Inefficient ventilation and reduced respiratory muscle capacity in congestive heart failure

The extent and time-course of changes in lung volumes, ventilatory efficiency at rest and during exercise, and respiratory muscle function and their influence on exercise limitation in congestive heart failure (CHF) are unclear. It is unknown whether respiratory muscle function may predict changes in exercise limitation or may be impaired in patients with poor outcome. 145 male patients (54±1 years) suffering from CHF (NYHA class I–III, mean 2.3±0.1), with a LVEF of 23±1 %, and a mean peak O₂ uptake (V_O2peak) 15.0±:0.5 mL×min⁻¹×kg⁻¹, were studied. They were grouped in Weber functional classes A to D according to their V_O2peak. Significant increases in ventilatory equivalents for O₂ and CO₂ (V_E/V_CO2peak) and in dead space ventilation at rest and during exercise were found with increasing exercise limitation. Moreover, there was a correlation of static and dynamic lung volumes (inspiratory vital capacity, IVC, r = 0.43, P < 0.01), as well as of maximal inspiratory pressure (MIP; r = 0.46, P < 0.01) with V_O2peak. Patients who died (n = 26) or were heart transplanted (n = 20) during a follow-up (mean 800 ± 10 days) had a reduced MIP (6.4 ± 0.4 kPa) as compared with survivors (n = 82; 9.3±0.7 kPa, P < 0.01). In a subgroup of 33 patients re-evaluated after six months, individual changes in IVC and V_E/V_CO2peak, but not in MIP, correlated to changes in V_O2peak (r = 0.69 and r = 0.72 respectively; P < 0.01). In CHF, exercise limitation is associated with reversible lung restriction and inefficient ventilation at rest and during exercise. Patientss with severe CHF have a significant reduction in MIP, a finding that is associated with poor outcome. Received: 12 July 1999, Returned for 1. revision: 26 August 1999, 1. Revision received: 23 November 1999, Returned for 2. Revision: 16 December 1999, 2. Revision received: 28 January 2000, Accepted: 8 February 2000     

From the Cover: Preexisting CD8+ T-cell immunity to the H7N9 influenza A virus varies across ethnicities

The absence of preexisting neutralizing antibodies specific for the novel A (H7N9) influenza virus indicates a lack of prior human exposure. As influenza A virus–specific CD8⁺ T lymphocytes (CTLs) can be broadly cross-reactive, we tested whether immunogenic peptides derived from H7N9 might be recognized by memory CTLs established following infection with other influenza strains. Probing across multiple ethnicities, we identified 32 conserved epitopes derived from the nucleoprotein (NP) and matrix-1 (M1) proteins. These NP and M1 peptides are presented by HLAs prevalent in 16–57% of individuals. Remarkably, some HLA alleles (A*0201, A*0301, B*5701_, B*1801, and B*0801) elicit robust CTL responses against any human influenza A virus, including H7N9, whereas ethnicities where HLA-A*0101, A*6801, B*1501, and A*2402 are prominent, show limited CTL response profiles. By this criterion, some groups, especially the Alaskan and Australian Indigenous peoples, would be particularly vulnerable to H7N9 infection. This dissection of CTL-mediated immunity to H7N9 thus suggests strategies for both vaccine delivery and development.Emerging unexpectedly in February 2013, the H7N9 influenza A virus (IAV) has thus far caused 137 human infections with 45 deaths (1). Clinical manifestations include major respiratory compromise, multiorgan failure, and exceedingly high serum cytokine and chemokine levels (2). Although May through September saw only five such cases, two more were recorded in October (1), indicating that H7N9 may return during the northern winter. Furthermore, the presence of a natural avian reservoir and the severity of the disease emphasized the need to focus on protective immunity. Most patients had contact with poultry within a week before clinical onset (2), suggesting that domestic birds are the source (2, 3). Even so, the potential for person-to-person spread is highlighted by ferret experiments (4) and instances of infection via close family contact (3). A very real concern is that further mutations may facilitate human-to-human transmission (5).Evidence from animal (6) and human studies (7–9) suggests that, in the absence of neutralizing antibodies (NAbs), preexisting memory CD8⁺ T lymphocytes (CTLs) directed at conserved and/or cross-reactive IAV peptide + class I HLA (pHLA1) epitopes can diminish disease severity. The recall of IAV-specific CTLs promotes recovery manifested by milder symptoms, diminished virus shedding and transmission (6, 7). A comprehensive analysis of the 2009 pandemic H1N1 IAV (H1N1pdm-2009) indicated that CTL memory provided some protection for the antibody naïve (9). Thus, cross-reactive CTL memory generated after a prior encounter with seasonal or pandemic IAVs, or by a CTL-directed vaccine, could potentially limit the severity of an H7N9 pandemic.The present analysis probes the extent of preexisting CTL immunity in populations that have not been exposed to the H7N9 virus. This potential for CTL recall is defined for HLA1s that are differentially prominent in various ethnicities. Using an evolutionary and immunological approach, we show substantial levels of immunogenic peptide conservation for nucleoprotein (NP) and matrix-1 (M1), with estimated coverage according to known HLA1 presentation profiles ranging between 16% and 57% of the global population. Overall, the findings support the view that it is important to consider developing vaccines with a T cell–based component that has the potential to protect against severe novel IAV infections. Furthermore, given that some ethnicities, including Australia’s Indigenous and Alaskan people, show evidence of a diminished HLA1-related response capacity, it is essential that health policy development and planning gives such groups priority in IAV vaccination campaigns. The 2009 H1N1 pandemic caused higher attack rates and morbidity among Indigenous populations in the Americas, New Zealand, and Australia (10).     

Evaluation of saliva as an alternative matrix for monitoring plasma Zidovudine, Lamivudine and nevirapine concentrations in Rwanda

Saliva may provide interesting advantages as matrix for compliance measurements, pharmacokinetic studies and therapeutic drug monitoring in resource limited countries. We investigated the feasibility of using saliva for compliance monitoring of zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) in 29 HIV-1 infected patients from Rwanda. ZDV, 3TC and NVP drug levels were quantified by an LC/MS-MS method in plasma and stimulated saliva samples and compared using Bland-Altman analysis. Seven patients demonstrated undetectable saliva ZDV levels while five out of these seven also showed no 3TC salivary concentrations. For the other samples, we observed a good agreement between salivary and plasma concentrations of each antiretroviral drug. A significant relation between the difference in saliva and plasma ZDV concentrations and the average ZDV concentration in the two matrices was deduced as follow: y = -380.15 + 1.79 x. The log saliva and plasma concentration difference of both 3TC and NVP was consistent across the range of average log concentration. Overall, we showed large agreement limits suggesting a wide inter patient variability that may result to non-reliable plasma level predictions from saliva drug measurements. Therefore, our results indicate that saliva may serve as a valuable tool only for NVP compliance testing because of its high salivary concentration.     

Anti-T-cell antibodies for the treatment of acute rejection after renal transplantation

INTRODUCTION: Given the central role of T cells in the alloimmune response, anti-T-cell antibodies retain a prominent place in the treatment of renal allograft rejection. During the past decades, many anti-T-cell antibodies have emerged and subsequently left the field of solid organ transplantation, but rabbit-antithymocyte globulin (ATG) and the humanized anti-CD52 monoclonal rat antibody alemtuzumab have remained. AREAS COVERED: This article reviews the literature about the use of ATG and alemtuzumab for the treatment of acute rejection after renal transplantation. Furthermore, it discusses possible side effects, including infusion reactions. A literature search using PubMed and Embase databases was undertaken using search words alemtuzumab, antithymocyte globulin, rejection, kidney and renal transplantation. EXPERT OPINION: Treatment of severe or steroid-resistant renal allograft rejections with ATG is very effective, but is also associated with frequent infusion reactions and an increased incidence of infections and posttransplant lymphoproliferative disease. Alemtuzumab may prove to be an attractive alternative. It can be administered easily, is relatively cheap and nearly devoid of acute side effects, but the long-term efficacy and safety as anti-rejection treatment are currently difficult to judge. The increasing knowledge about lymphocyte subsets and their plasticity will drive the development of new, specific immunosuppression that lacks side effects of ATG and alemtuzumab. TOL101, a monoclonal antibody specifically directed against the human αβ T cell receptor, might be of potential value.     

Activation of endothelinA receptors in frog adrenocortical cells stimulates both calcium mobilization from intracellular stores and calcium influx through L-type calcium channels

We have previously shown that endothelin (ET)-1 stimulates corticosterone and aldosterone secretion by the frog adrenal gland through activation of ETA receptors positively coupled to both the adenylyl cyclase and phospholipase C (PLC) pathways. The purpose of the present study was to investigate the involvement of calcium in ET-1-induced stimulation of corticosteroid secretion. Cytoautoradiographic labeling using [125I]ET-1 as a tracer revealed the presence of ET-1 binding sites on adrenocortical cells. Administration of graded concentrations of ET-1 in the vicinity of adrenocortical cells provoked a dose-dependent increase in cytosolic calcium concentrations ([Ca2+]i). ET-1 induced a biphasic response consisting of an immediate and transient peak of [Ca2+]i followed by a plateau phase. Preincubation of the cells with the calcium-ATPase inhibitor thapsigargin or the PLC inhibitor U-73122 reduced the amplitude of the transient phase. Administration of the calcium chelator EGTA or the protein kinase A inhibitor H-89 attenuated the plateau phase. The [Ca2+]i response to ET-1 was markedly reduced during concomitant administration of U-73122 and H-89. Preincubation of the cells with the L-type calcium channel blocker nifedipine attenuated the plateau phase. Corticosteroid secretion from perifused frog adrenal slices was almost completely suppressed by thapsigargin and reduced by nifedipine. Taken together, these data indicate that activation of ETA receptors in frog adrenocortical cells provokes immediate stimulation of PLC, which causes an early mobilization of calcium from intracellular stores, and activates adenylyl cyclase, which results in delayed calcium influx through L-type calcium channels. The resulting increase in [Ca2+]i plays a pivotal role in ET-1-induced corticosteroid secretion.     

Cytokine response of B lymphocytes from splenic lymphoma with villous lymphocytes: correlation with TNF-RII (p75) and CD11c expression

We studied the immunophenotype and the functional reactivity to cytokines of blood cells from eight patients with Splenic Lymphoma with Villous Lymphocytes (SLVL). Cells from all cases exhibited moderate to high levels of membrane immunoglobulin, CD22 and CD40 antigens and light chain restriction (kappa/lambda: 1.7/1). CD44, CD54 and CD11b expression was detected in all cases whereas CD11c was expressed in only four cases (50%). CD11c+ cells lacked CD21 and CD23 expression whereas CD11c- ce lls expressed both these antigens. Cells from most patients (7/8) responded to IL2 whereas only four responded to IL4 and three to TNFalpha. The response to TNFalpha correlated with spontaneous TNF-RII and CD11c expression. Although two days of culture induced the TNF-RII expression in CD11c- cells, they remained unresponsive to TNFalpha. These two groups of SLVL patients also differed by IL10 mRNA content: the former (CD11c+, TNF-RII+) contained TNFalpha and IL10 mRNA whereas the latter (CD11c-, TNF-RII-) lacked IL10 mRNA, even after two days of culture. There were thus two groups of SLVL patients: CD11c+ and CD11c-, exhibiting different patterns of cytokine response and production. These groups may correspond to different cell origins or different progression stages of the disease.This work was supported by grants from the Institut National de la santé et de la Recherche, the Association Claude Bernard and the Université Paris-Sud.     

Significant improvement of quality of life following atrioventricular synchronous pacing in patients with hypertrophic obstructive cardiomyopathy. Data from 1 year of follow-up. PIC study group. Pacing In Cardiomyopathy.

AIMS: Atrioventricular synchronous pacing exerts beneficial effects, including reduction of left ventricular outflow tract gradients, in patients with hypertrophic obstructive cardiomyopathy. The Pacing in Cardiomyopathy study was initiated to explore the effects of pacing in a double-blind randomized crossover fashion. The aims were to ascertain the beneficial effects of pacing in a controlled study and to rule out a placebo effect by pacing. This paper deals with the outcome of pacing on quality of life during 1 year of follow-up. METHODS: Quality of life was evaluated with the Karolinska questionnaire, validated for patients paced for bradyarrhythmias and ischaemic heart disease. Drug-refractory patients with hypertrophic obstructive cardiomyopathy were recruited for the study and after a temporary pacing procedure implanted with permanent pacemakers. Patients were randomized to two study arms defining the sequence of pacemaker programming. In one arm the pacemaker was inactive, in the other active. After 3 months the pacemaker was reprogrammed to the alternate mode and a further 3 months followed. After this period subsequent pacemaker programming corresponded to the mode preferred by the patient. A last assessment was made 1 year after baseline examinations. RESULTS: Eighty patients completed the first crossover period and 75 completed the full 1 year of follow-up. Active pacing induced significant quality of life improvements, in the order of 9-44%, regardless of programming sequence. Discontinuation of pacing after a first active period resulted in the return of symptoms. Fourteen patients requested early reprogramming after having been programmed to inactive pacing after a first period of active pacing. Seventy-six patients preferred active pacing after the crossover period. A further 6 months of pacing induced progressive improvement in symptoms already favourably influenced. CONCLUSION: Atrioventricular synchronous pacing has a profound beneficial effect on most domains of quality of life in patients with hypertrophic obstructive cardiomyopathy refractory to drug treatment.     

The use of telescoping guide catheters for coronary sinus cannulation and sub-selecting tributaries in left ventricular lead placement

Introduction Failure to enter the coronary sinus (CS) with a guiding catheter and entering its tributaries remains challenging in left ventricle (LV) pacing lead implants for cardiac resynchronization therapy (CRT). A dual telescoping catheter system (8F outer/6F inner) is designed to provide the ability to adjust the catheter curve size, shape and/or reach to the patients’ anatomy avoiding the need for catheter change. Methods Five different designs for CS cannulation were randomly tested in 64 patients scheduled for CRT device implant. Results In 33 consecutive patients three adaptable telescoping guiding catheter systems were tested per patient, the adaptable catheters had higher overall cannulation success rates (68, 63 and 62%) compared to the fixed shape catheter (46%) and an greater cannulation success rate when the CS location was not known (70, 53 and 72% vs 33% for the fixed shape). In a second group of 31 CRT patients the two telescoping catheters had similar high levels of success (71–80%), with or without using the inner catheter. Conclusions The telescopic system is adaptable to a wide range of anatomical variations in patients and can result in a higher CS cannulation success rate due to its adjustability in the RA in search for the CS ostium. On top of this the inner catheter allows for sub-selecting the CS tributaries.     

Efficient ex vivo gene transfer into non-human primate hepatocytes using HIV-1 derived lentiviral vectors

BACKGROUND/AIMS: Lentivirus-mediated ex vivo gene therapy is becoming a promising approach for the treatment of liver metabolic disorders. However, the feasibility of this approach needs to be studied in large animal models. The purpose of this study was to evaluate the efficacy of ex vivo gene transfer into Macaca hepatocytes with two different HIV-1 derived lentiviral vectors. METHODS: A self-inactivating lentivector was constructed to express GFP under the control of the hepatic apolipoprotein A-II promoter. Freshly isolated and thawed hepatocytes were transduced in suspension with lentiviral vectors expressing the GFP gene under the control of a ubiquitous promoter (EF1-alpha) and the apolipoprotein A-II promoter. Transduced thawed hepatocytes were transplanted into the spleen of newborn mice, and livers analyzed 4 and 12 weeks after transplantation. RESULTS: We show that lentivectors are efficient in transducing hepatocytes in suspension either freshly isolated or cryopreserved. We also show that thawed and transduced hepatocytes engrafted and participated in liver growth after transplantation into newborn mice and that the apolipoprotein A-II promoter is functional. CONCLUSIONS: Our data show that transplantation of transduced hepatocytes into monkeys should allow to evaluate the fate of transplanted cells and transgene expression in a pre-clinical model of ex vivo gene therapy.