An integrated approach to diagnosis and management of severe haemoptysis in patients admitted to the intensive care unit: a case series from a referral centre

Background

Limited data are available concerning patients admitted to the intensive care unit (ICU) for severe haemoptysis. We reviewed a large series of patients managed in a uniform way to describe the clinical spectrum and outcome of haemoptysis in this setting, and better define the indications for bronchial artery embolisation (BAE).

Methods

A retrospective chart review of 196 patients referred for severe haemoptysis to a respiratory intermediate care ward and ICU between January 1999 and December 2001. A follow-up by telephone interview or a visit.

Results

Patients (148 males) were aged 51 (± sd, 16) years, with a median cumulated amount of bleeding averaging 200 ml on admission. Bronchiectasis, lung cancer, tuberculosis and mycetoma were the main underlying causes. In 21 patients (11%), no cause was identified. A first-line bronchial arteriography was attempted in 147 patients (75%), whereas 46 (23%) received conservative treatment. Patients who underwent BAE had a higher respiratory rate, greater amount of bleeding, persistent bloody sputum and/or evidence of active bleeding on fiberoptic bronchoscopy. When completed (n = 131/147), BAE controlled haemoptysis in 80% of patients, both in the short and long (> 30 days) terms. Surgery was mostly performed when bronchial arteriography had failed and/or bleeding recurred early after completed BAE. Bleeding was controlled by conservative measures alone in 44 patients. The ICU mortality rate was low (4%).

Conclusion

Patients with evidence of more severe or persistent haemoptysis were more likely to receive BAE rather than conservative management. The procedure was effective and safe in most patients with severe haemoptysis, and surgery was mostly reserved to failure of arteriography and/or early recurrences after BAE.     

LaPO4 nanoparticles doped with actinium-225 that partially sequester daughter radionuclides

Nanoscale materials have been envisioned as carriers for various therapeutic drugs, including radioisotopes. Inorganic nanoparticles (NPs) are particularly appealing vehicles for targeted radiotherapy because they can package several radioactive atoms into a single carrier and can potentially retain daughter radioisotopes produced by in vivo generators such as actinium-225 ((225)Ac, t(1/2) = 10 d). Decay of this radioisotope to stable bismuth-209 proceeds through a chain of short-lived daughters accompanied by the emission of four α-particles that release >27 MeV of energy. The challenge in realizing the enhanced cytotoxic potential of in vivo generators lies in retaining the daughter nuclei at the therapy site. When (225)Ac is attached to targeting agents via standard chelate conjugation methods, all of the daughter radionuclides are released after the initial α-decay occurs. In this work, (225)Ac was incorporated into lanthanum phosphate NPs to determine whether the radioisotope and its daughters would be retained within the dense mineral lattice. Further, the (225)Ac-doped NPs were conjugated to the monoclonal antibody mAb 201B, which targets mouse lung endothelium through the vasculature, to ascertain the targeting efficacy and in vivo retention of radioisotopes. Standard biodistribution techniques and microSPECT/CT imaging of (225)Ac as well as the daughter radioisotopes showed that the NPs accumulated rapidly in mouse lung after intravenous injection. By showing that excess, competing, uncoupled antibodies or NPs coupled to control mAbs are deposited primarily in the liver and spleen, specific targeting of NP-mAb 201B conjugates was demonstrated. Biodistribution analysis showed that ～30% of the total injected dose of La((225)Ac)PO(4) NPs accumulated in mouse lungs 1 h postinjection, yielding a value of % ID/g >200. Furthermore, after 24 h, 80% of the (213)Bi daughter produced from (225)Ac decay was retained within the target organ and (213)Bi retention increased to ～87% at 120 h. In vitro analyses, conducted over a 1 month interval, demonstrated that ～50% of the daughters were retained within the La((225)Ac)PO(4) NPs at any point over that time frame. Although most of the γ-rays from radionuclides in the (225)Ac decay chain are too energetic to be captured efficiently by SPECT detectors, appropriate energy windows were found that provided dramatic microSPECT images of the NP distribution in vivo. We conclude that La((225)Ac)PO(4)-mAb 201B conjugates can be targeted efficiently to mouse lung while partially retaining daughter products and that targeting can be monitored by biodistribution techniques and microSPECT imaging.     

Autophagy-independent function of MAP-LC3 during intracellular propagation of Chlamydia trachomatis

Microtubule-associated protein 1 (MAP1) light chain 3 (LC3) has proven useful as autophagosomal marker in studies on the interaction between pathogens and the host autophagic machinery. However, the function of LC3 is known to extend above and beyond its role in autophagosome formation. We previously reported that intrinsic LC3 is associated with the intracellular Chlamydia trachomatis inclusion in human epithelial cells. Here we show that LC3, most likely the cytoplasmic nonlipidated form, interacts with the C. trachomatis inclusion as a microtubule-associated protein rather than an autophagosome-associated component. In contrast, N-terminally GFP-tagged LC3 exclusively targets autophagosomes rather than chlamydial inclusions. Immunofluorescence analysis revealed an association of LC3 and MAP1 subunits A and B with the inclusion as early as 18 h post infection. Inclusion-bound LC3 was connected with the microtubular network. Depolymerization of the microtubular architecture disrupted the association of LC3/MAP1s with the inclusion. Furthermore, siRNA-mediated silencing of the MAP1 and LC3 proteins revealed their essential function in the intracellular growth of C. trachomatis. Interestingly, defective autophagy remarkably enhanced chlamydial growth, suggesting a suppressive effect of the autophagic machinery on bacterial development. However, depletion of LC3 in autophagy-deficient cells noticeably reduced chlamydial propagation. Thus, our findings demonstrate a new function for LC3, distinct from autophagy, in intracellular bacterial pathogenesis.     

Effect of microwave radiation on the biophysical properties of liposomes

Steadily growing use of electromagnetic fields, especially in conjunction with wireless communication systems, has led to increasing public concern about possible health effects of electromagnetic radiation. However, besides the well-known thermal effect of electromagnetic fields on biological tissue, there is no clear evidence of further athermal interaction mechanisms with biological systems. The present study was designed to determine the changes in bilayer permeability in egg lecithin multilamellar vesicles after exposure to 900 MHz microwave radiation for a period of 5 h. Specific absorption rate (SAR) of the radiation for the investigated liposome sample was found to be 12 +/- 1 W/kg. Liposomal changes in permeability were monitored using a light scattering technique. Optical anisotropy of the liposome sample decreased dramatically upon exposure to microwave radiation, indicating structural changes in acyl chain packing. IR and NMR ((1)H NMR) studies, which have been employed to reveal structural alterations in microwave, exposed vesicles showed an increased damage upon exposure to microwave. The changes observed in the (1)H NMR spectrum of the microwave exposed sample indicated hydrolysis of carboxylic and phosphoric esters. IR study showed conformational changes in the acyl chains of the lipids upon microwave exposure. However, both IR and (31)P NMR did not show any appreciable changes in the head group part of the lipids.     

Synthesis of some new 1,3/ or 1,4-bis(glucopyranosyl-1,2,4-triazol-5-ylthio)propanes/ or butanes as potential antimicrobial agents

Glucosidation of the appropriate 1,3 or 1,4-bis(4-amino or arylideneamino-2,4-dihydro-3-thioxo-3H-1,2,4-triazol-5-ylthio)propanes or butanes with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide followed by chromatographic separation gave the corresponding N-, S-, and N,S-bis(glucosides). Chemical transformation leading to new functionalities has been achieved. Antimicrobial screening of 10 selected compounds resulted in their activity against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, and Escherichia coli.     

Synthesis of some novel N-ribosyl-1,2,4-triazin-6(1H)-/ones or thiones as potential antibacterial and antifungal chemotherapeutics

Ribosylation of 3-aryl-5-benzyl(or substituted benzyl)-1,2,4-triazin-6(1H)-/ones or thiones with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose gave the corresponding 3-aryl-5-benzyl(or substituted benzyl)-1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4-triazin-6(1H)-/ones or thiones. The structure of the new ribosides was confirmed chemically and spectroscopically.     

Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-beta1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK

Idiopathic pulmonary fibrosis (IPF; a progressive lung disease) is characterized by parenchymal remodeling with enlarged air spaces called honeycomb cysts and palisades of fibroblasts called fibroblast foci. In IPF, lung epithelial cells covering honeycomb cysts and fibroblast foci aberrantly express the active conformation of the potent fibrogenic cytokine transforming growth factor-beta1 (TGF-beta1). Using explanted rat lung slices, we transfected alveolar epithelial cells with the retrovirus pMX containing a site-directed mutation in which Cys223 and Cys225 were substituted with serines, resulting in release of biologically active TGF-beta1 and fibroblast proliferation and remodeling that resembled IPF. Fibroblasts obtained from transfected explants and in culture for 6 weeks incorporated 6.59 +/- 1.55-fold more [3H]thymidine compared with control fibroblasts without transfection or fibroblasts obtained from transfected explants cultured with antibody to fibroblast growth factor-2 (FGF-2). Primary lung fibroblasts obtained from normal rat lungs cultured with TGF-beta1 expressed increased levels of phosphorylated p38 MAPK and JNK, but not ERK1/2. The presence of TGF-beta1 caused an immediate release of extracellular FGF-2 from primary pulmonary fibroblasts; and in the presence of anti-FGF-2 antibody, phosphorylated p38 MAPK and JNK were abrogated. TGF-beta inhibits cell proliferation by suppression of c-Myc and induction of p15INK46, p21CIP1, or p27KIP. Fibroblasts cultured with TGF-beta1 showed no regulation of c-Myc or induction of p15INK46, p21CIP1,or p27KIP. These findings suggest that pulmonary fibroblasts may not respond to the anti-proliferative effects of TGF-beta1, but proliferate in response to TGF-beta1 indirectly by the release of FGF-2, which induces phosphorylation of p38 MAPK and JNK.