Possible role of nitric oxide in malarial immunosuppression

We have tested the hypothesis that nitric oxide may be responsible for the immunosuppression reported during malaria infections. We first showed that reactive nitrogen intermediates, which indicate nitric oxide generation, were increased in the plasma of Plasmodium vinckei-infected mice. We next found that Concanavalin A-induced proliferation of spleen cells from these mice was reduced compared with that observed in uninfected animals. The addition of N^G-methyl-L-arginine (L-NMMA) for the duration of the cultures restored the malarial proliferative response to normal. We then tested the effect of oral L-NMMA on the proliferative response of P. chabaudi-infected mice to a human red blood cell lysate. The secondary response to this antigen, measured as spleen cell proliferation in vitro ten days after immunization and when there was no discernible parasitaemia, remained normal in L-NMMA- treated P. chabaudi mice, but was decreased in the untreated infected mice. These results suggest a role for nitric oxide in malarial immunosuppression.     

Decreased erythropoietin response in Plasmodium falciparum malaria-associated anaemia

Abstract: One of the most serious manifestations of Plasmodium falciparum malaria is anaemia. Its established causes are increased red cell destruction and ineffective erythropoiesis. Since proinflammatory cytokines have been shown to suppress the in vitro synthesis of erythropoietin (Epo), we measured serum immunoreactive Epo in 90 Sudanese patients suffering from malaria. Even in severe cases of anaemia (blood haemoglobin <80 g/l), serum Epo levels rarely exceeded 300 U/l. For comparison, serum Epo was increased up to 12,000 U/l in a reference group of Caucasian patients with anaemia not associated with infection. Moreover, the slope of the log Epo/haemoglobin regression line was less steep in malarial anaemia. Thus, as documented for other chronic inflammatory disorders, there is a relative lack of Epo in malaria-associated anaemia. Treatment with the antimalarial drug chloroquine may aggravate the defect in Epo production, because chloroquine inhibited Epo synthesis when tested in cell culture.     

Chloroquine is not a risk factor for seizures in childhood cerebral malaria

OBJECTIVES: There are a number of case reports in the medical literature suggesting an association between the ingestion of chloroquine and subsequent seizure activity. Our study was designed to investigate the relationship between blood levels of chloroquine (CQ), its metabolite desethylchloroquine (DCQ), and seizures in children admitted to hospital with cerebral malaria. METHODS: Serial blood levels of CQ and DCQ were measured over the first 24 h of hospital admission in children with cerebral malaria. The number and duration of all seizures was recorded, and statistical analysis subsequently performed to determine the relationship between seizure activity and blood concentrations of CQ and DCQ. RESULTS: Chloroquine was detected in 92% (100/109) of admission blood samples. 54% (59/109) of the patients had one or more seizures after admission, while 8% (9/109) had an episode of status epilepticus. Median (interquartile range) baseline concentrations of CQ and DCQ were, respectively, 169.4 microg/ml (75.1-374.9) and 352.3 microg/ml (81.9-580.1) for those children who had seizures after admission, compared to CQ 227.5 microg/ml (79.4-430.2) and DCQ 364.0 microg/ml (131.3-709.4) for those who did not have seizures (P > 0.5 for all comparisons). Baseline concentrations of CQ and DCQ were not significantly associated with the occurrence of seizures lasting for 5 min or more. The nine children who had an episode of status epilepticus had significantly lower median admission levels of CQ than those without status epilepticus: 75.1 microg/l (7.4-116.5) vs. 227.5 microg/l (85.6-441.2), P = 0.02. Multivariate logistic regression analysis, taking into account factors likely to affect the risk of seizures in hospital, failed to change the significance of these results. CONCLUSIONS: These findings suggest that chloroquine does not play an important role in the aetiology of seizures in childhood cerebral malaria.     

Modulation by malaria infection of the induction of T lymphocyte-dependent delayed-type hypersensitivity and antibody formation to sheep erythrocytes in mice

A profound alteration of the inductive phase of delayed-type hypersensitivity and antibody formation to SRBC was found in malaria infected mice when sensitization with this antigen was performed intravenously at a critical time of the disease, but not after subcutaneous immunization, suggesting a major role for the spleen in the mechanism of immunodepression.     

Cytomegalovirus infection and disease in the new era of immunosuppression following solid organ transplantation

Abstract: As the most prevalent pathogen among transplant patients, cytomegalovirus (CMV) affects up to three-quarters of all solid organ transplant recipients. While we have made great strides in preventing CMV infection and disease in the early post-transplant period, late CMV infection and indirect effects due to viral immunomodulation remain problematic. Changing immunosuppression practices, including the increasing use of T-cell depleting induction antibodies, have the potential to affect the risk for CMV infection and disease, even in the face of good prophylactic and preemptive therapy. The purpose of this review article is to discuss the impact of CMV infection on long-term allograft outcomes and to re-evaluate the risks and management strategies for prevention of CMV in the framework of evolving modern immunosuppressive strategies.     

Hemodynamics is a key epigenetic factor in development of the cardiac conduction system

The His-Purkinje system (HPS) is a network of conduction cells responsible for coordinating the contraction of the ventricles. Earlier studies using bipolar electrodes indicated that the functional maturation of the HPS in the chick embryo is marked by a topological shift in the sequence of activation of the ventricle. Namely, at around the completion of septation, an immature base-to-apex sequence of ventricular activation was reported to convert to the apex-to-base pattern characteristic of the mature heart. Previously, we have proposed that hemodynamics and/or mechanical conditioning may be key epigenetic factors in development of the HPS. We thus hypothesized that the timing of the topological shift marking maturation of the conduction system is sensitive to variation in hemodynamic load. Spatiotemporal patterns of ventricular activation (as revealed by high-speed imaging of fluorescent voltage-sensitive dye) were mapped in chick hearts over normal development, and following procedures previously characterized as causing increased (conotruncal banding, CTB) or reduced (left atrial ligation, LAL) hemodynamic loading of the embryonic heart. The results revealed that the timing of the shift to mature activation displays striking plasticity. CTB led to precocious emergence of mature HPS function relative to controls whereas LAL was associated with delayed conversion to apical initiation. The results from our study indicate a critical role for biophysical factors in differentiation of specialized cardiac tissues and provide the basis of a new model for studies of the molecular mechanisms involved in induction and patterning of the HPS in vivo.     

Epstein-Barr virus-positive aggressive lymphoma as a consequence of immunosuppression after multiple salvage treatments for follicular lymphoma

We report on a patient with follicular non-Hodgkin's lymphoma (NHL) who developed a fatal high-grade Epstein-Barr virus (EBV)-positive NHL after conventional chemotherapies. The sudden onset of the high-grade lymphoma was accompanied by increasing circulating EBV genome copies and was complicated by spontaneous rupture of the spleen. Splenic tissue was diffusely infiltrated by large B cells. In situ hybridization for Epstein-Barr-encoded RNA (EBER) 1-2 was positive in 70% of cells, and molecular analysis revealed the presence of EBV DNA and a monoclonal IgH gene rearrangement. This case shows that the immunosuppression of multiple treatments may induce uncontrolled reactivation of a latent EBV infection, contributing to high-grade transformation in heavily treated lymphoma patients.     

New approaches to immunosuppression in liver transplantation

With the continued improvements in outcome following liver transplantation, the drawbacks associated with conventional immunosuppression regimens become increasingly apparent. Although up to 70% of patients develop a histological infiltrate of the graft (acute rejection), many of these will resolve spontaneously, and chronic rejection is rare. If a robust form of allograft acceptance or tolerance can be established, then immunosuppression can be withdrawn along with all the accompanying risks. The liver is already known to be associated with downregulated immune responses; the mechanism for this is unclear, but may be related to a number of mechanisms known to be involved in peripheral tolerance. There are many strategies being studied for achieving allograft tolerance, including the use of modern immunosuppressants, antibodies that target key molecules in the immune response, and recruitment of leukocytes to allografts. In the interim, it is necessary to look for safe protocols that allow trials of tolerance strategies without putting patients at increased risk.     

Myocardial ischemia is a key factor in the management of stable coronary artery disease

Previous studies demonstrated that coronary revascularization,especially percutaneous coronary intervention(PCI),does not significantly decrease the incidence of cardiac death or myocardial infarction in patients with stable coronary artery disease.Many studies using myocardial perfusion imaging(MPI) showed that,for patients with moderate to severe ischemia,revascularization is the preferred therapy for survival benefit,whereas for patients with no to mild ischemia,medical therapy is the main choice,and revascularization is associated with increased mortality.There is some evidence that revascularization in patients with no or mild ischemia is likely to result in worsened ischemia,which is associated with increased mortality.Studies using fractional flow reserve(FFR) demonstrate that ischemia-guided PCI is superior to angiography-guided PCI,and the presence of ischemia is the key to decisionmaking for PCI.Complementary use of noninvasive MPI and invasive FFR would be important to compensate for each method's limitations.Recent studies of appropriateness criteria showed that,although PCI in the acute setting and coronary bypass surgery are properly performed in most patients,PCI in the non-acute set-ting is often inappropriate,and stress testing to identify myocardial ischemia is performed in less than half of patients.Also,some studies suggested that revascularization in an inappropriate setting is not associated with improved prognosis.Taken together,the presence and the extent of myocardial ischemia is a key factor in the management of patients with stable coronary artery disease,and coronary revascularization in the absence of myocardial ischemia is associated with worsened prognosis.     

TGF-β is not the principal immunosuppressive component in coagulation factor concentrates

Coagulation factor concentrates are known to inhibit a variety of immune reactions when assessed in vitro. This study assessed the immunomodulatory activity of a wide range of coagulation factor concentrates by measuring their inhibition of PHA-stimulated lymphocyte proliferation and reduction in IL-2 secretion. The hypothesis that TGF-beta is responsible for most of these effects was tested by measuring biologically active TGF-beta and immunoreactive TGF-beta1 in the concentrates and comparing the levels recorded with immunosuppressive activity. In addition, the coagulation factors were compared directly with a standard preparation of TGF-beta in a TGF-beta-specific bioassay and in lymphocyte proliferation assays. Although there was a broad correlation between levels of total or active TGF-beta and immunosuppressive activity across all of the coagulation factors tested, individual data sets showed clear discrepancies. Implying that TGF-beta probably serves as a surrogate marker for other immunomodulatory contaminants and that neither TGF-beta nor any other single substance could account for all of the immunosuppressive activity observed. Furthermore, there was a difference of more than 100-fold in the relative potencies of coagulation factors and pure TGF-beta, when compared in immunosuppression assays, indicating that the different assays did not measure the same substance. Whereas anti-TGF-beta antibody almost completely blocked the activity of coagulation factor concentrates (TGF-beta-specific bioassay) and abrogated the effect of authentic TGF-beta (immunosuppression assays) at high concentrations it achieved <50% reversal of the immunosuppressive effects of coagulation factors in immunosuppression assays. These findings indicated that TGF-beta accounted for only a minor proportion of the immunosuppressive activity in most coagulation factor concentrates.     

Rhodococcus equi pulmonary infection in a pancreas‐alone transplant recipient: consequence of intense immunosuppression

Abstract We report the case of a pancreas‐alone transplant recipient who developed Rhodococcus equi pneumonia after receiving multiple courses of antilymphocyte therapy for the treatment of recurrent acute pancreas allograft rejection. We also review and discuss the diagnosis, clinical course, and treatment of 18 cases of R. equi infection reported in solid organ transplant recipients. The lung is the most common primary site of infection, but R. equi infection is difficult to diagnose because of the pleomorphic, gram‐positive, and partially acid‐fast nature of the organism. Treatment usually involves a combination of antibiotics including rifampin, macrolides, vancomycin, and ciprofloxacin. The optimal duration of therapy is unknown, but relapse is common if the duration of treatment is less than 14 days. The duration of therapy should be guided by clinical recovery, culture results, and radiographic findings. Monitoring levels of immunosuppressive agents—such as tacrolimus and cyclosporine—is needed in order to avoid clinically significant drug interactions with rifampin or the macrolides when these agents are used in order to treat R. equi infection in the transplant population.     

Spatial dispersion of repolarization is a key factor in the arrhythmogenicity of long QT syndrome

INTRODUCTION: The occurrence of significant spatial dispersion of repolarization in vivo as it relates to the mechanism of arrhythmia formation in the long QT syndrome (LQTS) continues to be questioned. Methods AND RESULTS: We investigated a guinea pig model of LQT3 using anthopleurin-A (AP-A) to study the contribution of rate-dependent spatial dispersion of repolarization in the intact heart to the arrhythmogenicity of LQTS. Optical action potentials were measured using potentiometric fluorescent dye di-4ANEPPS in Langendorff-perfused hearts with induced AV block. AP-A exacerbated the normal uniform epicardial apex-base action potential duration (APD) gradient, resulting in rate-dependent increased APD dispersion and nonuniform APD gradient. Spontaneous focal premature beats induced functional conduction block along boundaries where large nonuniform APD gradient occurred setting the stage for circulating wavefronts and ventricular tachyarrhythmia (VT). Endocardial ablation abolished spontaneous VT, but nonuniform epicardial APD gradient persisted and could be challenged by a stimulated premature stimulus to induce VT. CONCLUSION: The study shows that in LQT3, spatial variations in steady-state properties result in zones of nonuniform APD gradients. These provide a substrate for functional conduction block and reentrant excitation when challenged by subendocardial "early afterdepolarization-triggered" premature beats. The study emphasizes the key importance of spatial dispersion of repolarization, whether located in epicardial or intramyocardial layers, in arrhythmia formation in LQTS.     

Selective resistance of mucosal T-cell activation to immunosuppression in Crohn''s disease

BACKGROUND & AIMS: The inappropriately high state of T-cell activation found in Crohn's disease could be due to failure to respond to inhibitory signals. We tested the hypothesis that Crohn's disease mucosal T-cells are resistant to the immunosuppressive action of interleukin4. PATIENTS: Patients with Crohn's disease, ulcerative colitis, and other malignant and non-malignant conditions undergoing bowel resection. METHODS: The effect of interleukin-4 on lamina propria mononuclear cells from Crohn's disease, ulcerative colitis and control mucosa was assessed on various T-cell functions: interleukin-2-induced cytotoxicity, soluble interleukin-2 receptor and interleukin-2 production, and expression of mRNA for interleukin-2R and interferon-gamma. RESULTS: Cytotoxicity of control and ulcerative colitis cells was markedly decreased by interleukin-4, whereas Crohn's disease cells failed to be inhibited. Addition of interleukin-4 to interleukin-2-stimulated cultures decreased soluble interleukin-2R production significantly less in Crohn's disease and ulcerative colitis than control cells. In the same cultures, residual levels of interleukin-2 were significantly increased in control and ulcerative colitis, but not Crohn's disease cultures. Finally, Crohn's disease cells were significantly more resistant to interleukin-4-mediated inhibition of spontaneous and interleukin-2-induced expression of interleukin-2Ralpha and interferon-gamma mRNA compared to control cells. CONCLUSIONS: The effector function, receptor expression and cytokine production of Crohn's disease mucosal T-cells are resistant to interleukin4-mediated inhibition. Failure to respond to down-regulatory signals may contribute to persistent T-cell activation and chronicity of inflammation in Crohn's disease.     

稿件质量是办好杂志的重要保证

在2009年的元旦钟声敲响之际,我们又迎来了新的一年,<中华消化杂志>编委会和编辑部全体成员在此向全国读者问好:祝大家新年愉快,万事如意,让我们共同携手在新的一年里将<中华消化杂志>办得更好,并希望一年更比一年好!