Cytoprotective and Antioxidant Effects of Steen Solution on Human Lung Spheroids and Human Endothelial Cells.

Respiratory diseases represent a major healthcare burden worldwide. Lung transplantation (LTx) is the "gold standard" for end-stage patients, strongly limited by shortage of available/suitable donor lungs. Normothermic ex vivo lung perfusion (EVLP) has significantly increased the number of lungs suitable for transplantation. Steen solution is used for EVLP, but the mechanisms involved in its beneficial properties remain to be clarified. We investigated the effects of Steen solution in an in vitro protocol of cold starvation and normothermic recovery on human lung spheroids, named pneumospheres (PSs), containing epithelial/basal cells, and on endothelial human umbilical vein endothelial cells (HUVEC). Steen solution significantly preserved the viability of PSs, reduced reactive oxygen species (ROS) release by PSs and HUVECs, decreased NADPH-oxidase (NOX) activity in PSs, and reduced inflammatory cytokines expression levels in HUVECs. Steen solution was able to specifically reduce NADPH oxidase 2 (NOX2) isoform activation, particularly in PSs, as detected by soluble-NOX2 peptide and p47-phosphorylation. Interestingly, a specific NOX2 inhibitor could partly mimic the pro-survival effect of Steen on PSs. We provide the first evidence that Steen solution can preserve lung epithelial/progenitor cells viability partially through NOX2 downregulation, and exert antioxidant effects on parenchymal cells, with consequent ROS reduction. These results suggest that NOX2 inhibition might be an additional strategy to reduce cellular damage during LTx procedures.

A convenient method for the stereoselective conversion of aryl peptidyl ketones into the corresponding aryl aminomethin derivatives, a novel class of modified peptides.

In this paper we describe a reductive amination procedure that can be employed in the preparation of a novel class of pseudopeptides in which a specific amide bond is replaced by a CH(Ar)NH group. The developed methodology, performed using NaBH(3)CN and TiCl(4), is characterized by the formation of diastereomeric intermediates in a relative 1:1 ratio. It provides aryl aminomethin pseudopeptides in moderate but satisfactory yields and with definite stereochemistry on the asymmetric centres next to the modified peptide bond.

Structural characterization of isoxazolidinyl nucleosides by fast atom bombardment tandem mass spectrometry.

4'-Aza-2',3'-dideoxyerythrofuranosyl derivatives of thymine (AdT, 1) and uracil (AdU, 2) are analogues of 2',3'-dideoxyribofuranosyl thymine (ddT, 3) and uracyl (ddU, 4). Compounds 1 and 2 are representative of a new class of antiviral agents where the sugar moiety is replaced by an isoxazolidine ring. The increasing importance of isoxazolidinyl nucleosides has encouraged the exploitation of simple mass spectrometric rules for unambiguously assigning their structure. The species 1, 2, 5 and 6 were therefore synthesized in order to evaluate the role of the basic centre of the modified sugar moiety in their gas-phase chemistry. The tandem mass spectra of these compounds are similar to those of the wild-type nucleosides and display fragment ions corresponding to [B + 2H](+),[M - BH](+) and [B + 27](+) species, where B is the nucleobase. The last species derives from a retrocycloaddition process which is less evident in 2'-deoxyribosides. This behaviour is consistent with protonation of the analytes at the pyrimidine rings. Model isoxazolidines, in which the nucleobase was replaced by a phenyl or a naphthyl moiety, displayed the expected behaviour of species with a localized charge on the N-O moiety of the isoxazolidine ring.

Hindsight bias: an impediment to accurate probability estimation in clinicopathologic conferences.

Although clinicopathologic conferences (CPCs) have been valued for teaching differential diagnosis, their instructional value may be compromised by hindsight bias. This bias occurs when those who know the actual diagnosis overestimate the likelihood that they would have been able to predict the correct diagnosis had they been asked to do so beforehand. Evidence for the presence of the hindsight bias was sought among 160 physicians and trainees attending four CPCs. Before the correct diagnosis was announced, half of the conference audience estimated the probability that each of five possible diagnoses was correct (foresight subjects). After the correct diagnosis was announced the remaining (hindsight) subjects estimated the probability they would have assigned to each of the five possible diagnoses had they been making the initial differential diagnosis. Only 30% of the foresight subjects ranked the correct diagnosis as first, versus 50% of the hindsight subjects (p less than 0.02). Although less experienced physicians consistently demonstrated the hindsight bias, more experienced physicians succumbed only on easier cases.

Resident knowledge of charges: are we asking the right questions?

Physician knowledge of costs and charges for medical services is thought to have substantial relevance for cost containment. Unfortunately, numerous studies have demonstrated the difficulties in using educational techniques to improve knowledge and reduce charges. Furthermore, reductions in charges, when achieved, have not correlated with improved physician knowledge. The authors examined several methods of ascertaining physician knowledge of charges and they suggest that previous methods may have been too insensitive. Previous reports may have underestimated physician knowledge of costs and charges.

Reactivity models of 1-N-vinyluracil and synthesis of a new class of potential antiviral agents by the use of 1,3-dipolar cycloaddition reactions.

By the use of a convergent approach based on 1,3-dipolar cycloaddition reactions between N-protected formylnitrones generated in situ and 1-N-vinyluracil, a new class of 4'-aza-analogues of 2',3'-dideoxynucleosides is synthesized. Competitive reaction for the endocyclic bond of uracil also brings to a new isoxazolidine derivative fused with the pyrimidine nucleus.

Possibility of in-hospital infection by Cryptococcus neoformans in patients with AIDS.

The objective of the present work was to carry out a survey of soil samples taken from different areas of a hospital of infectious disease located in the city of Córdoba, where three AIDS patients were hospitalized during different periods in the same ward. The three of them returned with meningeal cryptococcosis between three or five months after having been discharged. Cryptococcus neoformans was isolated in 8/10 samples collected outside the hospital, near the pigeon house. The samples collected from the AIDS patients ward and its surroundings were negative. These findings suggest that the patients may have been infected by the fungus during their first stay in hospital.

Suicide using a hand grenade.

The authors describe an unusual case of suicide that required particular attention to establish whether the victim was murdered, was preparing a terrorist attack or had committed suicide. Examination of the corpse and the crime scene, as well as testimonies, led the authors to determine the real cause of death, namely, an unusual method of suicide.

Aorto-oesophageal fistula and intestinal infarction secondary to volvulus following ingestion of foreign bodies in a schizophrenic patient.

We present a case of death caused by voluntary ingestion of non-organic foreign bodies observed at the Institute of Legal Medicine of the University of Trieste. The victim was a young schizophrenic patient whose death, at first giving rise to suspicions of murder by another psychiatric patient, was found to be caused by an uncommon chronic permanence of foreign bodies at different locations of the digestive tract which suddenly evolved into a series of simultaneous lethal complications as yet never described. The case also raised the issue of possible responsibilities of the subject's healthcare providers.

Rheumatoid-like nodules presenting as Haglund's deformity in an adult, nonarthritic patient.

The authors present the case of an adult female patient with bilateral posterior heel masses. These were removed and histologically found to be rheumatoid-like nodules. There was no clinical or laboratory evidence of rheumatoid disease. A review of the literature is presented.

Removal of an intraosseous metallic foreign body in the calcaneus utilizing a fluoroscopically guided bone trephine.

The authors present the case of an adult female patient with an embedded needle in the calcaneus. The use of the Michele hand trephine under fluoroscopy for removal of an intracalcaneal metallic foreign body is described. Care must be taken not to violate the subtalar joint or leave osseous defects if multiple trephine attempts are required.

Facile approach to enantiomerically pure alpha-amino ketones by Friedel-Crafts aminoacylation and their conversion into peptidyl ketones.

In this article we describe a versatile and straightforward preparative approach to chiral aryl alpha-amino ketones via a Friedel-Crafts-type reaction of stable and enantiomerically pure N-Fmoc protected L-amino acid chlorides with toluene in the presence of aluminum trichloride. The developed methodology provided aryl alpha-amino-p-methylphenyl ketones, which can be obtained and isolated as free bases or recovered as their N-acetyl derivatives, after treatment with acetic anhydride in chloroform at room temperature, subsequent to the Lewis acid induced removal of the 9-fluorenylmethoxycarbonyl protecting group. The Friedel-Crafts-like process and the cleavage of the amino function masking group can selectively be performed since, as verified in all cases, the alpha-aminoacylation step occurred with kinetics that were faster than those required to remove the N-protection. The presented approach was also explored as a facile and useful synthetic tool for the preparation of optically pure ketone di- and tripeptides. These compounds can be obtained in exceptionally overall yields without need of chromatographic purification. Moreover, either aryl alpha-amino ketones or modified di- and tripeptides, in all cases, can be isolated in very high chemical and optical purity without recourse to resolution of diastereomeric mixtures, since the chiralities of the asymmetric amino acid educts were completely conserved throughout the entire process.

Site selectivity in the synthesis of O-methylated hydroxamic acids with diazomethane.

In this paper we report the results obtained by treating some selected hydroxamic acids with diazomethane in ethereal media. The multitask reagent diazomethane was used either as a base to induce deprotonation of the chosen hydroxamic acids or as conjugated acid which undergoes one-pot methylation processes of the generated anions. Product distributions clearly showed that a high site selectivity is expressed by the different deprotonated species in the alkylation processes. Under the adopted conditions, the prevalent site of methylation is in all the cases the oxygen of the hydroxamic acid. While in aliphatic hydroxamic acids only O-alkylation is observed, in the aromatic substrates, the NH group competes with the OH function as the nucleophilic site, although the OH reactivity still dominates.

Comparison of physician judgment and decision aids for ordering chest radiographs for pneumonia in outpatients.

STUDY OBJECTIVES: To compare physician judgment in the use of chest radiographs for diagnosing pneumonia with decision rules developed by Diehr, Singal, Heckerling, and Gennis. DESIGN: Propsective observational investigation with preradiograph survey of physicians' intent to order chest radiographs for patients presenting with respiratory complaints. All patients had uniform clinical data collected, including chest radiographs and sufficient information to retrospectively apply the four clinical prediction rules. SETTING: The emergency department and medical outpatient clinic of a major urban teaching hospital. PARTICIPANTS: Adult patients presenting with recent history of acute cough or exacerbation of chronic cough plus either fever, sputum production, or hemoptysis. RESULTS: Of 290 patients, 21 (7%) had pneumonia. The sensitivity of physician judgment (0.86) exceeded that of all four decision rules. The specificity of the Diehr (0.67), Heckerling (0.67), and Gennis (0.76) rules exceeded that of physician judgment (0.58). The accuracy of the Gennis (0.76) and Heckerling (0.68) rules also exceeded that of the physicians (0.60). DISCUSSION: Physicians' diagnostic and therapeutic decisions were characterized by high sensitivity but lower specificity for ordering chest radiographs to diagnose pneumonia. The higher specificity and accuracy of two of the decision rules suggest that they may have a role in patient evaluation.

An efficient and highly selective deprotection of N-Fmoc-alpha-amino acid and lipophilic N-Fmoc-dipeptide methyl esters with aluminium trichloride and N,N-dimethylaniline.

A novel procedure for the deprotection of the carboxyl group of amino acid methyl esters is presented. The process is carried out by the reagent system aluminium trichloride/N,N-dimethylaniline that can successfully be applied to unblock the carboxyl moiety either of N-Fmoc-protected amino acid methyl esters and N-Fmoc-protected short dipeptide methyl esters. The chiralities of the optically pure amino acid or peptide precursors are maintained totally unchanged.

Synthesis of isoxazolidino analogues of 2',3'-dideoxynucleosides.

The complete set of the 4'-aza analogues of 2',3'-dideoxynucleosides was synthesized by cycloaddition of N-tetrahydropiranyl or N-trityl methylene nitrones on suitably protected vinyl nucleobases. The convertible nucleoside approach was used in the preparation of cytosine and 5-methyl cytosine analogues.

Effect of an academic group practice on patient show rates: a randomized controlled trial.

Ambulatory medical clinics at academic centers are reputed to be expensive, inefficient, and poorly regarded by the medical residents who staff them. In an effort to address these problems, some centers have reorganized their traditional clinics into group practices. These group practices are thought to be more effective for teaching and providing services than are the traditional clinics. This is a report on the results of a study in which the authors reorganized two of four firm clinics into group practices in order to test the influence of the organizational changes on the various aspects of ambulatory care. During this controlled prospective trial of the group practice model, higher show rates were observed for patients in the group practices than in the traditional clinics (70% vs 65%, P less than 0.0005). The possible reasons for the higher rates are discussed.