35 research outputs found
CMV Late Phase-Induced mTOR Activation Is Essential for Efficient Virus Replication in Polarized Human Macrophages : Antiviral Effects of mTOR Inhibitors
Human cytomegalovirus (CMV) remains one of the
most important pathogens following solid-organ
transplantation. Mounting evidence indicates that
mammalian target of rapamycin (mTOR) inhibitors
may decrease the incidence of CMV infection in solid-
organ recipients. Here we aimed at elucidating the
molecular mechanisms of this effect by employing
a human CMV (HCMV) infection model in human
macrophages, since myeloid cells are the principal
in
vivo
targets of HCMV. We demonstrate a highly di-
vergent host cell permissiveness for HCMV with opti-
mal infection susceptibility in M2 but not M1 polarized
macrophages. Employing an ultrahigh purified HCMV
stock we observed rapamycin-independent viral entry
and induction of IFN-b transcripts, but no proinflam-
matory cytokines or mitogen-activated protein kinases
and mTOR activation early after infection. However,
in the late infection phase, sustained mTOR activa-
tion was observed in HCMV-infected cells and was
required for efficient viral protein synthesis including
the viral late phase proteins pUL-44 and pp65. Accord-
ingly, rapamycin strongly suppressed CMV replication
3 and 5 days postinfection in macrophages. In conclu-
sion, these data indicate that mTOR is essential for
virus replication during late phases of the viral cycle in
myeloid cells and might explain the potent anti-CMV
effects of mTOR inhibitors after organ transplantatio
Supplementary Material for: Significance of Interdialytic Weight Gain versus Chronic Volume Overload: Consensus Opinion
Predialysis volume overload is the sum of interdialytic weight gain (IDWG) and residual postdialysis volume overload. It results mostly from failure to achieve an adequate volume status at the end of the dialysis session. Recent developments in bioimpedance spectroscopy and possibly relative plasma volume monitoring permit noninvasive volume status assessment in hemodialysis patients. A large proportion of patients have previously been shown to be chronically volume overloaded predialysis (defined as >15% above ânormal' extracellular fluid volume, equivalent to >2.5 liters on average), and to exhibit a more than twofold increased mortality risk. By contrast, the magnitude of the mortality risk associated with IDWG is much smaller and only evident with very large weight gains. Here we review the available evidence on volume overload and IDWG, and question the use of IDWG as an indicator of ânonadherence' by describing its association with postdialysis volume depletion. We also demonstrate the relationship between IDWG, volume overload and predialysis serum sodium concentration, and comment on salt intake. Discriminating between volume overload and IDWG will likely lead to a more appropriate management of fluid withdrawal during dialysis. Consensually, the present authors agree that this discrimination should be among the primary goals for dialysis caretakers today. In consequence, we recommend objective measures of volume status beyond mere evaluations of IDWG
Supplementary Material for: Heart Failure with Preserved and Reduced Ejection Fraction in Hemodialysis Patients: Prevalence, Disease Prediction and Prognosis
<i>Background/Aims:</i> Heart failure (HF) is a main cause of mortality of hemodialysis (HD) patients. While HF with reduced ejection fraction (HFrEF) is known to only affect a minority of patients, little is known about the prevalence, associations with clinical characteristics and prognosis of HF with preserved ejection fraction (HFpEF). <i>Methods:</i>We included 105 maintenance HD patients from the Medical University of Vienna into this prospective single-center cohort study and determined the prevalence of HFpEF (per the 2013 criteria of the European Society of Cardiology) and HFrEF (EF <45%), using standardized post-HD transthoracic echocardiography. We also assessed clinical, laboratory and volume status parameters (by bioimpedance spectroscopy). These parameters served to calculate prediction models for both disease entities, while clinical outcomes (frequency of cardiovascular hospitalizations and/or cardiac death) were assessed prospectively over 27±4 months of follow-up. <i>Results:</i> All but 4 patients (96%) had evidence of diastolic dysfunction. 70% of the entire cohort fulfilled HF criteria (81% HFpEF, 19% HFrEF). Age, female sex, body mass index, blood pressure and dialysis vintage were predictive of HFpEF (sensitivity 86%, specificity 63%; AUC 0.87), while age, female sex, NT pro-BNP, history of coronary artery disease and atrial fibrillation were predictive of HFrEF (sensitivity 85%, specificity 90%; AUC 0.95). Compared to patients without HF, those with HFpEF and HFrEF had a higher risk of hospitalization for cardiovascular reason and/or cardiac death (adjusted HR 4.31, 95% CI 0.46-40.03; adjusted HR 3.24, 95% CI 1.08-9.75, respectively). <i>Conclusion:</i> Diastolic dysfunction and HFpEF are highly prevalent in HD patients while HFrEF only affects a minority. Distinct patient-specific characteristics predict diagnosis of either entity with good accuracy