In vivo autofluorescence imaging of early cancers in the human tracheobronchial tree with a spectrally optimized system

The changes in the autofluorescence characteristics of the bronchial tissue is of crucial interest as a cancer diagnostic tool. Evidence exists that this native fluorescence or autofluorescence of bronchial tissues changes when they turn dysplastic and to carcinoma in situ. There is good agreement that the lesions display a decrease of autofluorescence in the green region of the spectrum under illumination with violet-light, and a relative increase in the red region of the spectrum is often reported. Imaging devices rely on this principle to detect early cancerous lesions in the bronchi. Based on a spectroscopic study, an industrial imaging prototype is developed to detect early cancerous lesions in collaboration with the firm Richard Wolf Endoskope GmbH, Germany. A preliminary clinical trial involving 20 patients with this spectrally optimized system shows that the autofluorescence can help to detect most lesions that would otherwise have remained invisible to an experienced endoscopist under white light illumination. A systematic off line analysis of the autofluorescence images pointed out that real-time decisional functions can be defined to reduce the number of false positive results. Using this method, a positive predictive value (PPV) of 75% is reached using autofluorescence only. Moreover, a PPV of 100% is obtained, when combining the white light (WL) mode and the autofluorescence (AF) mode, at the applied conditions. Furthermore, the sensitivity is estimated to be twice higher in the AF mode than in WL mode.     

Hearing impairment affects older people's ability to drive in the presence of distracters

OBJECTIVES: To investigate the effects of hearing impairment and distractibility on older people's driving ability, assessed under real‐world conditions. DESIGN: Experimental cross‐sectional study. SETTING: University laboratory setting and an on‐road driving test. PARTICIPANTS: One hundred seven community‐living adults aged 62 to 88. Fifty‐five percent had normal hearing, 26% had a mild hearing impairment, and 19% had a moderate or greater impairment. MEASUREMENTS: Hearing was assessed using objective impairment measures (pure‐tone audiometry, speech perception testing) and a self‐report measure (Hearing Handicap Inventory for the Elderly). Driving was assessed on a closed road circuit under three conditions: no distracters, auditory distracters, and visual distracters. RESULTS: There was a significant interaction between hearing impairment and distracters, such that people with moderate to severe hearing impairment had significantly poorer driving performance in the presence of distracters than those with normal or mild hearing impairment. CONCLUSION: Older adults with poor hearing have greater difficulty with driving in the presence of distracters than older adults with good hearing.     

Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata

Rhizomelic chondrodysplasia punctata is a human autosomal recessive disorder characterized by skeletal, eye and brain abnormalities. The disorder is caused by mutations in the PEX7 gene, which encodes the receptor for a class of peroxisomal matrix enzymes. We describe the generation and characterization of a Pex7 mouse knockout (Pex7(-/-)). Pex7(-/-) mice are born severely hypotonic and have a growth impairment. Mortality in Pex7(-/-) mice is highest in the perinatal period although some Pex7(-/-) mice survived beyond 18 months. Biochemically Pex7(-/-) mice display the abnormalities related to a Pex7 deficiency, i.e. a severe depletion of plasmalogens, impaired alpha-oxidation of phytanic acid and impaired beta-oxidation of very-long-chain fatty acids. In the intermediate zone of the developing cerebral cortex Pex7(-/-) mice have an increase in neuronal density. In vivo neuronal birthdating revealed that Pex7(-/-) mice have a delay in neuronal migration. Analysis of bone ossification in newborn Pex7(-/-) mice revealed a defect in ossification of distal bone elements of the limbs as well as parts of the skull and vertebrae. These findings demonstrate that Pex7 knockout mice provide an important model to study the role of peroxisomal functioning in the pathogenesis of the human disorder.     

Contributions of Psychological Well-Being and Social Support to an Integrative Model of Subjective Health in Later Adulthood

This study examined the contributions of psychological well-being and social support to an integrative model of subjective health among older adults. Structural equation modeling was used to test the proposed model of subjective health which included age, education, physical health problems, functional status, psychological well-being and social support. Partial support for the model was found. Psychological well-being had both a direct effect on subjective health and an indirect effect mediated by physical health problems. Social support had an indirect association with subjective health via its effect on psychological well-being. Functional status had only a weak effect on subjective health. Longitudinal data at a six-year interval revealed the same direct and/or indirect effects of these variables on subjective health. This study sheds light on how psychological and social resources are linked with subjective health in later adulthood.     

Phagocytosis and intracellular fate of Aspergillus fumigatus conidia in alveolar macrophages

Aspergillus fumigatus is the most prevalent airborne fungal pathogen responsible for fatal invasive aspergillosis in immunocompromised patients. Upon arrival in the lung alveolus, conidia of A. fumigatus are phagocytosed by alveolar macrophages, the major phagocytic cells of the lung. Engulfment and intracellular trafficking of A. fumigatus conidia in alveolar macrophages of two different origins, the murine cell line MH-S and human pulmonary alveolar macrophages, were analyzed by electron microscopy and immunofluorescence. Phagocytosis of A. fumigatus conidia required actin polymerization and phosphatidylinositol 3-kinase activity. Fusion of A. fumigatus phagosomes with early and late endosomes was shown by immunolabeling with specific markers for the transferrin receptor, early endosome antigen, and Rab7. Maturation of A. fumigatus phagolysosomes was monitored by using a fixable acidotropic probe, LysoTracker Red DND-99, and an anti-cathepsin D antibody. Bafilomycin A-induced inhibition of lysosomal acidification abolished the conidial killing by the macrophages. These data suggest that the maturation of A. fumigatus phagosomes results from fusion with the compartments of the endocytic pathway and that the killing of conidia depends on phagolysosome acidification. A model for the phagocytosis of A. fumigatus conidia by alveolar macrophages is proposed on the basis of these results.     

Differential inhibitory effect of fondaparinux on the procoagulant potential of intact monocytes and monocyte-derived microparticles

Monocytes and monocyte-derived microparticles (MMPs) play a major role in acute coronary syndrome (ASC). Activated monocytes (ac-M) and MMPs support thrombin generation via tissue factor (TF). The aim of this study was to evaluate the inhibitory effect of fondaparinux, a selective Xa inhibitor, on thrombin generation supported by activated monocytes and MMPs. Monocytes were purified by elutriation. They were activated by LPS, allowing to obtain both ac-M and MMPs. Thrombin generation was performed using Fluoroscan^® in these two cell models, in comparison with a cell-free model (TF 5 pM final). Two concentrations of ac-M (0.2 × 10⁶ and 1 × 10⁶/well) and four concentrations of MMPs (40,000; 80,000; 120,000 and 160,000/well) were tested. TGT was evaluated for increasing fondaparinux concentrations (0, 0.1, 0.4, 0.7 and 1.2 μg/ml). Without fondaparinux, 0.2 × 10⁶ ac-M and 160,000 MMPs induced comparable results. Fondaparinux inhibited thrombin generation in the three models. Inhibition was fondaparinux concentration dependent. Rate index was the most sensitive parameter, compared to lag-time, peak and endogenous thrombin potential. The rate index IC₅₀ were 0.69 ± 0.03 μg/ml for ac-M, 0.20 ± 0.03 μg/ml for MMPs, and 0.22 ± 0.02 μg/ml for cell-free model. Fondaparinux exerted an inhibitory effect at all concentrations, including the lowest (0.1 μg/ml). The extend of inhibition was similar between MMPs and cell-free models, and stronger than ac-M model. We assume that the efficacy of fondaparinux 2.5 mg once daily in ACS patients may be in part attributed to its inhibitory effect on MMPs.     

Selective tibial neurotomy in the treatment of spastic equinovarus foot: a 2-year follow-up of three cases

OBJECTIVE: To objectively assess the decrease in spasticity and the improvement in gait after tibial nerve neurotomy performed to treat spastic equinovarus foot. DESIGN: Before-after trial with a 2-yr follow-up. Three hemiplegic patients with spastic equinovarus foot were treated with a selective peripheral neurotomy of the tibial motor nerve branches (soleus, lateral and medial gastrocnemius and tibialis posterior nerves). Evaluation included clinical assessment of spasticity (Ashworth scale), maximal Hoffmann reflex (H(max))/compound muscle action potential (M(max)) ratio measurement, gait analysis, and muscle stiffness evaluation performed before and 2 mos, 1 yr, and 2 yrs after the neurotomy. RESULTS: Spasticity, muscle stiffness, and H(max)/M(max) ratio decreased after neurotomy. The kinematic (ankle dorsal flexion and knee recurvatum) and kinetic variables (maximum ankle muscle moment and external work) of the gait were permanently improved after neurotomy. Interestingly, kinetic variables seemed to gradually improve with time after the neurotomy. CONCLUSION: Tibial neurotomy is an effective and durable treatment for spastic equinovarus foot.     

Escherichia coli strains from pregnant women and neonates: intraspecies genetic distribution and prevalence of virulence factors

To determine the extent to which the vagina, endocervix, and amniotic fluid screen the Escherichia coli strains responsible for neonatal infections, we studied the genetic relationships among 105 E. coli strains isolated from all of the ecosystems involved in this infectious process. Twenty-four strains were isolated from the intestinal flora, and 25 strains were isolated from the vaginas of pregnant women. Twenty-seven strains were isolated from the amniotic fluid, blood, and cerebrospinal fluid (CSF) of infected neonates. The intraspecies genetic characteristics of all of the isolates were determined by random amplified polymorphic DNA (RAPD) analysis, PCR ECOR (E. coli reference) grouping, and PCR virulence genotyping. A correlation was found between the intraspecies distributions of the strains in the A, B1, B2, and D ECOR groups and in the two major RAPD groups (I and II). Nevertheless, the distribution of the E. coli strains in the RAPD groups according to their anatomical origins was more significant than their distribution in the ECOR groups. This may be explained by the existence of an E. coli subpopulation, defined by the RAPD I group, within the ECOR B2 group. This RAPD I group presents a major risk for neonates: 75% of the strains isolated from patients with meningitis and 100% of the strains isolated from patients with bacteremia were in this group. The vagina and the amniotic fluid are two barriers that favor colonization by highly infectious strains. Indeed, only 17% of fecal strains belonged to the RAPD I group, whereas 52% of vaginal strains and 67% of amniotic fluid strains belonged to this subpopulation. The ibeA and iucC genes were significantly associated with CSF strains, whereas the hly and sfa/foc genes were more frequent in blood strains. These findings could serve as a basis for developing tools to recognize vaginal strains, which present a high risk for neonates, for use in prophylaxis programs.     

Laboratory Models Available to Study Alcohol‐Induced Organ Damage and Immune Variations: Choosing the Appropriate Model

The morbidity and mortality resulting from alcohol‐related diseases globally impose a substantive cost to society. To minimize the financial burden on society and improve the quality of life for individuals suffering from the ill effects of alcohol abuse, substantial research in the alcohol field is focused on understanding the mechanisms by which alcohol‐related diseases develop and progress. Since ethical concerns and inherent difficulties limit the amount of alcohol abuse research that can be performed in humans, most studies are performed in laboratory animals. This article summarizes the various laboratory models of alcohol abuse that are currently available and are used to study the mechanisms by which alcohol abuse induces organ damage and immune defects. The strengths and weaknesses of each of the models are discussed. Integrated into the review are the presentations that were made in the symposium “Methods of Ethanol Application in Alcohol Model—How Long is Long Enough” at the joint 2008 Research Society on Alcoholism (RSA) and International Society for Biomedical Research on Alcoholism (ISBRA) meeting, Washington, DC, emphasizing the importance not only of selecting the most appropriate laboratory alcohol model to address the specific goals of a project but also of ensuring that the findings can be extrapolated to alcohol‐induced diseases in humans.     

Altered synchrony of right ventricular contraction in borderline pulmonary hypertension

Imaging studies have shown that pulmonary hypertension (PH) is associated with inhomogenous right ventricular (RV) regional contraction, or dyssynchrony, and that this is of prognostic relevance. This study aimed at the identification and functional significance of RV dyssynchrony in borderline PH defined by a mean pulmonary artery pressure between (mPAP) 20 and 25 mmHg. RV dyssynchrony was measured by 2-dimensional speckle tracking echocardiography in 17 patients with pulmonary arterial hypertension (PAH), 13 patients with borderline PH and 14 controls. Dyssynchrony was defined as the R-R interval-corrected standard deviation of the times to peak-systolic strain for the basal and medium segments of the RV. All the PH patients underwent a right heart catheterization. RV dyssynchrony amounted to 69?±?34 ms in PAH, 47?±?23 ms in borderline PH and 8?±?6 ms in controls, all different from each other (p?<?0.05). RV dyssynchrony in borderline PH was the only parameter of RV systolic dysfunction in 11 of 13 (85%) of the patients. RV dyssynchrony was accompanied by postsystolic shortening and correlated to RV fractional area change, not to mPAP or pulmonary vascular resistance. RV dyssynchrony occurs in borderline PH and may reflect early RV-arterial uncoupling.