Search

Donor brain death-induced lung injury may compromise graft function after transplantation. The mechanisms of this particular form of neurogenic lung edema and its possible prevention by immunomodulator Tacrolimus remain incompletely understood. Brain death was induced, by slow intracranial infusion of blood, in anesthetized pigs after randomisation to placebo (n=9) or to Tacrolimus (n=8). One, three, five and seven hours after brain death, pulmonary artery pressure (Pap), wedged Pap (Papo), right atrial pressure (Pra), effective pulmonary capillary pressure (Pcap), systemic artery pressure (Psa) and thermodilution cardiac output (Q) were measured. Blood and lung tissue were sampled and lung injury scored on pathological examination. Brain death was associated with marked increases in Pap, PVR and Pcap, decreases in Psa and Q with growing need for Noradrenaline while Ppao and Pra remained in a physiological range. Arterial O 2 pressure to fraction of inspired O 2 (PaO 2 /FiO 2) decreased. Brain death was associated with increased lung injury score together with increased gene expressions of interleukin (IL)-6 and IL-1βετα, heme-oxygenase-1, signal transducer and activator of transcription-3. Lung tissue pro-inflammatory IL-6/IL-10 ratio was decreased and pro-apoptotic Bax/Bcl2 ratio was increased. Tacrolimus partially corrected pulmonary hypertension and lung tissue biological perturbations. PaO 2 /FiO 2 was inversely correlated to PCP and lung injury score. Serum IL-6 and IL-1βετα were correlated to PCP. Brain death induced lung injury is related to effective pulmonary capillary hypertension with normal PAWP and pro-inflammatory and pro-apoptotic biological changes all partially reversed by preventive Tacrolimus treatment. [ABSTRACT FROM AUTHOR]

Right ventricular (RV) dysfunction remains the leading cause of early mortality after cardiac transplantation. Tacrolimus (FK506) is an immune suppressor that could preserve heart function via its anti-inflammation effect in animal models. We sought to determine whether Tacrolimus might prevent brain death-induced RV dysfunction, and biological changes in myocarditis caused by BD acting on inflammation and apoptosis. After randomisation to placebo (n=9) or to Tacrolimus (n=8; 0.05 mg.kg−1.day−1), seventeen pigs were assigned to a brain death procedure. One, three, five and seven hours after Cushing reflex, the animals underwent hemodynamic evaluation. After euthanasia of the animals, myocardial tissue was sampled. This was repeated in a control group (n=7). Seven hours after Cushing reflex, brain death had resulted in increased pulmonary artery pressure (29±2 versus 19±1 mmHg) and in a 33%-decreased RV ratio of end-systolic to pulmonary arterial elastances (Ees/Ea), while left ventriculo (LV)-arterial coupling did not change. This was prevented by Tacrolimus. Brain death-induced RV dysfunction was associated with increased RV expression of interleukin(IL)-6/IL-10, IL-1β, receptors for IL-1 and IL-6, β-3 adrenergic receptor, Toll-like receptor (TLR)-4 and neutrophil infiltration, while β-1 adrenergic receptor, TLR-2 and NLR family pyrin-domain-containing-3 expressions decreased. RV but not LV apoptosis was confirmed by TUNEL staining. Tacrolimus pre-treatment prevented RV-arterial uncoupling and changes in RV expression of IL-1 R, IL-6 R, RV apoptosis, as well as in neutrophil infiltration. Brain death-induced isolated RV dysfunction is associated with RV activation of inflammation and apoptosis, partly limited by Tacrolimus. [ABSTRACT FROM AUTHOR]

We report on a heart–lung transplant recipient who presented with pulmonary tuberculosis (TB) 2.5 months after transplantation and then developed a paradoxical reaction after 4 months of adequate anti-TB treatment. She eventually recovered with anti-TB and high-dose steroid treatments. Methods. Using sequential bronchoalveolar lavages, we assessed the inflammatory response in the lung and investigated the alveolar immune response against a Mycobacterium tuberculosis antigen. Results. The paradoxical reaction was characterized by a massive infiltration of the alveolar space by M. tuberculosis antigen-specific CD4+ T cells and by the presence of a CD4−CD8− T lymphocyte subpopulation bearing phenotypic markers (CD16+/56+) classically associated with NK cells. Conclusion. This case report illustrates that even solid organ transplant recipients receiving intense triple-drug immune suppression may be able to develop a paradoxical reaction during TB treatment. Transplant physicians should be aware of this phenomenon in order to differentiate it from treatment failure. [ABSTRACT FROM AUTHOR]

I. Simon, K.M. Wissing, V. Del Marmol, S. Antinori, M. Remmelink, E. Nilufer Broeders, J.L. Nortier, M. Corbellino, D. Abramowicz, A. Cascio. Recurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic review of the literature. Transpl Infect Dis 2011: 13: 397-406. All rights reserved Abstract: The characteristics of 8 episodes of leishmaniasis with atypical manifestations in 2 Italian kidney transplant recipients are analyzed and contextualized among those of 52 other episodes of leishmaniasis observed in 19 transplant recipients found through a systematic review of the international literature. In all the patients, the initial episode was visceral leishmaniasis, which was associated with mucocutaneous involvement in 2 cases. With the exception of 1 case of post kala-azar dermal leishmaniasis, 2 episodes of Leishmania endophthalmitis, and 3 episodes of mucocutaneous leishmaniasis, all the recurrences were characterized by visceral involvement. The potential role of polymerase chain reaction in monitoring the infection, the importance of a long follow-up, the potential benefit of chemoprophylaxis, and the therapeutic challenges are discussed. [ABSTRACT FROM AUTHOR]

The toxic galactoside-specific lectin from mistletoe, a component of proprietary extracts with unproven efficacy in oncology, exhibits capacity to trigger enhanced secretion of proinflammatory cytokines at low doses (ng/ml or ng/kg body weight) and reductions of cell viability with increasing concentrations. To infer any tumor selectivity of this activity, cytofluorimetric and cell growth assays with a variety of established human tumor cell lines were performed. Only quantitative changes were apparent, and the toxicity against tumor cells was within the range of that of the tested fibroblast preparations from 5 donors. No indication for any tumor selectivity was observed. In kinetic studies with 8 sarcoma and 4 melanoma lines, this evidence for quantitative variability of the response in interindividual comparison was further underscored. At 50 pg lectin/ml x 10(5) cells, even a growth-stimulatory impact was noted in 5 of 12 tested cases. To mimic in vivo conditions with presence of cytokine-secreting inflammatory and stromal cells, exposure to the lectin was extended to histotypic cultures established from 30 cases of surgically removed tumor. As salient result, 5 specimens from 4 of the 8 tested tumor classes responded with a significant increase of [3H]-thymidine incorporation relative to controls during the culture period of 72 hours, when the lectin was present at a concentration in the described immunomodulatory range (1 ng/ml). A relation of this activity to the extent of the actual proliferative status of the reactive samples could not be delineated. Therefore, a non-negligible percentage of the established tumor cell lines (e.g., 3 from 8 sarcoma lines) can be markedly stimulated by the lectin at a very low dose and with dependence on the cell type. Furthermore, the feasibility to elicit a significant growth enhancement is likewise documented for human tumor explants in 16.6% of the examined cases. In view of the uncontrolled application of lectin-containing extracts in alternative/complementary medicine, the presented results on unquestionably adverse lectin-dependent effects in two culture systems call for rigorous examination of the clinical safety of this unconventional, scientifically entirely experimental treatment modality. [ABSTRACT FROM AUTHOR]

Despite the advances in targeted therapies and immunotherapy for non-small cell lung cancer (NSCLC) patients, the intravenous administration of carboplatin (CARB) and paclitaxel (PTX) in well-spaced cycles is widely indicated for the treatment of NSCLC from stage II to stage IV. Our strategy was to add a controlled-release cisplatin-based dry-powder for inhalation (CIS-DPI-ET) to the conventional CARB-PTX-IV doublet, administered during the treatment off-cycles to intensify the therapeutic response while avoiding the impairment of pulmonary, renal and haematological tolerance of these combinations. The co-administration of CIS-DPI-ET (0.5 mg/kg) and CARB-PTX-IV (17–10 mg/kg) the same day showed a higher proportion of neutrophils in BALF (35 ± 7% vs 1.3 ± 0.8%), with earlier regenerative anaemia than with CARB-PTX-IV alone. A first strategy of CARB-PTX-IV dose reduction by 25% also induced neutrophil recruitment, but in a lower proportion than with the first combination (20 ± 6% vs 0.3 ± 0.3%) and avoiding regenerative anaemia. A second strategy of delaying CIS-DPI-ET and CARB-PTX-IV administrations by 24 h avoided both the recruitment of neutrophils in BALF and regenerative anaemia. Moreover, all these groups showed higher cytotoxicity (LDH activity, protein content) with no higher renal toxicities. These two strategies seem interesting to be assessed in terms of antitumor efficacy in mice. [Display omitted] • The repeated administrations of CIS-DPI at its MTD was overall well-tolerated. • The combination of CARB-PTX-IV and CIS-DPI did not increase the myelotoxicity. • The staggering of administrations and the reduction of IV dose improved the tolerance. • All combinations showed significant higher cytotoxicity in BALF than CARB-PTX-IV. [ABSTRACT FROM AUTHOR]

[Display omitted] • At MTD, CIS-DPI was better tolerated than an IV administration of cisplatin solution. • Adding CIS-DPI to CIS-IV at their respective MTD increased inflammation biomarkers. • Decreasing CIS-IV dose by 25% in combinations improved pulmonary and renal tolerance. • Staggering CIS-DPI administration from CIS-IV by 24 h improved the renal tolerance. Despite recent advances, platinum-based chemotherapy (partially composed of cisplatin, CIS) remains the backbone of non-small-cell lung cancer treatment. As CIS presents a cumulative and dose-limiting nephrotoxicity, it is currently administered with an interruption phase of 3–4 weeks between treatment cycles. During these periods, the patient recovers from the treatment side effects but so does the tumour. Our strategy is to increase the treatment frequency by delivering a cisplatin controlled-release dry powder for inhalation (CIS-DPI) formulation during these off-cycles to expose the tumour environment for longer to CIS, increasing its effectiveness. This is promising as long as the pulmonary and renal toxicities remain acceptable. The aim of the present investigation was to evaluate the pulmonary and renal tolerance of CIS-DPI (three times per cycle) and CIS using the intravenous (IV) route (CIS-IV) (one time per cycle) as monotherapies and to optimize their combination in terms of dose and schedule. At the maximum tolerated dose (MTD), combining CIS-DPI and CIS-IV impaired the pulmonary and the renal tolerance. Therefore, pulmonary tolerance was improved when the CIS-IV dose was decreased by 25% (to 1.5 mg/kg) while maintaining the MTD for CIS-DPI. In addition to this dose adjustment, a delay of 24 h between CIS-DPI and CIS-IV administrations limited the acute kidney injury. [ABSTRACT FROM AUTHOR]