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Modeling suites for Large-Eddy Simulations of soot evolution in turbulent flames include a number of submodels describing the chemistry of soot precursors, particle dynamics, heterogeneous soot chemistry, turbulent mixing, and combustion. To understand the reasons for model failure and to enhance the overall model performance, it is necessary to identify and subsequently improve model components with a leading order effect on the overall error. In this work, errors in soot predictions associated with flamelet-based combustion models are isolated and quantified in a combined a-priori and partial a-posteriori analysis using large-scale Direct Numerical Simulation (DNS) data of a sooting turbulent jet diffusion flame. Gas-phase quantities entering the calculation of the soot source terms and hence coupling the combustion model to the soot model are analyzed in the DNS first. The performance of a Flamelet/Progress Variable model with respect to these quantities is then analyzed a-priori for two DNS cases employing a mixture-averaged transport model and unity Lewis numbers. Then, the soot evolution along Lagrangian trajectories extracted from the DNS is re-computed using rate coefficients directly taken from the DNS and from the flamelet table. In the context of this partial a-posteriori analysis, flamelet-induced errors are also compared to errors induced by the chemical soot model. The soot surface growth and oxidation rate coefficients are reasonably well predicted by the flamelet library. Considerably larger errors in the model-predicted soot mass originate from the tabulated quantities entering the calculation of PAH-based soot growth rates. However, these errors can be reduced to a few percent if the rate is appropriately scaled with the mass fraction of polycyclic aromatic hydrocarbons (PAH). However, this requires the solution of a transport equation for the PAH mass fraction, and modeling the source term in this equation is shown to be challenging. Overall, the largest uncertainties can be attributed to the chemical mechanism for PAH formation and the model for the PAH source term.

The aim of the present study is to validate the Acoustic Voice Quality Index version 03.01 in the Italian language (AVQIv3-IT).A total of 150 native Italian speakers with normal voices (n = 50) and with various voice disorders (n = 100) were enrolled. Voice samples of a sustained vowel (SV) [a:] and five phonetically balanced continuous speech (CS) samples were recorded. The most appropriate syllable number for a standardized voiced CS approximating 3 seconds was identified. Perceptual evaluations of the overall voice quality were performed by three expert voice clinicians using the G score of the GRBAS scale. AVQIs were calculated using a 3 seconds mid-vowel selection of the SV [a:] and the standardized syllable number of the CS. Finally, concurrent validity and diagnostic accuracy of AVQIv3-IT were analysed.The most appropriate syllable number for a standardized CS approximating 3 seconds in Italian was identified as 25. The perceptual ratings showed robust intra- and inter-rater reliability. A strong correlation was found between AVQI scores and overall voice quality perceptual evaluations (r = 0.81, P0.001). The best diagnostic outcome for AVQIv3-IT was found for a threshold of 2.35 (sensitivity of 90% and specificity of 92%).AVQIv3-IT was demonstrated to be a valid and robust tool for quantifying overall acoustic voice quality in the Italian speaking population.

Coflow diffusion flames are a canonical laboratory-scale flame configuration, which is routinely employed in fundamental combustion studies on flame stabilization, chemical kinetics, and pollutants’ emissions. In particular, pressurized coflow flames are used to study the effect of pressure on soot formation. In this work, we explore the opportunity to scale sooting coflow flames at constant Reynolds and Grashof numbers as pressure increases. This is achieved by decreasing the bulk velocity and the diameter of the fuel nozzle with increasing pressure. Despite some minor departures from the ideal scaling due to the effect of radiative heat losses from soot, the coflow flames are shown to be self-similar to a very good approximation. By keeping the Reynolds and Grashof numbers constant, one obtains a set of pressurized flames, which have self-similar nondimensional flow fields. Self-similarity is observed experimentally via direct photography and documented thoroughly by direct numerical simulation of steady axisymmetric coflow flames of methane and air at pressures from 1 to 12 atm. Although the study does not include data on soot yields, the implications for soot formation are explored with emphasis on the field of scalar dissipation rate and on the residence time, temperature, and mixture fraction experienced by a parcel of fluid moving along the centerline and along a streamline on the flame’s wing. We explain how the proposed approach to scaling pressurized flames facilitates the analysis of the effect of pressure on soot formation.

This paper expresses the views of a group of experts within the Italian Study Group on Dysphagia (GISD) concerning the role of the Audiologist–Phoniatrician in performing the dynamic endoscopic study of swallowing. This paper expresses the views of a group of experts within the Italian Study Group on Dysphagia (GISD) concerning the role of the Audiologist-Phoniatrician in performing the dynamic endoscopic study of swallowing.

The formation, growth, and oxidation of soot are studied in a set of laminar coflow diffusion flames at pressures ranging from 1 to 8 atm. The modeling approach combines detailed finite rate chemical kinetics mechanisms that model the formation of Polycyclic Aromatic Hydrocarbon (PAH) species up to pyrene, and a bivariate method of moments that describes soot particles and aggregates by their volume and surface area. The spatial distribution of soot observed experimentally and that predicted numerically are in good qualitative agreement with the peak soot volume fraction located at the flame tip and soot appearing on the flame wings and closer to the nozzle as pressure increases. A detailed analysis of the effect of hydrodynamics and mixing on soot formation is presented. We show that the scalar dissipation rate is lower for the higher pressure flames, promoting the formation of PAH species and soot. Thus, the observed increase in soot volume fraction across flames with increasing pressure is not due solely to mixture density and kinetics effects, rather is affected by hydrodynamics and mixing processes also. Similarly, our results indicate that the decrease in the scalar dissipation rate contribute to changing the location where soot forms in the flame, with soot formation occurring closer to the nozzle and outward on the flame’s wings as pressure increases. Radiative heat losses are found to lower the flame temperature, inducing a reduction of the PAH species and associated rates of soot formation. However, heat losses are responsible for a slightly longer flame, which allows for more soot. The overall effect is a modest variation of soot volume fraction if radiation is included.

A modeling framework based on Direct Simulation Monte Carlo (DSMC) is employed to simulate the evolution of the soot particle size distribution in turbulent sooting flames. The stochastic reactor describes the evolution of soot in fluid parcels following Lagrangian trajectories in a turbulent flow field. The trajectories are sampled from a Direct Numerical Simulation (DNS) of a n-heptane turbulent nonpremixed flame. The DSMC method is validated against experimentally measured size distributions in laminar premixed flames and found to reproduce quantitatively the experimental results, including the appearance of the second mode at large aggregate sizes and the presence of a trough at mobility diameters in the range 3–8 nm. The model is then applied to the simulation of soot formation and growth in simplified configurations featuring a constant concentration of soot precursors and the evolution of the size distribution in time is found to depend on the intensity of the nucleation rate. Higher nucleation rates lead to a higher peak in number density and to the size distribution attaining its second mode sooner. The ensemble-averaged PSDF in the turbulent flame is computed from individual samples of the PSDF from large sets of Lagrangian trajectories. This statistical measure is equivalent to time-averaged, scanning mobility particle size (SMPS) measurements in turbulent flames. Although individual trajectories display strong bimodality as in laminar flames, the ensemble-average PSDF possesses only one mode and a long, broad tail, which implies significant polydispersity induced by turbulence. Our results agree very well with SMPS measurements available in the literature. Conditioning on key features of the trajectory, such as mixture fraction or radial locations does not reduce the scatter in the size distributions and the ensemble-averaged PSDF remains broad. The results highlight and explain the important role of turbulence in broadening the size distribution of particles in turbulent sooting flames.

Turbulence statistics from two three-dimensional direct numerical simulations of planar n -heptane/air turbulent jets are compared to assess the effect of the gas-phase species diffusion model on flame dynamics and soot formation. The Reynolds number based on the initial jet width and velocity is around 15, 000, corresponding to a Taylor scale Reynolds number in the range 100 ≤ Re λ ≤ 150. In one simulation, multicomponent transport based on a mixture-averaged approach is employed, while in the other the gas-phase species Lewis numbers are set equal to unity. The statistics of temperature and major species obtained with the mixture-averaged formulation are very similar to those in the unity Lewis number case. In both cases, the statistics of temperature are captured with remarkable accuracy by a laminar flamelet model with unity Lewis numbers. On the contrary, a flamelet with a mixture-averaged diffusion model, which corresponds to the model used in the multi-component diffusion three-dimensional DNS, produces significant differences with respect to the DNS results. The total mass of soot precursors decreases by 20–30% with the unity Lewis number approximation, and their distribution is more homogeneous in space and time. Due to the non-linearity of the soot growth rate with respect to the precursors’ concentration, the soot mass yield decreases by a factor of two. Being strongly affected by coagulation, soot number density is not altered significantly if the unity Lewis number model is used rather than the mixture-averaged diffusion. The dominant role of turbulent transport over differential diffusion effects is expected to become more pronounced for higher Reynolds numbers.

Background Advance directives (AD) offer the opportunity for goal-concordant care at the end of life (EOL). However, fewer than half of HCT recipients have a documented AD. We hypothesized that the use of a novel AD-the Stanford What Matters Most Letter (Letter AD)-developed to assess patients' values, goals, and EOL wishes would result in a greater proportion of AD completion among HCT recipients. We therefore conducted a prospective, randomized, controlled study of the traditional California AD vs. the Letter AD in adult allogeneic HCT recipients. Methods Patients >= 18 years old undergoing first allogeneic HCT at Stanford University were eligible. Prior to HCT conditioning, enrolled patients were randomly assigned to complete either the traditional California AD or the Letter AD, and all patients received a sociodemographic survey and a survey evaluating their opinions regarding the AD form they received. Patients were asked to return all research forms at the time of their transplant admission; a research assistant placed a reminder call to each patient prior to scheduled transplant. The primary endpoint was AD completion; secondary endpoints included EOL wishes as documented on the AD and patient preferences and opinions regarding the AD version they received. Results Between March 2017 and August 2018, 212 patients were eligible, of whom 126 (59.4%) were enrolled and randomized. Among the 84 who declined, the primary reason was already having an AD (N=34). The median age was 57 years (IQR 45-64); 54.8% were male; 58.7% were non-Hispanic White; and 72.3% had AML/MDS. There were no statistically significant differences in baseline socio-demographics between study arms. The overall AD completion rate was 71.6% and did not differ between the Traditional and Letter AD study arms (70.3% vs 72.6%, P=0.78). Preferences for EOL among responders are described in Table 1. The Letter AD uncovered that 66.7%, 42.2%, and 46.7% of patients actively wished to die gently/naturally, at home, and/or with hospice, respectively, whereas the traditional AD found that 62.2% wished to not prolong life if recovery was unlikely. Figure 1 portrays participant responses to the AD opinion survey; non-significant trends suggested that patients found the Letter AD favorable in terms of identifying what matters most to them, describing medical preferences to family, and stimulating thinking about the topic. Conclusion Completion rates of AD amongst allogeneic HCT recipients on this study were high and did not differ based upon AD version. Most patients wish to die naturally/do not wish to prolong care at EOL. Non-significant trends favored the Letter AD over the Traditional AD across several domains of patient preference.

Topic Significance & Study Purpose/Background/Rationale Blood and Marrow Transplantation (BMT) is a potentially curative therapy, but despite clinical advancements it continues to be associated with significant morbidity and mortality. Advance Directives (AD) ensure that patients receive the care that is consistent with their values, goals, and preferences at end of life (EOL). Yet, fewer than a quarter of BMT recipients at this Academic Medical Center have a documented AD. This leads to an increase in unnecessary treatments, care escalations, and discrepancy of care expectations which heightens distress for the patient, family, and provider. In May 2019, a nurse driven interprofessional team was assembled to conduct a performance improvement project. Methods, Intervention, & Analysis The goal was to increase the percent of completed AD for BMT recipients at this Center before transplant (Day 0), from 21% to 40% by September 2019. Through team-based problem solving, analyzation of possible causes for gaps in practice related to AD completion was performed. The identified key focus areas included: the absence of AD discussions in both the clinic and inpatient settings, lack of staff training and education, and no standard workflow for AD completion or collection. These findings were addressed in June 2019, by implementing a standard operating procedure within the BMT program for AD completion, delivery, and submission into the electronic health record. Training was also developed and provided to all BMT interprofessional teams. Findings & Interpretation Between July 2019 and September 2019, 74 patients received a transplant at this center, of those patients 30 had an AD completed by Day 0. The overall AD completion rate was 40.5% (Table 1). Furthermore, an increase in patients providing their Social Workers with a completed AD in the clinic setting was identified as well as the referrals to inpatient Spiritual Care services for assistance with AD completion. Discussion & Implications Early completion of AD offers the opportunity for goal-concordant care at EOL, and the BMT population can greatly benefit from this care. This has the potential to reduce hospitalization at the EOL, decrease ICU utilization and costly invasive interventions, increase utilization of hospice services, and promote a higher satisfaction with the quality of care.

This work deals with an investigation on the Cepstral Peak Prominence Smoothed (CPPS) as a discriminator of vocal health in continuous speech. Individual CPPS distribution and its descriptive statistics in reading and free speech acquired with a headworn microphone were investigated. Two groups of subjects were involved: 72 dysphonic and 39 control volunteers according to videostroboscopy examinations. The 95th percentile showed the highest diagnostic precision in both the speech materials (Area Under Curve of 0.86), with lower values indicating a pathological status of voice. Similar best thresholds were found for both reading and free speech (18.1 dB and 17.9 dB, respectively), but the identical phonemic contents of the reading task allowed higher sensitivity and specificity to be obtained. The voice self-assessment was also evaluated in the healthy and pathological groups by means of a questionnaire, namely the Italian version of the Voice Activity And Participation Profile. Significantly different scores were obtained by the two groups in all the sections of the questionnaire, thus highlighting that vocal problems are actually perceived by dysphonic people. Moreover, the 95th percentile resulted in a strong correlation with the sections of self-perceived voice problem and daily communication.

The effect of Damkohler number on turbulent nonpremixed sooting flames is investigated via large scale direct numerical simulation in three-dimensional n -heptane/air jet flames at a jet Reynolds number of 15,000 and at three different Damkohler numbers. A reduced chemical mechanism, which includes the soot precursor naphthalene, and a high-order method of moments are employed. At the highest Damkohler number, local extinction is negligible, while flames holes are observed in the two lowest Damkohler number cases. Compared to temperature and other species controlled by fuel oxidation chemistry, naphthalene is found to be affected more significantly by the Damkohler number. Consequently, the overall soot mass fraction decreases by more than one order of magnitude for a fourfold decrease of the Damkohler number. On the contrary, the overall number density of soot particles is approximately the same, but its distribution in mixture fraction space is different in the three cases. The total soot mass growth rate is found to be proportional to the Damkohler number. In the two lowest Da number cases, soot leakage across the flame is observed. Leveraging Lagrangian statistics, it is concluded that soot leakage is due to patches of soot that cross the stoichiometric surface through flame holes. These results show the leading order effects of turbulent mixing in controlling the dynamics of soot in turbulent flames.

This paper focuses on Cepstral Peak Prominence Smoothed (CPPS) as a possible indicator of vocal health status, considering individual CPPS distribution and its descriptive statistics. 31 voluntary patients and 22 control subjects performed the same protocol, which includes the simultaneous acquisition of three repetitions of the sustained vowel /a/ with a microphone in air and a contact sensor, the perceptual assessment of voice and the videolaringoscopy examination. The best logistic regression models have been applied and preliminary results showed that the fifth percentile and the standard deviation of CPPS distributions are the best parameters that discriminate healthy and unhealthy voice for the microphone in air and the contact sensor, respectively. The Area Under Curve (AUC) revealed the diagnostic precision of the selected CPPS parameters: AUC of 0.96 and 0.83 have been found for the microphone in air and the contact sensor, showing strong to moderate discrimination power, respectively. The repeatability of the selected CPPS parameters has been also estimated. For each selected CPPS parameter, the Monte Carlo method has been implemented in order to evaluate the uncertainty of the threshold, which was identified by means of the Receiver Operating Curve analysis.

The formation, growth, and transport of soot is investigated via large scale numerical simulation in a three-dimensional turbulent non-premixed n -heptane/air jet flame at a jet Reynolds number of 15,000. For the first time, a detailed chemical mechanism, which includes the soot precursor naphthalene and a high-order method of moments are employed in a three-dimensional simulation of a turbulent sooting flame. The results are used to discuss the interaction of turbulence, chemistry, and the formation of soot. Compared to temperature and other species controlled by oxidation chemistry, naphthalene is found to be affected more significantly by the scalar dissipation rate. While the mixture fraction and temperature fields show fairly smooth spatial and temporal variations, the sensitivity of naphthalene to turbulent mixing causes large inhomogeneities in the precursor fields, which in turn generate even stronger intermittency in the soot fields. A strong correlation is apparent between soot number density and the concentration of naphthalene. On the contrary, while soot mass fraction is usually large where naphthalene is present, pockets of fluid with large soot mass are also frequent in regions with very low naphthalene mass fraction values. From the analysis of Lagrangian statistics, it is shown that soot nucleates and grows mainly in a layer close to the flame and spreads on the rich side of the flame due to the fluctuating mixing field, resulting in more than half of the total soot mass being located at mixture fractions larger than 0.6. Only a small fraction of soot is transported towards the flame and is completely oxidized in the vicinity of the stoichiometric surface. These results show the leading order effects of turbulent mixing in controlling the dynamics of soot in turbulent flames. Finally, given the difficulties in obtaining quantitative data in experiments of turbulent sooting flames, this simulation provides valuable data to guide the development of models for Large Eddy Simulation and Reynolds Average Navier Stokes approaches.

In idiopathic pulmonary fibrosis (IPF), lung accumulation of excessive extracellular iron and macrophage haemosiderin may suggest disordered iron homeostasis leading to recurring microscopic injury and fibrosing damage.The current study population comprised 89 consistent IPF patients and 107 controls. 54 patients and 11 controls underwent bronchoalveolar lavage (BAL). Haemosiderin was assessed by Perls' stain, BAL fluid malondialdehyde (MDA) by high-performance liquid chromatography, BAL cell iron-dependent oxygen radical generation by fluorimetry and the frequency of hereditary haemochromatosis HFE gene variants by reverse dot blot hybridisation.Macrophage haemosiderin, BAL fluid MDA and BAL cell unstimulated iron-dependent oxygen radical generation were all significantly increased above controls (pversus22.4%, OR 2.35, p=0.008) and was associated with higher iron-dependent oxygen radical generation (HFE variant 107.4±56.0, HFE wild type (wt) 59.4±36.4 and controls 16.7±11.8 fluorescence units per 105BAL cells; p=0.028 HFE variantversusHFE wt, p=0.006 HFE wtversuscontrols).The data suggest iron dysregulation associated with HFE allelic variants may play an important role in increasing susceptibility to environmental exposures, leading to recurring injury and fibrosis in IPF.

Cardiac resynchronization therapy (CRT), combined with optimal medical therapy (OMT), is an established treatment for patients with advanced chronic heart failure (ACHF). In ACHF, carvedilol at the dose used in clinical trials, reduces morbidity and mortality. However, patients often do not tolerate the drug at the targeted dosage. The aim of the CARIBE-HF prospective observational study was to investigate the role of CRT in the implementation of carvedilol therapy in patients with ACHF.One hundred and six patients (aged 65 12 [mean +/- SD] years) with ACHF were enrolled and treated with OMT, in which carvedilol was titrated up to the maximal dose (phase 1). Subsequently, patients with left ventricular (LV) ejection fractionor = 35%, NYHA class III-IV and QRS intervalor =120 msec were assigned to CRT. Both CRT and NO-CRT patients underwent a long-term follow-up of 7 years (1193.98 +/- 924 days), while efforts to up titrate the carvedilol dose were continued during the second phase (471 + 310 days). Phase 1 was completed by 84 patients (79%), and 15 (18%) underwent CRT. The mean carvedilol dose in the CRT group was 19.0 +/- 17.8 mg, against 32.7 +/- 19.1 mg in the remaining 69 patients (P = 0.018). At the end of phase 2, CRT patients presented a significantly greater variation of increasing in the carvedilol dose than NO-CRT patients (+20.0 +/- 19.8 mg vs. -0.3 +/- 20.5 mg; P = 0.015), a greater NYHA class reduction (-0.8 +/- 0.6 vs. -0.2 +/- 0.7; P = 0.011), and a greater increase in LV ejection fraction (10.8 +/- 9 vs. 3.1 +/- 6.1; P = 0.018).The data from the CARIBE study suggest that, in ACHF, CRT may be effective in enabling the target dose of carvedilol to be reached. The significant improvement seen in LV function was probably due to a synergistic effect of CRT and carvedilol. During the extended follow-up (mean 1193.98 +/- 924 days) the mean dosage of carvedilol in the CRT group was significantly higher (P0.02).

Soot particles are formed during rich combustion of fossil fuels in technical devices such as internal combustion

In 1998 a network of 20 regional tuberculosis (TB) laboratories (the Italian Multicentre Study on Resistance to Antituberculosis drugs (SMIRA) network) was established in Italy to implement proficiency testing and to monitor the prevalence of drug resistance nationwide. The network managed 30% of all TB cases reported in Italy each year. The aim of the present report is to describe: 1) the accuracy of drug-susceptibility testing in the network; 2) the prevalence of drug resistance for the period 1998-2000. Data were collected from the network laboratories. Sensitivity to streptomycin and ethambutol increased from the first survey (1998-1999) to the second survey (2000) from 87.7 to 91.9%. Specificity, predictive values for resistance and susceptibility, efficiency and reproducibility were consistent in both surveys. In previously untreated cases, the prevalence of multidrug-resistance was the same in both surveys (1.2%), while a slight decrease from the first to the second survey was observed for monoresistance to rifampicin (from 0.8 to 0.4%) and isoniazid (from 2.9 to 2%). The significant association found between isoniazid resistance and immigration is a useful indicator for both clinicians managing individual tuberculosis cases and public health services planning control strategies.

AIMS Cardiac resynchronization therapy (CRT) is a well established therapy in heart failure patients who are on optimal medical therapy and have reduced left ventricular ejection fraction (LVEF) and wide QRS complexes. Although women and patients with nonischemic cardiomyopathy are under-represented in CRT trials and registries, there is evidence that these two groups of patients can benefit more from CRT. The aim of our analysis was to investigate the impact of female sex on mortality in a population that included a high percentage of patients (61%) with nonischemic cardiomyopathy. METHODS We analyzed data on 507 consecutive patients (20% women) who received CRT at two Italian Heart Transplant centers and were followed up for a maximum of 48 months. RESULTS After multivariate adjustment, women showed a trend toward better survival with regard to all-cause mortality [hazard ratio (HR) 0.32, confidence interval (CI) 0.10-1.04; P = 0.059]. However, this benefit was limited to nonischemic patients with regard to all-cause mortality (HR 0.20, CI 0.05-0.87, P = 0.032) and cardiovascular mortality (HR 0.14, CI 0.02-1.05, P = 0.056). CONCLUSION Female CRT recipients, at mid-term, have a favorable prognosis than male patients and this benefit appears to be more evident in nonischemic patients. Thus, we strongly believe that the apparent under-utilization of CRT in females is an anomaly that should be corrected.

Combustion of fossil fuels is likely to continue for the near future due to the growing trends in energy consumption worldwide. The increase in efficiency and the reduction of pollutant emissions from combustion devices are pivotal to achieving meaningful levels of carbon abatement as part of the ongoing climate change efforts. Computational fluid dynamics featuring adequate combustion models will play an increasingly important role in the design of more efficient and cleaner industrial burners, internal combustion engines, and combustors for stationary power generation and aircraft propulsion. Today, turbulent combustion modelling is hindered severely by the lack of data that are accurate and sufficiently complete to assess and remedy model deficiencies effectively. In particular, the formation of pollutants is a complex, nonlinear and multi-scale process characterized by the interaction of molecular and turbulent mixing with a multitude of chemical reactions with disparate time scales. The use of direct numerical simulation (DNS) featuring a state of the art description of the underlying chemistry and physical processes has contributed greatly to combustion model development in recent years. In this paper, the analysis of the intricate evolution of soot formation in turbulent flames demonstrates how DNS databases are used to illuminate relevant physico-chemical mechanisms and to identify modelling needs.

Pulmonary tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. This microorganism is capable of inducing a delayed hypersensitivity reaction in the lung, with subsequent expression of the disease. This reaction depends on the presence of different cytokines that exert specific functions. The aim of this study was to evaluate the presence and the concentrations of nine different modulators in bronchoalveolar lavage fluid (BALF). For this purpose, 15 patients with active pulmonary tuberculosis were enrolled at the time of diagnosis, prior to institution of antituberculous therapy. All the patients demonstrated M. tuberculosis in the sputum, and their disease extention was defined by high-resolution computed tomography (HRCT) using a score which included the presence of six findings: miliary nodules, nodules10 mm, consolidation, ground glass, cavity and bronchial wall thickening. This score was more sensitive than an equivalent score calculated on the basis of chest radiology. HRCT score was calculated for each area of the two lungs in order to define the more and the less affected lung for each patient. The bronchoalveolar lavage (BAL) was performed in the more affected area for each lung. The HRCT total score for each washed area ranged between 1 and 15, and showed more significant differences between the more and less affected lungs (p = 0.0004) than those obtained with the individual radiologic findings (p ranged between 0.60 and 0. 004). The BAL concentrations of the nine cytokines evaluated for the more and less affected lungs were compared: interleukin-6 (IL-6), IL-8, IL-12, tumor necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) showed significant differences (p ranged between 0. 016 and 0.0007). In addition, each cytokine concentration was correlated with the HRCT score. Significant correlations were found with IL-12, IL-6, IL-8, IL-2, and TNF-alpha. The correlations between cytokines and HRCT total score were better than those observed with the individual radiologic findings. A correlation matrix for the different cytokines evaluated one against each other, has also been added to show common behavior of these modulators. A similar analysis was also performed for the radiologic abnormalities.

Interferon-alpha (IFN-alpha) is a cytokine exerting pleiotropic activities, including antimicrobial effects, especially directed against intracellular infectious bacteria. It may be administered by aerosol to reach the lower respiratory tract without systemic side effects. The aim of the study reported here was the evaluation of aerosolized IFN-alpha treatment (3 MU/dose, given three times a week; total study dose: 72 MU/2 mo) in combination with conventional antimycobacterial therapy in patients with pulmonary tuberculosis. Two groups of 10 patients each were compared before and after 2 mo of conventional antituberculous chemotherapy with or without inhaled IFN-alpha. Several biologic (bronchoalveolar lavage fluid [BALF] cellularity, Mycobacterium tuberculosis [MT] number in sputum), biochemical (BALF concentrations of 10 cytokines, BALF IFN-alpha receptor levels), and clinical (fever, vital signs, high-resolution computed tomography [HRCT] images) measures were made in these patients at the time of their enrollment and at the end of the observation period of the study. Fever, MT number in sputum, and abnormalities in HRCT images showed significantly earlier resolution in the IFN-alpha-treated group, together with a more significant decrease in BALF interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) concentrations and significantly greater pre- versus posttreatment variations in IL-2 and IFN-gamma. These data, taken together, suggest that IFN-alpha administration may favorably affect the evolution of pulmonary tuberculosis when combined with antimycobacterial therapy.

Pulmonary alveolar microlithiasis (PAM) is a rare disease characterized by widespread localization of calcispherites in the alveolar spaces. The patients are symptomless for a long time. Nevertheless, this disease slowly develops into pulmonary fibrosis and cardiac failure. The chest X-rays and high-resolution computed tomography strongly point towards a diagnosis of PAM. As for therapeutic approaches, repeated broncho-alveolar lavages (BAL) have been performed with improvement of symptoms but without recovery, and a new oral drug treatment is still under way. We report 2 familial cases of PAM. Both patients underwent chest X-ray examination showing diffuse bilateral micronodular opacities of calcific density. After 5 years, in May 1993, one of them developed exertional dyspnoea, cyanosis, dry cough and was admitted to our Division. Cardiokinetic and diuretic drugs as well as oxygen were administered with satisfactory results. Then repeated BAL were performed. The chest X-ray after 6 months of sodium etidronate (300 mg t.i.d.) administration was unchanged.

Pulmonary alveolar microlithiasis (PAM) is a rare disease of unknown etiology, characterized by the presence of calcific concretions in the alveolar spaces. A familial occurrence is frequently found so that an inherited trait is thought to be involved. The chest X-ray is characterized by a 'sandstrom' picture while the clinical state undergoes to a slow and progressive impairment resulting in respiratory failure at the end stage. We have reviewed the Italian literature of the past 50 years detecting 48 case-reports of PAM (19 males and 29 females). Only 20 out of them were documented in international journals. A familial occurrence of 43.7% was found and 18 patients were under age fifteen. There was a prevalence in the female sex (60.4%) and in the second decade of life. Chest X-ray was the most important tool to diagnose PAM revealing the characteristic picture in all patient. Bronchoalveolar lavage (BAL) and open lung biopsy respectively show the characteristic calcospherites in the recovered fluid (BALF) and in the alveolar spaces. About 300 cases of PAM are reported in the international literature. We believe these data are probably underestimated because many case-reports are not published in international literature.

Reverse remodeling and increased LVEF after CRT correlate with survival and heart failure hospitalizations, but their relationship with the risk of SCD is unclear. We aimed to evaluate whether exceeding a threshold value of 35% for left ventricular ejection fraction (LVEF) 1 year after cardiac resynchronization therapy (CRT) predicts survival and freedom from sudden cardiac death (SCD).330 patients who survived ≥ 6 months after CRT (males 80%, age 62 ± 11 years) were grouped according to 1-year LVEF ≤ 35% (Group 1, n=187, 57%) or35% (Group 2, n=143, 43%). According to changes vs. baseline (reduction of left end-systolic volume [LVESV] ≥ 10% or increase of LVEF%10 units), patients were also classified as echocardiographic (Echo) non-responders (Group A, n=152, 46%) or responders (Group B, n=178, 54%).At baseline, LVESV volume was larger and LVEF was lower in Group 1 vs. Group 2 (p0.001). After 1 year, echocardiographic improvement was greater in Group 2 vs. Group 1 (p0.001 for changes in both LVESV and LVEF). Over a median follow-up of 49 months, 47 patients (14%) died, 36 in Group 1 vs. 11 in Group 2 (19% vs. 8%, p=0.004). A significantly higher rate of freedom from all-cause mortality (p=0.002), cardiovascular mortality (p0.001) and SCD (p0.001) was observed in Group 2. Multivariate analysis demonstrated that only 1-year LVEF35% was associated with freedom from SCD/VF.LVEF35% after 1 year of CRT characterizes a favorable long-term outcome, with a very low risk for SCD.

AIM: To study the actual exposure of pottery workers to silica particles, as their risk of silicosis is potentially high because of the presence of inhalable crystalline silica particles in the workplace. METHODS: Nine pottery workers underwent bronchoalveolar lavage. The recovered fluid was analysed for cytological and mineralogical content by analytical transmission electron microscopy. The data were compared with those obtained from a control group composed of seven patients with sarcoidosis and six patients with haemoptysis. RESULTS: Cytological results showed a similar profile in exposed workers and controls, whereas in patients with sarcoidosis a lymphocytic alveolitis was found. Microanalysis of the particulate identified the presence of silicates, CRSs, and metals. Pottery workers had higher numbers of total particles and CRSs, and had a higher silicate/metal ratio. In five workers, the presence of zirconium silicate was also detected. Patients with sarcoidosis had the lowest number of particles, and an inverted silicate/metal ratio. CONCLUSION: Microanalysis by transmission electron microscope can provide useful information to assess occupational exposure to dusts.

The classification of lung cancer into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) is essential for disease prognosis and treatment. For this purpose, we have tried to optimize the use of three tumour markers determined on pleural effusions, to differentiate SCLC from NSCLC by means of a canonic variable, generated by discriminant analysis, including subjects with histologically proven lung cancer. Discriminant analysis was performed by using carcinoembryonic antigen, neuron-specific enolase and tissue polypeptide antigen pleural levels, determined in 65 consecutive and unselected patients, histologically classified as 49 NSCLC and 16 SCLC. To validate the formula generated, a control group of 37 lung cancer patients (10 SCLC and 27 NSCLC), enrolled subsequently, was employed. Applying the discriminant analysis to SCLC and NSCLC patients a good classification was obtained (92% rate of correct classification). The aforementioned formula, applied to the validation group, showed a 92% rate of correct classification. This method, which is rapid, inexpensive and routinely applicable to malignant pleural effusions, may be reliably used to classify lung cancer patients.

Fructo-oligosaccharides (FOS) are a mixture of oligosaccharides consisting of glucose linked to fructose units. They are not digested in the human small intestine but fermented in the colon, where they could specifically promote the growth of some species of the indigenous microflora, especially bifidobacteria. We assessed in healthy humans the effects of FOS ingestion in fecal bifidobacteria and selected metabolic indexes potentially involved in colonic carcinogenesis. Twenty volunteers randomly divided into two groups were studied for three consecutive 12-day periods. During the ingestion period, they received 12.5 g/day FOS or placebo (saccharose) in three oral doses. Stools were regularly collected and analyzed. FOS ingestion led to an increase in fecal bifidobacterial counts [7.9 +/- 0.5 to 9.1 +/- 0.3 (SE) log colony-forming units/g wet wt, p < 0.01] and beta-fructosidase activity (9.6 +/- 1.9 to 13.8 +/- 1.9 IU/g dry wt, p < 0.01). In contrast, FOS ingestion had no significant effect on fecal total anaerobes, pH, the activities of nitroreductase, azoreductase, and beta-glucuronidase, and the concentrations of bile acids and neutral sterols. We conclude that ingestion of FOS, at a clinically tolerated dose of 12.5 g/day, led to an increase in colonic bifidobacteria. This effect was not associated in healthy humans with beneficial changes in various factors potentially involved in the pathogenesis of colonic cancer.

BackgroundThere’s scarce evidence about cardiovascular events (CV) in patients with hospitalization for acute heart failure (HF) and no indication for immediate device implant. ObjectiveThe CARdiac RhYthm monitorING after acute decompensatiON for Heart Failure study was designed to assess the incidence of prespecified clinical and arrhythmic events in this patient population. MethodsIn this pilot study, 18 patients (12 (67%) male; age 72±10; 16 (89%) NYHA II-III), who were hospitalized for HF with low left ventricular ejection fraction (LVEF) (

The relationship between chronic obstructive pulmonary disease (COPD) and cognitive functioning was analyzed in a study with 50 aging patients. A complex pattern of interactions was identified between emotional and cognitive functioning and chronic respiratory disease when the effects of age, sex, type and severity of disease were controlled. These patients did not show any global and diffuse cognitive impairment. Only a portion of COPD patients (about 30%) evidenced memory impairment which was confined to immediate memory. Memory impairment found in these patients did not appear to be associated with those changes present in the aging process but was mainly related to those specific clinical and instrumental parameters which are considered valid indicators of respiratory efficiency. Two types of cognitive and emotional problems were identified. A progressive stage-dependent set of characteristics was associated with the course of the disease and a fluctuating, probably reversible state-dependent set of characteristics was associated with the temporary condition of the patients during the period of examination. Patients who had received more recent medical treatment or who were under protection of vaccination for influenza showed a better cognitive and emotional efficiency.

A Direct Numerical Simulation (DNS) of soot formation in an n-heptane/air turbulent nonpremixed flame has been performed to investigate unsteady strain effects on soot growth and transport. For the first time in a DNS of turbulent combustion, Polycyclic Aromatic Hydrocarbons (PAH) are included via a validated, reduced chemical mechanism. A novel statistical representation of soot aggregates based on the Hybrid Method of Moments is used [M.E. Mueller, G. Blanquart, H. Pitsch, Combust. Flame 156 (2009) 1143–1155], which allows for an accurate state-of-the-art description of soot number density, volume fraction, and morphology of the aggregates. In agreement with previous experimental studies in laminar flames, Damkohler number effects are found to be significant for PAH. Soot nucleation and growth from PAH are locally inhibited by high scalar dissipation rate, thus providing a possible explanation for the experimentally observed reduction of soot yields at increasing levels of mixing in turbulent sooting flames. Furthermore, our data indicate that soot growth models that rely on smaller hydrocarbon species such as acetylene as a proxy for large PAH molecules ignore or misrepresent the effects of turbulent mixing and hydrodynamic strain on soot formation due to differences in the species Damkohler number. Upon formation on the rich side of the flame, soot is displaced relative to curved mixture fraction iso-surfaces due to differential diffusion effects between soot and the gas-phase. Soot traveling towards the flame is oxidized, and aggregates displaced away from the flame grow primarily by condensation of PAH on the particle surface. In contrast to previous DNS studies based on simplified soot and chemistry models, surface reactions are found to contribute barely to the growth of soot, for nucleation and condensation processes occurring in the fuel stream are responsible for the most of soot mass generation. Furthermore, the morphology of the soot aggregates is found to depend on the location of soot in mixture fraction space. Aggregates having the largest primary particles populate the region closest to the location of peak soot growth. On the contrary, the aggregates with the largest number of primary particles are located much further into the fuel stream.

Malignant mesothelioma is a rare neoplasm which could be favored by an hereditary predisposing factor. So far, malignant mesothelioma have never been described in patients with hereditary diseases of the connective tissue. Here, we report some cases of mesothelioma affecting subjects who were not exposed to inhalation of asbestos. One of these subjects was affected by Ehlers-Danlos syndrome, whereas in two brothers, mesothelioma was associated with Marfan’s syndrome. The observation of the same histologic subtype of mesothelioma in two brothers and the coexistence of two pathologic conditions of mesodermal origin indicate the presence of hereditary factors predisposing to the cancerogenic action of even small amounts of asbestos. Structural alterations of collagen and primary immunodeficiency may represent the host factor inducing development of the neoplasm. We conclude that the association between these rare disorders of the connective tissue and mesothelioma may not be coincidental, but could be the result of the exposition to small amounts of asbestos in predisposed individuals.

Brodimoprim is a new diaminopyridine derivative suitable for oral therapy which shows good in-vitro activity against most Gram-positive and Gram-negative pathogens. The efficacy and tolerability of brodimoprim in acute lower respiratory tract infections was tested in controlled clinical trials in comparison with different classes of antibiotics. Acute bacterial infections or infective exacerbations of chronic obstructive bronchitis were included in the studies. Brodimoprim in a single dose was compared to different oral treatments which included co-trimoxazole (trimethoprim 160 mg+sulphamethoxazole 800 mg every 12 hours) and erythromycin (600 mg three times a day). In the studies criteria of efficacy such as daily temperature curve, intensity and frequency of cough, degree of dyspnea, intensity of thoracic pain, difficulty of expectoration, sputum production, thoracic semiology were examined. Brodimoprim was more effective than cotrimoxazole and erythromycin at the end of the treatment, induring a more significant and prompt reduction of axillary temperature, daily sputum volume, degree of dyspnea. There was no difference among treatments in the mean period of therapy to obtain the resolution of the infective process (8 days on average). Brodimoprim had a significantly lower percentage of side effects during the treatment in comparison with cotrimoxazole or erythromycin. Hence brodimoprim was better accepted by patients.

Yogurt has been shown to inhibit, by various mechanisms, pathogenic bacterial growth in vitro, including that of the rabbit Escherichia coli strain RDEC-1. To determine whether this in vitro inhibition by yogurt has an in vivo counterpart, 60 newly weaned New Zealand rabbits were randomly assigned to receive a diet supplemented with either milk or yogurt. Four days later, rabbits were infected intragastrically with 10(8) E. coli strain RDEC-1. During the 30 days postinfection, animals were checked regularly for weight, stool characteristics, and fecal excretion of bacteria. Results show that the duration of diarrhea as well as bacterial excretion were the same in the milk and yogurt groups, indicating that in vivo, yogurt did not interfere with the growth of the pathogenic E. coli strain RDEC-1. The pattern of the survival curves was significantly different in the two groups (p less than 0.03), but the difference between their mortality at 30 days postinfection was not significant (80% in the milk group versus 67% in the yogurt group). These results indicate that the bactericidal activity of yogurt observed in vitro against the E. coli strain RDEC-1 does not have an in vivo counterpart in the model of the just-weaned rabbit infected by RDEC-1.

Atrial fibrillation and chronic heart failure often coexist. Asymptomatic atrial fibrillation is common in patients with known atrial fibrillation but also in patients with no history of previous atrial fibrillation. The enhanced diagnostic capabilities of modern implantable devices for cardiac resynchronization therapy allow collecting of data on the clinical status of the patient in addition to information on device performance and cardiac rhythm. We present a paradigmatic case of newly diagnosed atrial fibrillation with hemodynamic consequences detected by the diagnostics of a biventricular implantable cardioverter-defibrillator. We discuss the clinical utility of device-based monitoring and the potential advantages of wireless remote-control systems of implantable devices in the management of heart failure patients.

Objectives Flexible fiberoptic endoscopes have made pediatric laryngeal examinations an everyday practice, even though fiberoptic-flexible laryngoscopy (FFL) is not always well tolerated in young children because of limited cooperation. Laryngeal ultrasonography (LUS) has been applied to normal and pathological findings in infants and children, allowing the assessment of subglottic hemangiomas, laryngeal stenosis and paralysis. No previous study assessed benign vocal folds lesions by LUS in children. The aim of this study is to evaluate the possibility of LUS to detect benign vocal fold lesions in children by comparing the results of FFL in 16 children with those of LUS. Methods Sixteen children (9 males and 7 females) with a mean age of 7.5 ± 4.0 years were included in the study. Each child underwent FFL performed by a skilled phoniatrician and LUS performed blindly by an expert radiologist. Results On FFL bilateral vocal folds nodules were found in 9 patients, vocal fold cyst in 2 other patients, while in 2 children the vocal folds appeared normal. Laryngeal papyllomatosis, vocal fold polyp and vocal fold irregularity were found in only one patient. LUS enabled the diagnosis in all the 14 patients with vocal fold lesions. Bilateral hyperechoic lesions were visible in 10 patients, while hypoechoic lesions were found in three patients. No lesion were found in two children, while one patient presented with a monolateral hyperechoic lesion. Conclusions LUS was accurate, safe, well accepted and tolerated. LUS appears to be a useful diagnostic tool for supplementing FFL in the assessment of benign vocal fold lesions in children and may represent an interesting alternative in everyday clinical practice.

The authors illustrate their personal experience relating to 32 patients, aged between 12 and 74 years, undergoing cochlear implant, in whom vestibular reflexes were evaluated before and after surgery. This series did not include cases of areflexia, but only 1 case of reduced vestibular reflexia consequently to surgery. In this case, owing to the probable intervention of central compensation processes, labyrinthine hyporeflexia never became clinically significant. These personal results enable the authors to affirm that preoperative vestibular reflexes do not offer elements able to influence the choice of the ear in which to perform the cochlear implant. In the series of patients reported by the authors, a cochleostomy by removal of the floor of the round window niche, following the suggestions of O’Leary et al., always headed the electrode implant. This contrivance may reduce or eliminate the negative effects on vestibular receptors indirectly caused by the consequent and inevitable alteration of perilymph pressure produced by the implant.

The neurons of the lateral hypothalamus that contain hypocretin/orexin (hcrt/orx) are thought to promote arousal through the excitatory action they exert on the multiple areas to which they project within the CNS. We show here that the hcrt/orx peptides can also exert a strong action on the amygdala, a structure known for its implication in emotional aspects of behavior. Indeed, the hcrt/orx peptides, applied in acute rat brain slices, excite a specific class of "low threshold burst" neurons in the central medial (CeM) nucleus which is considered as a major output of the amygdala. These excitatory effects are postsynaptic, mediated by Hcrt2/OX2 receptors and result from the closure of a potassium conductance. They occur on a class of neurons that are also excited by vasopressin acting through V1a receptors. These results suggest that the hcrt/orx system can act through the amygdala to augment arousal and evoke the autonomic and behavioral responses associated with fear, stress or emotion.

The following is a report of CT and bronchoscopic findings in a 58-year-old man, a miner for approximately 30 years and suffering from pulmonary silicosis, admitted for a restaging of his lung disease. CT scans showed thickening of the interstitial structures and revealed a distorted trachea, with changes of its caliber, because of nodules of calcific density in the internal mucosa, clearly separated from the cartilaginous rings. The patient underwent fiberoptic bronchoscopy, confirming the presence of numerous nodules on the anterior and lateral walls, sparing the pars membranacea. Brushing and biopsies revealed a squamous metaplasia. 99mTc bone scintigraphy showed no abnormal mediastinal uptake. The radiological and endoscopic picture was compatible with the diagnosis of tracheobronchopathia osteochondroplastica.

By means of a mathematical score previously generated by discriminant analysis on 90 lung cancer patients, a new and larger group of 261 subjects [209 with non-small-cell lung cancer (NSCLC) and 52 with small-cell lung cancer (SCLC)] was analysed to confirm the ability of the method to distinguish between these two types of cancers. The score, which included the serum neuron-specific enolase (NSE) and CYFRA-21.1 levels, permitted correct classification of 93% of the patients. When the misclassifications were analysed in detail, the most frequent errors were associated with limited disease SCLC with low NSE levels and with advanced NSCLC with high NSE levels. This demonstrates the importance of the marker in correctly categorizing patients.

Supracricoid laryngectomy (SCL) is an efficient surgical procedure for the treatment of selected laryngeal carcinoma, presently being performed not only in Europe but also in North America. The functional goals of the technique are voice and swallowing without a permanent tracheostoma. Perceptual and acoustic voice characteristics after SCL have been reported by different authors, but self-assessment data together with subjective and objective data have only been reported for a small number of subjects. Twenty male subjects, with a mean age of 71 years (range: 51-82 years) who underwent a SCL at least one year before our observation, were included in the study. Each subject underwent a flexible laryngoscopy and his voice was perceptually rated using the GRBAS scale. Objective examination included: maximum phonation time (MPT), voice spectrograms and syllable diadochokinesis on a single breath. Finally, each subject assessed his own voice using the Voice Handicap Index (VHI). The mean values of the GRBAS scale were respectively 2.4, 2.6, 2.4, 0.8, 0.5, 0.8. Mean MPT was 7.5 s, while for voice spectrograms the mean value of the Yanagihara scale was 3.7. Mean syllable diadochokinesis appeared as 3.3 syllables/s. Mean value of the VHI was 29.9. Subjective and objective data show a severely dysphonic voice after SCL; self-assessment data, on the contrary, reveal only moderate functional and emotional consequences. While perceptual, aerodynamic and acoustic data are in line with previous reports, self-assessment data were less severe in our subjects compared to what appears in the literature. It is concluded that self-assessment explores a different dimension of the patient's voice and that even if a severe dysphonia is present the consequences on everyday oral communication are only moderate.

Cases of patients with markedly depressed CD4+ T-lymphocyte counts, with or without opportunistic infections, in the absence of any evidence of human immunodeficiency virus (HIV) have been described in recent years. In 1992, the definition of "idiopathic CD4+ T-lymphocytopenia" was formulated by the Centers for Disease Control and Prevention (CDC) of Atlanta (USA). The present case illustrates the occurrence of an unexplained Mycobacterium kansasii pneumonia in a white HIV-negative subject with a persistent depletion of CD4+ T-lymphocytes and suppression of cell-mediated immunity. To our knowledge, this is the first observation of idiopathic CD4+ T-lymphocytopenia with pulmonary mycobacteriosis due to Mycobacterium kansasii, and the sixth case of this kind of immunodeficiency described in Italy.

According to multiple lines of evidence, neurons in the ventrolateral preoptic area (VLPO) that contain GABA promote sleep by inhibiting neurons of the arousal systems. Reciprocally, transmitters used by these systems, including acetylcholine (ACh) and noradrenaline (NA), exert an inhibitory action on the VLPO neurons. Because nicotine, an agonist of ACh, acts as a potent stimulant, we queried whether it might participate in the cholinergic inhibition of these sleep-promoting cells. Indeed, we found that ACh inhibits the VLPO neurons through a nicotinic, as well as a muscarinic, action. As evident in the presence of atropine, the non-muscarinic component was mimicked by epibatidine, a nonselective nicotinic ACh receptor (nAChR) agonist and was blocked by dihydro-β-erythroidine, a nonselective nAChR antagonist. It was not, however, blocked by methyllycaconitine, a selective antagonist of the α7 subtype, indicating that the action was mediated by non-α7 nAChRs. The nicotinic inhibition was attributed to a presynaptic facilitation of NA release because it persisted in the presence of tetrodotoxin and was blocked by yohimbine and RS 79948, which are both selective antagonists of α2 adrenergic receptors. Sleep-promoting VLPO neurons are thus dually inhibited by ACh through a muscarinic postsynaptic action and a nicotinic presynaptic action on noradrenergic terminals. Such dual complementary actions allow ACh and nicotine to enhance wakefulness by inhibiting sleep-promoting systems while facilitating other wake-promoting systems.

The expression of neurotrophins (NTs) and related high- and low-affinity receptors was studied in surgical samples of histologically diagnosed human tumors of the lower respiratory tract. The experiment was conducted with 30 non-small cell lung cancer specimens and in eight small cell lung cancer specimens by Western blot analysis and immunohistochemistry to assess expression and distribution of NT and NT receptor proteins in tissues examined. Immunoblots of homogenates from human tumors displayed binding of anti-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and NT-3 antibodies as well as of anti-tyrosine-specific protein kinase (Trk) A, TrkB, and TrkC receptor antibodies, with similar migration characteristics than those displayed by human beta-NGF and proteins from rat brain. A specific immunoreactivity for NTs and NT receptors was demonstrated in vessel walls, stromal fibroblasts, immune cells, and sometimes within neoplastic cell bodies. Approximately 33% of bronchioloalveolar carcinomas exhibited a strong membrane NGF and TrkA immunoreactivity, whereas 46% adenocarcinomas expressed an intense TrkA immunoreactivity but a weak immunostaining for NGF within tumor cells. Moreover, squamous cell carcinomas developed an intense TrkA immunoreactivity only within stroma surrounding neoplastic cells. A faint BDNF and TrkB immunoreactivity was documented in adenocarcinomas, squamous cell carcinomas, and small cell lung cancers. NT-3 and its corresponding TrkC receptor were found in a small number of squamous cell carcinomas within large-size tumor cells. No expression of low-affinity p75 receptor protein was found in tumor cells. The detection of NTs and NT receptor proteins in tumors of the lower respiratory tract suggests that NTs may be involved in controlling growth and differentiation of human lung cancer and/or influencing tumor behavior.

Apoptosis has been observed in monocytes/macrophages in the course of in vivo and in vitro Mycobacterium tuberculosis (MTB) infection. In order to define the early events of MTB-induced apoptosis, membrane CD14 expression and the exposure of Annexin V-binding sites in MTB-infected monocytes/macrophages have been monitored. Moreover, the role of MTB-induced apoptosis was further analyzed in vitro in terms of mycobacterial viability. Results show that monocyte/macrophage apoptosis is a very early event that is strictly dependent on the MTB amount, and this apoptosis is associated with a selective down-regulation of surface CD14 expression. Furthermore, no statistically significant decrease in mycobacterial viability was observed, which indicates that the apoptotic pathway triggered by high doses of MTB is associated with parasite survival rather than with killing of the parasite.

Human immunodeficiency virus (HIV) replicates more efficiently in Mycobacterium tuberculosis (MTB)-infected macrophages than in uninfected controls. We investigated whether this may be partly explained by changes in expression of CCR5 in the course of mycobacterial infection, as this molecule has been shown to be a coreceptor for HIV entry. Since the lung is the preferential organ of HIV replication in the course of tuberculosis, we preliminarily analyzed beta-chemokine receptor expression in alveolar macrophages from patients with active tuberculosis, using flow cytometry based on an MIP-1alpha ligand-biotin/avidin-FITC detection system. Increased MIP-1alpha receptor (MIP-1alphaR) expression in alveolar macrophages from infected patients was observed whereas no detectable expression could be revealed in uninfected controls. Since MIP-la can also bind CCR1 and CCR4, the presence of CCR5 mRNA was investigated in bronchoalveolar lavage (BAL) cells and detected in alveolar macrophages from tuberculosis patients only. The study was then extended to in vitro MTB-infected macrophages. Monocyte-derived macrophages (MDMs) were left to differentiate for 7 days before MTB H37Rv infection, and CCR5 expression was monitored, by using a specific monoclonal antibody, on days 1, 6, and 11 after infection. Increased CCR5 expression in MTB-infected macrophages was observed, with a peak on day 6 (64% in MTB-infected versus 33% in control cultures) and a decrease by day 11 (25% in MTB infected versus 13% in control cultures). These results show that CCR5 expression is enhanced in the course of in vitro MTB infection and during active pulmonary tuberculosis.