31 However, the cost-effectiveness of screening for albuminuria was not compared to that of screening for proteinuria. Moreover, the proposed sensitivity and specificity of 1+ dip-stick proteinuria for detecting albuminuria or proteinuria was too optimistic in light of two recent studies.11,22 In contrast, several studies have found
that screening for albuminuria or proteinuria followed by treatment with ARB is cost-effective for preventing ESRD or death in diabetics.32 Moreover, a few studies have found that ACEI or ARB treatment in microalbuminuric diabetics is more cost-effective than that in proteinuric diabetics, including an Asian study.32,33 However, these studies made this comparison based on indirect comparisons between two separate RCT. Moreover, they did not account for the cost of screening Pembrolizumab for albuminuria click here or proteinuria. Thus, the relative cost-effectiveness
of screening for albuminuria or proteinuria in diabetics is not known. Due to a lack of a direct comparison, CKD guidelines differ in their opinions regarding the choice between ACR and PCR.2 For example, the UK CKD guidelines, Scottish Intercollegiate Guidelines Network and Caring for Australians with Renal Impairment Guidelines recommend that ACR should be used for diabetic patients, whereas PCR should be used for non-diabetic CKD.2 In contrast, the Kidney Disease Quality Outcomes Initiative Guidelines recommend ACR but
PCR is regarded as acceptable if the ACR is high (>0.5–1 g/g creatinine).2 For PAK5 diabetics, albuminuria should be used because it is a surrogate end-point for early diabetic nephropathy.3 In fact, screening for albuminuria is even more important for diabetic Asians because they have the highest prevalence of albuminuria (55%) in the world.34 Moreover, albuminuria is more sensitive than proteinuria in detecting CKD. For example, a direct comparison study found that 67.5% of albuminuria subjects were found to have no proteinuria whereas 8% of proteinuric subjects had no albuminuria (especially non-diabetics) in a cross-sectional study of the general population.35 Thus, measuring proteinuria misses 67.5% of albuminuric subjects for whom treatment with ARB is cost-effective. In contrast, there is no reason to measure albuminuria for patients with known proteinuria. For non-diabetics, proteinuria should be used because of the following reasons. First, the measurement of proteinuria is cheaper than that of albuminuria.9 Second, most renoprotective RCT in non-diabetics and the only renoprotective RCT with proteinuria as a treatment target (also in non-diabetics) measured proteinuria instead of albuminuria.2,28 Third, ACEI is efficacious in slowing progression of renal disease only in patients with proteinuria of more than 0.5 g/day.
6A). Treatment with CRIg-Fc in vivo (treatment from day 1 to day 22 p.i.) led to a marked reduction in in vitro
INF-γ, IL-6, IL-17A, and TNF-α production compared with cells from PBS-treated EAU mice (all cells were stimulated in vitro with 25 μg/mL pIRBP, Fig. 6A). In addition, in vitro treatment of CRIg-Fc also significantly reduced the production of pIRBP-induced IFN-γ, IL-2, IL-6, and IL-17A in cells of PBS-treated EAU mice (Fig. 6B). The production of IL-10, however, was slightly increased by the same concentration of CRIg-Fc (Fig. 6B). Interestingly, the INK 128 production of in vitro pIRBP-induced TNF-α was not affected by CRIg-Fc treatment (Fig. 6B). NO produced by infiltrating macrophages are one of the important mediators of retinal damage in EAU 29, 30. When stimulated with LPS, BM-derived macrophages (BMDM) expressed high levels of iNOS gene
(Fig. 7A) and produced large amounts of NO (Fig. 7B). In vitro CRIg-Fc treatment dose-dependently suppressed iNOS gene expression (Fig. 7A) as well as NO production induced by LPS in BMDM (Fig. 7B). Control protein (anti-gp120, selleck chemicals llc mouse IgG1) showed no effect on either iNOS gene expression (Fig. 7B) or NO production (Fig. 7B). Although complement activation is beneficial in clearing infection and is essential for tissue homeostasis, unregulated complement activation may contribute to the pathogenesis of autoimmune disease. The data reported in this article using EAU as a model disease support this view. During inflammation, complement-mediated damage is well recognised. Complement activation may amplify the inflammatory response not only by the formation of the membrane attack complex (C5b-9), but also by releasing a variety of complement fragments, particularly the anaphylatoxins C3a and C5a. The anaphylatoxin molecules C3a and C5a enhance vascular
permeability (i.e. breakdown of blood–retinal barrier in the retina), promote T-cell costimulatory and survival signals 31, 32, recruit immune cells, activate mononuclear ZD1839 phagocyte, and release inflammatory mediators 33, 34. A more recent study has shown that in the presence of IFN-γ, C5a is able to induce macrophage NO production and contributes to retinal damage in EAU 19. The C5a/C5aR pathway has also been shown to negatively regulate Th17- and Treg-cell differentiation via reduction in TGF-β secretion 35, 36. Dendritic cells deficient in C5aR produce high levels of TGF-β which promotes Treg production, or in the presence of IL-6 and IL-23, promotes the induction of Th17 cells and IL-17-associated inflammatory disease 35. In addition, C5a also promotes γδ T-cell IL-17A production and blocking of C5a with a neutralizing antibody suppresses T-cell IL-17 production 36. Control of complement activation in EAU is likely, therefore, to have beneficial action at multiple levels.
Among the others, IL-1 has been shown to be
a key cytokine in initiating and amplifying the inflammatory responses against H. pylori [37-39]. Very recently, IL-1β present in the gastric mucosa has been shown to play an important role in H. pylori-induced epigenetic changes linking inflammation to carcinogenesis . Finally, H. pylori virulence and IL-1B genes contribute to peptic ulcers and intestinal metaplasia . Elevation of Tregs at the site of infection and H. pylori-specific Tregs in the circulation [20, 21] has been suggested as a mechanism of pathogen persistence, on the assumption that Tregs are differentiated cells with professional suppressive function. In this study we show for the first time that H. pylori interacts with human Tregs indirectly via DCs and modifies their function. Our data show that H. pylori-treated DCs stimulate Treg proliferation, diminish their suppressive Y-27632 manufacturer Antiinfection Compound Library ic50 function and that DC-derived IL-1β drives this process. Biopsy data from in-vivo H. pylori-infected antrum corroborated these findings, showing that a significant portion of Tregs found in infected gastric biopsies are actively undergoing mitosis. The persistence of H. pylori in the gastric mucosa may allow continual restimulation of the Treg population. This restimulation may allow for expansion of the Treg population beyond the 3-day peak observed in vitro. In this model it is not the presence of Tregs that promote the
PtdIns(3,4)P2 persistence of infection, but rather the persistence of infection that expands the Treg population in an attempt to limit the damage caused by a prolonged and excessive inflammatory response. Demonstrations that suppressive function of Tregs can be undermined by pathogens have been shown previously in the context of L. major and H. hepaticus infections, limiting inflammation while hindering pathogen clearance [18, 19]. Although pathogens can influence Treg function directly, such as through engagement of TLR-2, -4 and -8 [42-44], we found that H. pylori had no direct effect on Tregs and that the changes induced in Treg behaviour could be explained by cytokine production from DCs. We have found that IL-1β plays a central role in mediating the effects of H. pylori on Tregs. This is of particular interest, as virulent strains of H. pylori expressing cagPAI are associated with elevated levels of IL-1β [13, 45]. As a result, the influence of H. pylori DCs on Tregs may be enhanced by the local microenvironment. In addition, IL-1β has a significant inhibitory effect on gastric acid production , which encourages H. pylori colonization to spread and downstream pathological events (gastritis and gastric cancer). As IL-1β appears to have a central role in H. pylori biology and its mechanisms of immune evasion and chronic inflammation, it may be revealing to study the relationship between polymorphisms in IL-1β and interactions between H.
02). Comparison of Kaplan–Meier
curves of PM patients with risk scores of >22 (n = 27) vs. ≤22 (n = 48) confirmed a significantly higher rate of mortality within 28 days of initial PM presentation (HR 8.2, 3.6–18.9, P < 0.0001) and higher cumulative 28-day mortality (14.6% vs. 78%, P < 0.001). The estimated median survival time in PM patients with a risk score >22 was 7 days. selleck chemicals llc The majority of patients [47 (73%)] received Mucorales-active antifungal therapy, either amphotericin B formulation [54 (72%)] (as monotherapy or in combination with other antifungal regimens) or posaconazole [10 (13%)] (as monotherapy or in combination with other antifungal regimens) within 5 days after symptoms initiation. Administration of appropriate therapy (over 5 days) was delayed in 28 patients (37%). Immune augmentation therapy included white blood cell (WBC) transfusions, and administration of haematopoietic growth factors (granulocyte-macrophage colony-stimulating factor/granulocyte colony-stimulating factor) or interferon-γ. Thirty-one per cent of the patients received a colony-stimulating factor during treatment, 8% WBC transfusions and 7% interferon-γ. Surgical management, including debridement and wedge resection, was performed in 28 patients (37%). Overall, 28 of 75 patients (37%) died
within 4-week follow-up [median time of death, 34 days after diagnosis (range, 0–94 days)]. No treatment variables were found to be independently associated with improved survival when patients selleckchem were stratified by the mortality risk score. Mucormycosis has emerged as the second most common invasive mould infection after aspergillosis in patients with haematological malignancies and allogeneic HSCT. In this 12-year retrospective study, we identified 75 such patients with PM. The most important conditions predisposing to mucormycosis,
Phenylethanolamine N-methyltransferase according to various studies, include malignant haematological diseases with or without HSCT, prolonged and severe neutropenia, poorly controlled diabetes mellitus with or without diabetic ketoacidosis, iron overload, major trauma, prolonged use of corticosteroids, illicit intravenous drug use, neonatal prematurity and malnourishment.[3, 11, 12] Not surprisingly, 57% and 64% of our patients, respectively, were profoundly neutropenic and lymphocytopenic. Prior corticosteroid therapy (55%) and diabetes mellitus (31%) appeared to be common additional risk factors for PM. Moreover, 57% of the patients had refractory haematological disease and thus received intensive cytotoxic chemotherapy. Also, 48% of the patients underwent HSCT, 81% of whom were allogeneic transplant recipients. We stratified our patient population according to the probability of death using easily available clinical, laboratory and radiological variables at the time of diagnosis.
In addition, co-transfer of CD122-depleted spleen cells exhibited no effect on the tumor-growth and survival of melanoma-bearing mice after treatment with transfer of pmel-1 T cells and DC vaccination (Supporting Information Fig.
4), further supporting the notion that CD122+ cells were the major suppressor cells in naïve spleens. Since CD122+CD8+ T cells that functioned as Treg have been described in autoimmune disease models (see review 20), we will hereafter refer to these cells as the CD122+CD8+ Treg. The beneficial antitumor selleck screening library effects that follow depletion of CD4+CD25+ natural Treg have been well described 21. We sought to determine whether depletion of CD122+CD8+ Treg in addition to CD4+CD25+ natural Treg would further enhance the expansion and survival of pmel-1 T cells. Since NK cells and NK T cells were the other major CD122+ populations, their contribution to immune regulation was also investigated. Spleen cells from WT mice were subjected to depletion of CD25+ cells alone, CD25+ and NK1.1+ cells, and CD25+ and CD122+ T cells using magnetic beads. As expected, depletion with anti-CD25 or NK1.1 antibodies resulted in near-complete disappearance
of cells expressing CD25 or NK1.1, respectively. NK depletion resulted in elimination of both NK and NKT cells, while the CD122+ non-NK1.1 expressing cells remained. CD122− depletion resulted in near complete elimination of both NK1.1+ cells and CD8+CD122+ T cells (Fig. 2A). ZD1839 solubility dmso At wk 4 after vaccination, depletion of CD25+ cells from naïve spleen before adoptive transfer
had no effect on the number of pmel-1 T cells in blood (13% of CD8+ T cells) or spleen (400/106 spleen cells) (Fig. 2B and C). However, CD25- and CD122-depleted mice also exhibited a pronounced increase in the Erastin concentration number of endogenous peptide-specific T cells, identified by hgp9-Db tetramer staining (GFP-tetramer+) (Fig. 2B). In addition, 7% of total CD8+ T cells in the blood of mice with CD25 and CD122 depletion were positive for hgp9-tetramer+ GFP−, compared with 2 or 3% of CD8+ T cells in the control or CD25 only depletion group. Thus, the removal of CD122+ cells in addition to CD25+ cells led to expansion of both transgenic pmel-1 T cells and non-transgenic peptide-specific T cells. Four weeks after adoptive transfer the number of pmel-1 T cells in the spleen of mice from the CD25 and CD122 depletion group was threefold greater than in the control or CD25 depletion group (Fig. 2C). The function of pmel-1 T cells found in spleens among all three groups of mice was comparable as demonstrated by a similar production of IFN-γ upon ex vivo stimulation with peptide (Fig. 2D). Taken together, these experiments showed that lymphopenia-driven proliferation of CD4+CD25+ and CD122+CD8+ T cells negatively regulated proliferation of Ag-specific pmel-1 T cells and non-transgenic T cells in lymphodepleted mice.
1), similar to other NOD mouse lines congenic for a resistant Idd3 locus 37–39. Consistent with previous findings 38 naïve CD4+ T cells
isolated from the spleen of NOD.B6Idd3 mice exhibited increased IL-2 secretion upon in vitro stimulation relative to NOD CD4+ T cells (Supporting Information Fig. 1). To determine the influence of Idd3 on FoxP3+Tregs, the frequency and number of gated CD4+CD3+ T cells expressing FoxP3 and CD25 (Fig. 2A) were assessed in the thymus, spleen, PaLN, and islets of age-matched NOD and NOD.B6Idd3 female mice via FACS. No difference in the frequency of FoxP3+Tregs was detected in the thymus of NOD and NOD.B6Idd3 mice suggesting that thymic development of FoxP3+Tregs is unaffected by IL-2 expression Olaparib levels. On the other hand, an increased frequency and number of FoxP3+Tregs was detected in the PaLN and spleen of older NOD.B6Idd3 mice relative to age-matched NOD mice (Fig. 2A–C). In addition, the frequency of FoxP3+Tregs was significantly increased in the islets of Apitolisib concentration 10- and 16-wk-old NOD.B6Idd3 versus NOD female mice (Fig. 2B). Notably, however, a greater number of FoxP3+Tregs were detected in the islets of older NOD mice (Fig. 2C) reflecting increased T-cell infiltration of the islets relative to age-matched NOD.B6Idd3
mice. These data demonstrate that the frequency of FoxP3+Tregs is increased in the PaLN and islets of NOD.B6Idd3 mice compared with NOD mice. We and others have shown that for CD62Lhi- versus CD62Llo-expressing FoxP3+Tregs exhibit increased suppressor activity 7, 19. Accordingly, CD62Lhi- and CD62Llo-expressing FoxP3+Tregs were examined
temporally in age-matched NOD.B6Idd3 and NOD female mice. Interestingly, age-dependent differences in the frequency and number of CD62Lhi- and CD62Llo-expressing FoxP3+Tregs were detected in the PaLN and islets of the respective groups of mice. NOD female mice exhibited a temporal decrease in the frequency of CD62LhiFoxP3+Tregs and a concomitant increase in CD62LloFoxP3+Tregs in PaLN (Fig. 3B). Although the number of CD62LhiFoxP3+Tregs progressively increased in the PaLN of NOD female mice (5.2×104 (4 wk) versus 9.0×104 (16 wk)), a greater increase in CD62LloFoxP3+Tregs numbers was detected (6.3×104 (4 wk) versus 14.9×104 (16 wk)) (Fig. 3C). In the PaLN of NOD.B6Idd3 mice, however, the frequency and number of CD62LhiFoxP3+Tregs showed no marked change with age, which were increased relative to age-matched NOD females (Fig. 3B and C). A similar scenario was observed in the islets of NOD and NOD.B6Idd3 female mice. A temporal increase in the frequency of CD62LloFoxP3+Tregs was detected in the islets of NOD female mice which was due to elevated numbers relative to CD62LhiFoxP3+Tregs (Fig. 3D and E). Despite a progressive decline, the frequency of CD62LhiFoxP3+Tregs in the islets of NOD.B6Idd3 female mice was elevated relative to age-matched NOD female mice (Fig. 3D and E).
58 The reduction in antiviral capacity in the presence of SP may in part be explained by electrostatic interactions between cationic SP polyamines and the polyanions of the microbicide candidates. This reduction in the inhibitory activity of polyanionic microbicides has also been observed in clinical trials.59,60 Semen from HIV-1-positive individuals contains CF HIV-1 particles and soluble complement components.61 Opsonization with complement was previously shown to enhance HIV-1 infection of T and B cells, monocytes and macrophages.61 Complement receptors are expressed on the apical surface of epithelial cells, DCs, and macrophages.61 Bouhlal et al.61
showed that both R5- and X4-tropic HIV-1 strains can Raf inhibition activate complement in seminal fluid in vitro. They found that enhancement of HIV-1 infection in colorectal cell lines (HT-29) was complement dependent. Infection of HT-29 cells with HIV-1 that was pre-opsonized with complement (C3 and C9) in seminal fluid resulted in an enhanced (1.5–2-fold) rate of HIV-1 infection compared to infection of these cells in the presence of virus alone.61 R5- and X4- strains activate complement in seminal fluid and generate HM781-36B order C3 cleavage fragments (C3a/C3adesArg).61 The immediate reaction of semen deposition into the mammalian reproductive tract is
a dramatic influx of inflammatory cells.62–64 Changes in the leukocyte population of the female reproductive tract (FRT) after introduction of the male ejaculate have been well documented in mice, pigs, rabbits, and women.63,65–67 Most of these pro-inflammatory effects in animals are attributed to the presence of transforming growth factor (TGF)-β in SP.68,69 The majority of TGF-β present in male SP is synthesized in latent form and appears to be
activated by plasmin and other enzymes in the FRT.69 Women respond to semen deposition with a similar influx of leukocytes, especially to the cervix, called leukocytic reaction. These leukocytes predominantly include neutrophils and to a lesser extent macrophages and T lymphocytes.63,64 SP is also considered a cause of recurrent vaginitis in certain sexually active women, a condition possibly related to SP protein allergy and Non-specific serine/threonine protein kinase associated with localized irritation and inflammation.70 The etiology of this inflammatory response, however, is not well understood. The semen-induced leukocyte influx to the FRT is believed to be mediated by chemoattracting factors released by the epithelial lining of the FRT in response to sperm and SP.62 Although a transient, semen-induced inflammation of the FRT is probably necessary for a successful establishment of pregnancy, it also recruits and activates HIV target cells to the portals of virus entry, thus facilitating mucosal infection and HIV transmission. SP induces differential expression of inflammatory genes in human cervical and vaginal epithelial cells.71 In ectocervical cells, these genes include IL-8, IL-6, CSF2, CCL2, GM-CSF, and MCP-1.
DNA cassette encoding the conserved epitope in CMV AD2 site I was cloned into the expression vector pGEX-5X (Amersham Bioscience [now GE Healthcare], Piscataway, NJ, USA). GST fusion proteins containing the gH epitopes from the AD169 and Towne strain were used to detect CMV gH type-specific antibodies
as previously reported . OD values specific to each antigen were obtained by subtracting the OD values for GST as described previously . An arbitrary cutoff for ELISA (OD = 0.25) was defined as the mean plus two standard deviations of OD values of a panel of healthy CMV seronegative volunteers . Detection of strain-specific gH-antibodies in the recipients’ serum samples, which matched those of their donors, was considered gH-m antibody positivity. The basic characteristics of the renal transplant recipients are summarized in Table 1. Fifty-two of the 77 recipients check details had antibodies against gB. There were no differences between patients with
and without gB antibodies in other relevant variables, namely age, sex, number of HLA mismatches and immunosuppression protocols. The transplant recipients were followed up for 6 months after transplantation. Rejection was suspected when serum creatinine concentrations increased more than 25% above the basal level in the absence of urinary tract obstruction or renal Terminal deoxynucleotidyl transferase graft artery stenosis, as described previously . The first rejection episode
was confirmed histologically by biopsying the grafts. RG7420 Preemptive therapy was employed when CMV infection and/or CMV end-organ disease were diagnosed, as described previously . Using StatView 5.0, Fisher’s exact test was used to evaluate the rate of acute rejection in different gB serostatus groups. Statistical significance was set at P < 0.05. The incidence of biopsy-proven acute rejection was calculated using the Kaplan–Mayer method, and comparisons were carried out by the log-rank test using SPSS. Subsequent to their entry into the study, 27/77 recipients (35%) in a D + /R+ setting experienced biopsy-proven rejection during the 6 months after transplantation. Among these 27 D + /R+ patients with rejection, 23 (85%) had antibodies against CMV gB. The incidences of acute rejection among recipients with (gB+) and without (gB−) antibodies against gB AD2 were 44% and 16%, respectively. The rate of acute rejection was significantly higher in gB+ recipients than in gB− recipients (Table 2). Figure 1 shows Kaplan–Meier curves for the cumulative probability of freedom from biopsy-proven acute rejection. There were significant differences between the gB+ group and the gB− group according to the log-rank test (P = 0.025).
In the Atm−/− mouse model of ataxia-telengiectasia, the variation in intestinal microbiota due to either differences in the environments of various animal Alvelestat order facilities or to experimentally induced modifications was shown to profoundly modify lymphoma incidence and
survival of the mice . The intestinal microbiota appears to affect carcinogenesis in distant organs, in part by modulating the tumor necrosis factor (TNF) dependent systemic inflammatory tone, oxidative stress, and leukocyte or epithelial cell genotoxicity [161, 162, 164, 165]. Dysbiosis or antibiotics treatment could alter the ability of the microbiota to metabolize estrogens, an activity that has been inferred to be a possible noninflammatory
mechanism by which the microbiota modulates distant malignancies . However, unlike the induction of mammary carcinoma in APCmin/+/Rag2−/− mice by H. hepaticus, the evidence for an association between antibiotics usage and breast cancer in humans remains tenuous . Recently, it has also been shown in mice that the overgrowth of fungal Candida species due to antibiotics treatment-driven gut dysbiosis Selleck PF2341066 increases plasma prostaglandin E2 concentrations and M2 macrophage polarization in the lung . Although this effect of antibiotics treatment has been evaluated in terms of induction of allergic airway inflammation , one may speculate that the induction of tumor-promoting M2 macrophages indirectly via antibiotics treatment may also play a role in tumor progression. In recent murine studies, the gut microbiota has been shown to affect the response to both immune and chemotherapy by regulating different myeloid-derived cell functions in the tumor microenvironment. Intratumoral CpG-oligodeoxynucleotides (ODN) immunotherapy selleck chemical combined with antibody neutralization of IL-10 signaling effectively
treats sterile transplanted subcutaneous tumors in conventional mice, but not in GF or antibiotic-treated mice . This treatment induces, within hours, extensive hemorrhagic tumor necrosis that is dependent on TNF and NO production by tumor-associated innate myeloid cells, followed by CD40-mediated DC activation, IL-12 production, and the generation of a CD8+ T-cell-mediated tumor-specific adaptive immunity required for persistent tumor eradication . In the absence of gut commensal microbiota, however, the tumor-infiltrating myeloid-derived cells recruited after CpG-ODN treatment have impaired production of various inflammatory cytokines, including TNF and IL-12  (Fig. 2).
6/100 patient-years and 89.9/100 patient-years vs 58/100 patient-years and 144.3/100 patient-years, P = 0.001, respectively). Left ventricular click here mass index (LVMI) improved to
a similar degree in both treatment arms. The reduced event rate seen with atenolol treatment may be mediated by way of an anti-arrhythmic effect. However, β-blockers are cautiously used in dialysis patients. In a cross-sectional study that included 89 haemodialysis patients with established coronary artery disease (CAD), only 40 (44.9%) were prescribed a β-blocker. This reluctance to prescribe may stem from a fear of potential adverse events, for example, intra-dialytic hypotension, hyperkalaemia and bradycardia. Summary of this evidence suggests that β-blockers are underused in dialysis patients despite major potential benefits for patients, albeit the mechanism of benefit has not been fully established. Calcium channel blockers (CCBs) may have potential cardioprotective effects by preventing coronary artery spasm after cardiac arrest and normalizing intracellular calcium concentration, thereby limiting injury and preventing fatal arrhythmia. There are limited data on CCB and prevention of SCD. In one analysis of 729 cardiac EPZ-6438 arrests in haemodialysis outpatient
clinics, after adjustment for case mix factors, tunnelled catheters and concomitant medications, CCB treatment was associated with a significant survival advantage at 24 h (odds ratio, OR = 0.42, 95% CI = 0.23–0.76). The authors also found an association between β-blocker (OR = 0.32, 95% CI = 0.17–0.61), angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment (ACEI/ARB) (OR = 0.5, 95% CI = 0.28–0.95) and improved survival. These data therefore suggest that dihydropyridine CCB may have a protective role in increasing survival after cardiac arrest. Digoxin inhibits cellular sodium potassium ATPase activity and reduces sympathetic tone. In non-CKD patients with heart failure, the incidence of ventricular tachycardia and fibrillation is higher in digoxin-treated patients compared with control.
Digoxin is renally excreted and therefore doses frequently need to be reduced in dialysis patients PD184352 (CI-1040) to avoid drug toxicity. This is particularly so in patients with low pre-dialysis potassium concentrations. In 120 864 incident haemodialysis patients, the use of digoxin and increasing digoxin levels were associated with increased mortality (HR = 1.28, 95% CI = 1.25–1.31 and HR = 1.19/ng/mL increase, 95% CI = 1.05–1.35, respectively). The mortality risk increases with low pre-dialysis potassium (HR = 2.53 for potassium <4.3 mmol/L vs HR = 0.86 for potassium >4.6 mmol/L). Therefore, digoxin is unlikely to be a useful preventative therapy for SCD. Amiodarone has multiple anti-arrhythmic actions (class Ia, II, II, IV).