorescence microscopy to screen 10,100 loss-of-function transposon mutants of Mtb for their impact on the expression of promoter-reporter constructs for 12 host immune response genes in a mouse macrophage cell line. The screen identified 364 candidate immunoregulatory genes. To illustrate the utility of the candidate list, we confirmed the impact of 35 Mtb mutant strains on expression of endogenous immune response genes in primary macrophages. Detailed analysis focused on a strain of Mtb in which a transposon disrupts Rv0431, a gene encoding a conserved protein of unknown function. This mutant elicited much more macrophage TNFα, IL-12p40 and IL-6 in vitro than wild type Mtb, and was attenuated in the mouse. The mutant list provides a platform for exploring the immunobiology of tuberculosis, for example, by combining immunoregulatory mutations in a candidate vaccine strain

Management of Hypertension in Chronic Kidney Disease

Chronic kidney disease (CKD) is an increasingly prevalent condition globally and is strongly associated with incident cardiovascular disease (CVD). Hypertension is both a cause and effect of CKD and affects the vast majority of CKD patients. Control of hypertension is important in those with CKD as it leads to slowing of disease progression as well as reduced CVD risk. Existing guidelines do not offer a consensus on optimal blood pressure (BP) targets. Therefore, an understanding of the evidence used to create these guidelines is vital when considering how best to manage individual patients. Non-pharmacological interventions are useful in reducing BP in CKD but are rarely sufficient to control BP adequately. Patients with CKD and hypertension will often require a combination of antihypertensive medications to achieve target BP. Certain pharmacological therapies provide additional BP-independent renoprotective and/or cardioprotective action and this must be considered when instituting therapy. Managing hypertension in the context of haemodialysis and following kidney transplantation presents further challenges. Novel therapies may enhance treatment in the near future. Importantly, a personalised and evidence-based management plan remains key to achieving BP targets, reducing CVD risk and slowing progression of CKD.</p

Projected sensitivities of the LUX-ZEPLIN experiment to new physics via low-energy electron recoils

LUX-ZEPLIN is a dark matter detector expected to obtain world-leading sensitivity to weakly-interacting massive particles interacting via nuclear recoils with a ∼ 7 -tonne xenon target mass. This paper presents sensitivity projections to several low-energy signals of the complementary electron recoil signal type: 1) an effective neutrino magnetic moment, and 2) an effective neutrino millicharge, both for p p -chain solar neutrinos, 3) an axion flux generated by the Sun, 4) axionlike particles forming the Galactic dark matter, 5) hidden photons, 6) mirror dark matter, and 7) leptophilic dark matter. World-leading sensitivities are expected in each case, a result of the large 5.6 t 1000 d exposure and low expected rate of electron-recoil backgrounds in the < 100     keV energy regime. A consistent signal generation, background model and profile-likelihood analysis framework is used throughout

The Data Acquisition System of the LZ Dark Matter Detector: FADR

The Data Acquisition System (DAQ) for the LUX-ZEPLIN (LZ) dark matter detector is described. The signals from 745 PMTs, distributed across three subsystems, are sampled with 100-MHz 32-channel digitizers (DDC-32s). A basic waveform analysis is carried out on the on-board Field Programmable Gate Arrays (FPGAs) to extract information about the observed scintillation and electroluminescence signals. This information is used to determine if the digitized waveforms should be preserved for offline analysis. The system is designed around the Kintex-7 FPGA. In addition to digitizing the PMT signals and providing basic event selection in real time, the flexibility provided by the use of FPGAs allows us to monitor the performance of the detector and the DAQ in parallel to normal data acquisition. The hardware and software/firmware of this FPGA-based Architecture for Data acquisition and Realtime monitoring (FADR) are discussed and performance measurements are described

New constraints on cosmic ray-boosted dark matter from the LUX-ZEPLIN experiment

While dual-phase xenon time projection chambers have driven the sensitivity toward weakly interacting massive particles at the GeV=c2 to TeV=c2 mass scale, the scope for sub-GeV=c2 dark matter particles is hindered by a limited nuclear recoil energy detection threshold. One approach to probe for lighter candidates is to consider cases where they have been boosted by collisions with cosmic rays in the Milky Way, such that the additional kinetic energy lifts their induced signatures above the nominal threshold. In this Letter, we report first results of a search for cosmic ray-boosted dark matter (CRDM) with a combined 4.2 metric ton=yr exposure from the LUX-ZEPLIN experiment. We observe no excess above the expected backgrounds and establish world-leading constraints on the spin-independent CRDM-nucleon cross section as small as 3.9 × 10−33 cm2 at 90% confidence level for sub-GeV=c2 masses