Corticosteroids and inhaled salbutamol in patients with reversible airway obstruction markedly decrease the incidence of bronchospasm after tracheal intubation

BACKGROUND: In patients with bronchial hyperreactivity, airway instrumentation can evoke life-threatening bronchospasm. However, the best strategy for the prevention of bronchospasm has not been defined. Therefore, in a randomized, prospective, placebo-controlled study, the authors tested whether prophylaxis with either combined salbutamol-methylprednisolone or salbutamol alone (1) improves lung function and (2) prevents wheezing after intubation. METHODS: Thirty-one patients with partially reversible airway obstruction (airway resistance > 180%, forced expiratory volume in 1 s [FEV1] < 70% of predicted value, and FEV1 increase > 10% after two puffs of salbutamol), who were naive to anti-obstructive treatment, were randomized to receive daily for 5 days either 3 x 2 puffs (0.2 mg) of salbutamol alone (n = 16) or salbutamol combined with methylprednisolone (40 mg/day orally) (n = 15). Lung function was evaluated daily. Another 10 patients received two puffs of salbutamol 10 min before anesthesia. In all patients, wheezing was assessed before and 5 min after tracheal intubation. RESULTS: Within 1 day, both salbutamol and salbutamol-methylprednisolone treatment significantly improved airway resistance (salbutamol, 4.3+/- 2.0 [SD] to 2.9+/-1.3 mmHg x s x l(-1); salbutamol-methylprednisolone, 5.5+/-2.9 to 3.4+/-1.7 mmHg x s x l(-1)) and FEV1 (salbutamol, 1.79+/-0.49 to 2.12+/-0.61 l; salbutamol-methylprednisolone, 1.58+/-0.66 to 2.04+/-1.05 l) to a steady state, with no difference between groups. However, regardless of whether single-dose salbutamol preinduction or prolonged salbutamol treatment was used, most patients (8 of 10 and 7 of 9) experienced wheezing after intubation. In contrast, only one patient receiving additional methylprednisolone experienced wheezing (P = 0.0058). CONCLUSIONS:: Pretreatment with either salbutamol alone or salbutamol combined with methylprednisolone significantly and similarly improves lung function within 1 day. However, only combined salbutamol-methylprednisolone pretreatment decreases the incidence of wheezing after tracheal intubation. Therefore, in patients with bronchial hyperreactivity, preoperative treatment with combined corticosteroids and salbutamol minimizes intubation-evoked bronchoconstriction much more effectively than the inhaled beta2-sympathomimetic salbutamol alone.     

Diverse effects of eosinophil cationic granule proteins on IMR-32 nerve cell signaling and survival

Activated eosinophils release potentially toxic cationic granular proteins, including the major basic proteins (MBP) and eosinophil-derived neurotoxin (EDN). However, in inflammatory conditions including asthma and inflammatory bowel disease, localization of eosinophils to nerves is associated with nerve plasticity, specifically remodeling. In previous in vitro studies, we have shown that eosinophil adhesion to IMR-32 nerve cells, via nerve cell intercellular adhesion molecule-1, results in an adhesion-dependent release of granule proteins. We hypothesized that released eosinophil granule proteins may affect nerve cell signaling and survival, leading to nerve cell remodeling. Culture in serum-deprived media induced apoptosis in IMR-32 cells that was dose-dependently abolished by inclusion of MBP1 but not by EDN. Both MBP1 and EDN induced phosphorylation of Akt, but with divergent time courses and intensities, and survival was independent of Akt. MBP1 induced activation of neural nuclear factor (NF)-kappaB, from 10 min to 12 h, declining by 24 h, whereas EDN induced a short-lived activation of NF-kappaB. MBP1-induced protection was dependent on phosphorylation of ERK 1/2 and was related to a phospho-ERK-dependent upregulation of the NF-kappaB-activated anti-apoptotic gene, Bfl-1. This signaling pathway was not activated by EDN. Thus, MBP1 released from eosinophils at inflammatory sites may regulate peripheral nerve plasticity by inhibiting apoptosis.     

Light and lithium effects in the rat retina: modification by the PAF antagonist BN 52021

We tested the effect of an antagonist of platelet-activating factor (PAF), BN 52021, on both acute light-induced and light plus lithium-induced rod outer segment (ROS) lesions. Rats were fed lithium carbonate (2.6 g/kg chow) for 3 weeks. Half of the lithium-treated rats received BN 52021 (25 mg/kg) via gastric intubation prior to light exposure. Control and treated rats were exposed to 400–450 lux (measured at the eye level of the rats) of diffuse, white fluorescent light for 30 min, followed by 2 h of darkness and then decapitated. The eyes were removed and prepared for light and electron microscopic observation. The structural alterations of ROS were quantified from electron micrographs using a multifunctional computer image-analysis system. Our data show a significant reduction of ROS lesions by BN 52021, and this is most pronounced in light plus lithium-treated rats. Furthermore, in confirmation of previous studies, chronic lithium treatment significantly augmented light-elicited phagosome numbers, and BN 52021 reduced this effect. Our findings thus suggest that light and lithium may act via PAF responses in the rat retina.Supported by the Swiss National Science Foundation, Centre de recherche IHB/IPSEN, and the Wilhelm Sander-Stiftung, München, FRG, Le Plessis-Robinson, France     

Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes

Cutis laxa (CL) is a condition characterized by redundant, pendulous, and inelastic skin. Acquired CL has been reported in patients with inflammatory diseases. The goal of this study was to investigate whether genetic lesions predispose patients to the development of acquired CL. We report a patient who developed CL following a Toxocara canis parasitism. He later had an aortic root aneurysm that required surgical correction. Histological evaluation showed inflammation followed by destruction of elastic fibers in both the skin and the aorta. Mutational analysis showed that the patient was heterozygous for an inherited fibulin-5 (FBLN5) allele G202R and compound heterozygous for elastin (ELN) alleles A55V and G773D. Western blotting indicated abnormal proteolytic processing of tropoelastin (TE) in patient fibroblasts. The FBLN5 202R allele on the other hand led to increased interaction of FBLN5 and TE and increased deposition of insoluble ELN partially rescuing the deficiency conferred by ELN mutation G773D. We demonstrated that the interaction of ELN and FBLN5 alleles results in elastic fibers susceptible to inflammatory destruction. These results suggest that the pathogenesis of acquired CL involves an underlying genetic susceptibility and highlight the importance of molecular genetic analysis in patients with idiopathic connective tissue disorders.     

Aristolochic acid exposure in Romania and implications for renal cell carcinoma

Background:

Aristolochic acid (AA) is a nephrotoxicant associated with AA nephropathy (AAN) and upper urothelial tract cancer (UUTC). Whole-genome sequences of 14 Romanian cases of renal cell carcinoma (RCC) recently exhibited mutational signatures consistent with AA exposure, although RCC had not been previously linked with AAN and AA exposure was previously reported only in localised rural areas.

Methods:

We performed mass spectrometric measurements of the aristolactam (AL) DNA adduct 7-(deoxyadenosin-N⁶-yl) aristolactam I (dA-AL-I) in nontumour renal tissues of the 14 Romanian RCC cases and 15 cases from 3 other countries.

Results:

We detected dA-AL-I in the 14 Romanian cases at levels ranging from 0.7 to 27 adducts per 10⁸ DNA bases, in line with levels reported in Asian and Balkan populations exposed through herbal remedies or food contamination. The 15 cases from other countries were negative.

Interpretation:

Although the source of exposure is uncertain and likely different in AAN regions than elsewhere, our results demonstrate that AA exposure in Romania exists outside localised AAN regions and provide further evidence implicating AA in RCC.     

Identification of an Alu-mediated tandem duplication of exons 8 and 9 in a patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency

A tandem repeat of exons 8 and 9 was identified in the cDNA for mitochondrial acetoacetyl-CoA thiolase (T2) in a typical T2 deficient patient. Routine mutation analysis using PCR at the genomic level had failed to identify any mutations. Alu element-mediated unequal homologous recombination between an Alu-Jo in intron 7 and another Alu-Jo in intron 9 appears to be responsible for this duplication.     

Association between placental pathology and neonatal outcome in preeclampsia: a large cohort study

Objective: To study associations between placental histopathology and neonatal outcome in preeclampsia (PE). Study design: The cohort consisted of 544 singleton pregnancies complicated by PE and managed at Karolinska University Hospital, Stockholm, Sweden during 2000–2009. Evaluation of placental histopathology was made by one senior perinatal pathologist, blinded to outcome. Clinical outcome was obtained from prospectively collected medical registry data and medical records. Main outcome measures were intrauterine fetal death, smallness for gestational age, admission to neonatal unit, major neonatal morbidity (defined as presence of intraventricular hemorrhage ≥grade 3, retinopathy of prematurity ≥grade 3, necrotizing enterocolitis, cystic periventricular leucomalacia and/or severe bronchopulmonary dysplasia) and neonatal mortality. Logistic regression analyses including gestational age were performed. Results: Abnormal placental weight, both low (adjusted odds ratio (OR) [95% confidence interval] 5.2 [1.1–24], p?=?0.03) and high (adjusted OR 1048 [21–51?663], p?p?=?0.02). Decidual arteriopathy increased the odds for admission to neonatal care (adjusted OR 2.7 [1.1–6.5], p?=?0.03). Infarction involving ≥5% of the placenta was associated with intrauterine fetal death and small for gestational age infants (adjusted OR’s 75 [5.5–1011], p?=?0.001 and 3.2 [1.7–5.9], p?Conclusion: Placental pathology in PE reflects adverse perinatal events and deviant placental weight predicts adverse neonatal outcome in preeclamptic women delivering preterm. Placental investigation without delay can contribute to neonatal risk assessment.     

Antitumor effect of donor marrow graft rejection induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: critical role for recipient-derived IFN-gamma

Some patients lose chimerism following nonmyeloablative hematopoietic cell transplantation (HCT), yet, surprisingly, enjoy sustained tumor remissions. We hypothesized that host-versus-graft (HVG) alloresponses might induce antitumor effects against recipient tumors. We explored this question in mice by administering recipient leukocyte infusions (RLIs) to mixed chimeras established with nonmyeloablative conditioning. Mixed chimeras were prepared in the B10.A (H2a)-->B6 (H2b) strain combination using depleting anti-T-cell monoclonal antibodies (mAbs), cyclophosphamide, and thymic irradiation. B6 myeloid leukemia cells (MMB3.19) were administered 7 days following donor lymphocyte infusion (DLI) or RLI on day 35. Conversion to full donor chimerism occurred without graft-versus-host disease (GVHD) following DLI, whereas RLI led to loss of chimerism. Both RLI and DLI significantly delayed tumor mortality. In another strain combination (B10.BR [H2k]-->BALB/c [H2d]), RLI-induced or spontaneous loss of chimerism was associated with antitumor effects against the host-type B-cell lymphoma A20. HCT was essential for the antitumor effect of RLI. RLI induced elevated serum interferon-gamma (IFN-gamma) levels, and recipient-derived IFN-gamma was critical for their antitumor effects. Thus, HVG reactions (spontaneous or induced by RLI) mediate antitumor effects against hematologic malignancies via a recipient-derived IFN-gamma-mediated mechanism. A novel approach to achieving anti-tumor effects without the risk of GVHD is suggested.