Impact of multidisciplinary hip fracture program on timing of surgery in elderly patients.

UNLABELLED: The effect of patient characteristics and organizational and system factors on time to surgery were studied using Emilia Romagna Region database and hospital survey. The results showed that the implementation of a Hip Fracture Program significantly increased the probability of early surgery while single intervention had only slight effect INTRODUCTION: The purpose of this study is to evaluate the effect of formal Hip Fracture Program (HFP) on timing of surgery in hip fracture older patients. METHODS: This is a retrospective cohort study based on Emilia Romagna administrative databases. Data on organizational and system factor were also obtained through a hospital survey. A multilevel logistic regression analysis was carried out to assess the effect of covariates on early surgery, taking into account patient level, hospital level, and trust level variability. RESULTS: From 1 January to 31 December 2011, 5,520 subjects over 65 years old underwent surgical repair for hip fracture in Emilia Romagna. The mean waiting time to surgery was 3.4 ± 12.3 days, and the overall percentage of patients operated within 2 days was 52.2%. In the adjusted multilevel logistic model, significant risk factors affecting the timing of surgical intervention at patient level were age, comorbidity, day of admission, and antiplatelet or warfarin therapy while no significant single variables were found at hospital level including dedicated operation theater, hospital volume, dedicated orthogeriatric beds, and geriatrician involvement. The most significant variable was the implementation of HFP at trust level that increased three times the probability of early surgery after adjusting for confounding variables (OR 3.216, 95% CI 0.582-6.539). CONCLUSIONS: Several modifiable organizational factors may affect the proportion of patients with hip fracture undergoing early surgery. This study suggests that the development and the implementation of an evidence-based HFP at trust level are a key point of the strategy of quality of care.

Antitumour efficacy of MEK inhibitors in human lung cancer cells and their derivatives with acquired resistance to different tyrosine kinase inhibitors.

BACKGROUND: To study the molecular mechanisms regulating cancer cell resistance to four different tyrosine kinase inhibitors (TKIs): erlotinib, gefitinib, vandetanib and sorafenib. METHODS: An in vitro model of acquired resistance to these TKIs was developed by continuously treating the human lung adenocarcinoma cell line CALU-3 with escalating doses of each drug. Transcriptional profiling was performed with Agilent whole genome microarrays. Western blot analysis, enzyme-linked immunosorbent (ELISA), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation, migration, invasion and anchorage-independent colony growth assays were conducted in vitro and experiments with established xenografts in athymic nude mice were performed in vivo in parental (P) and TKI-resistant (R) CALU-3 cell lines. RESULTS: As compared with P-CALU-3 cells, in TKI-R CALU-3 cell lines a significant increase in the expression of activated, phosphorylated MET, IGF-1R, AKT, MEK, MAPK and of survivin was observed. Downregulation of E-cadherin and amphiregulin mRNAs and upregulation of vimentin, VE-cadherin, HIF-1α and vascular endothelial growth factor receptor-1 mRNAs were observed in all four TKI-R CALU-3 cell lines. All four TKI-R CALU-3 cells showed increased invasion, migration and anchorage-independent growth. Together, these data suggest epithelial to mesenchymal transition (EMT) in TKI-R CALU-3 cells. Treatment with several agents that target AKT, MET or IGF-1R did not affect TKI-R CALU-3 cell proliferation. In contrast, treatment with MSC19363669B and selumetinib, two selective MEK inhibitors, caused inhibition of cell proliferation, invasion, migration, anchorage-independent growth in vitro and of tumour growth in vivo of all four TKI-R CALU-3 cell lines. CONCLUSION: These data suggest that resistance to four different TKIs is characterised by EMT, which is MEK-inhibitor sensitive in human CALU-3 lung adenocarcinoma.

Use of antagonist peptides to inhibit in vitro T cell responses to Par j1, the major allergen of Parietaria judaica pollen.

Antigenic peptides with substituted side chains inhibit immune responses to a number of recall Ags from infectious agents in vitro. Here we show that the same strategy can be applied to peptides derived from a pollen protein, the major allergen of Parietaria judaica(Par j1), a plant responsible for most allergenic sensitization in the southern Mediterranean area. Three T cell lines responding to Par j1 protein were used to identify a stimulatory peptide. Two different monosubstituted altered peptide ligands (APL) were identified that bound to the HLA-DR of the responders, did not stimulate the T cell lines on their own, and decreased the response to subsaturating amounts of the unmodified stimulatory peptide. Most important, these APL were able to inhibit the response of these cell lines to intact Par j1 protein. A third monosubstituted peptide bound to the HLA-DR but did not show inhibitory activity. The two APL had a lower affinity than the unsubstituted peptide for the HLA-DR. The last two observations make MHC blockade an unlikely explanation for the observed effect. These results indicate the action of a specific peptide-mediated antagonism that may be useful in controlling the T cell component of an allergic response.

Major histocompatibility complex-independent recognition of a distinctive pollen antigen, most likely a carbohydrate, by human CD8+ alpha/beta T cells.

We have isolated CD8+ alpha/beta T cells from the blood of atopic and healthy individuals which recognize a nonpeptide antigen present in an allergenic extract from Parietaria judaica pollen. This antigen appears to be a carbohydrate because it is resistant to proteinase K and alkaline digestion, is hydrophilic, and is sensitive to trifluoromethane-sulphonic and periodic acids. In addition, on a reverse-phase high performance liquid chromatography column the antigen recognized by CD8(+) T cells separates in a fraction which contains >80% hexoses (glucose and galactose) and undetectable amounts of proteins. Presentation of this putative carbohydrate antigen (PjCHOAg) to CD8+ T cell clones is dependent on live antigen presenting cells (APCs) pulsed for >1 h at 37 degrees C, suggesting that the antigen has to be internalized and possibly processed. Indeed, fixed APCs or APCs pulsed at 15 degrees C were both unable to induce T cell response. Remarkably, PjCHOAg presentation is independent of the expression of classical major histocompatibility complex (MHC) molecules or CD1. CD8+ T cells stimulated by PjCHOAg-pulsed APCs undergo a sustained [Ca2+]i increase and downregulate their T cell antigen receptors (TCRs) in an antigen dose- and time-dependent fashion, similar to T cells stimulated by conventional ligands. Analysis of TCR Vbeta transcripts shows that six independent PjCHOAg-specific T cell clones carry the Vbeta8 segment with a conserved motif in the CDR3 region, indicating a structural requirement for recognition of this antigen. Finally, after activation, the CD8+ clones from the atopic patient express CD40L and produce high levels of interleukins 4 and 5, suggesting that the clones may have undergone a Th2-like polarization in vivo. These results reveal a new class of antigens which triggers T cells in an MHC-independent way, and these antigens appear to be carbohydrates. We suggest that this type of antigen may play a role in the immune response in vivo.

[Microparticulate aerosols and respiratory allergy]. / Microparticolato aerosolico e allergopatie respiratorie.

The assessment of allergenic activity in submicronic particles could explain some unknown aspects of pollinosis pathogenesis. Twenty-five 0.5 discs have been obtained using a high volume sampler (Hi Vol Andersen) equipped with 0.3 micron Whatman paper filters. These discs have been challenged with a concentrated pool of sera of Parietaria allergic patients by RIA in order to evaluate the presence of allergenic activity on filters. Discs of non sampled filters and discs of sampled filters challenged with serum pool of patients sensitized to house dust mites were used as controls. The percentage of bound radioactivity was detected by gamma-counter. The radioactivity bound to sampled discs with Parietaria sera was 2.3 +/- 0.55 (Standard Deviation); radioactivity detected on control discs was comparable to background values detected by counter. These preliminary date might suggest that submicronic particles of Parietaria can retain some allergenic activity.

Effects of a new loop diuretic (muzolimine) in cirrhosis with ascites: comparison with furosemide.

Muzolimine is a loop diuretic with both the dose-dependent increasing effectiveness of loop diuretics and the long-lasting effect of thiazides. This is a potential advantage in the treatment of ascites in advanced cirrhosis since these patients have a low tolerance to sudden reductions of blood volume. Equivalent single, oral doses of furosemide (40 mg) and muzolimine (30 mg) were given to 10 cirrhotic patients with ascites and reduced renal perfusion (glomerular filtration rate = 30 to 75 ml per min). The study was preceded by 4 days of equilibration (dietary sodium 40 mmoles per day), and the drugs were alternated via a single-blind, cross-over protocol after a wash-out period of 3 days. Renal function was monitored under basal conditions and after diuretic administration through 4-hr clearance periods for 24 hr. The renin-aldosterone axis was evaluated before diuretic administration and after 8 and 24 hr. Muzolimine led to a 12-hr cumulative diuresis [AUC0-12 = 2.52 +/- 0.42 (S.E.) ml per min] and natriuresis (5.14 +/- 1.05 mmoles per hr), which were comparable to those of furosemide (2.85 +/- 0.29 ml per min and 6.75 +/- 1.63 mmoles per hr). Its effect, however, was distributed over a longer period (8 hr) than furosemide (4 hr). Muzolimine activity mainly differed from furosemide because of: significantly lower 12-hr potassium excretion (AUC0-12 = 0.28 +/- 0.82 vs. 2.69 +/- 0.46 mmoles per hr; p less than 0.005); greater sodium/chloride excretion ratio (0.45 +/- 0.08 vs. 0.26 +/- 0.06; p less than 0.025), and absence of rebound phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)