CARDIOVASCULAR COMPLICATIONS OF ACROMEGALY.

Acromegaly is associated with increased mortality and decreased life expectancy. Cardiovascular disease is the principal cause of premature mortality in patients with acromegaly, accounting for about 60% of deaths. GH and/or IGF-I exert direct cardiac effects: enhance cardiac contractility, stimulate cardiomyocyte growth, influence calcium influx in cardiomyocytes. Cardiac remodelling is influenced by hypertension and insulin resistance. Among cardiovascular risk factors arterial hypertension, reported in 35% of patients with acromegaly, ranks among most important negative prognostic factors for mortality. Hypertension plays significant role in the development of cardiac hypertrophy, especially in older acromegalic patients and diastolic blood pressure is best predictive factor for cardiac hypertrophy. Therefore, early and aggressive hypertension treatment is essential for prognosis in acromegaly. Other important risk factors are: valvular defects, arrhythmias, endothelial dysfunction, heart failure, lipid abnormalities and coronary artery disease. Numerous studies suggest that patients with acromegaly are under threat of arrhythmias, especially those with structural heart abnormalities. Congestive heart failure as end-stage acromegalic cardiomyopathy occurs usually in older patients, with long-term uncontrolled disease and other cardiovascular and metabolic complications. Relation between acromegaly and coronary artery disease is controversial as it seems to be connected rather with classical cardiovascular risk factors than GH and IGF-1 overexpresion.

A simple kinetic model with explicit predictions for nuclear transport.

Molecular exchange between the cell nucleus and cytoplasm is one of the most fundamental features of eukaryotic cell biology. The nuclear pores act as a conduit of this transport, both for cargo that crosses the pore autonomously as well as that whose translocation requires an intermediary receptor. The major class of such receptors is regulated by the small GTPase Ran, via whose interaction the nucleo-cytoplasmic transport system functions as a selective molecular pump. We propose a simple analytical model for transport that includes both translocation and receptor binding kinetics. The model is suitable for steady-state kinetics such as fluorescence recovery after photobleaching. Time constants appear as a combination of parameters whose effects on measured kinetics are not separable. Competitive cargo binding to receptors and large cytoplasmic volume buffer the transport properties of any particular cargo. Specific limits to the solutions provide a qualitative insight and interpretation of nuclear transport in the cellular context. Most significantly, we find that under realistic conditions receptor binding, rather than permeability of the nuclear pores, may be rate-limiting for nucleo-cytoplasmic exchange.

Enzymatically driven transport: a kinetic theory for nuclear export.

Nuclear import and export are often considered inverse processes whereby transport receptors ferry protein cargo through the nuclear pore. In contrast to import, where the reversible binding of receptor to nuclear RanGTP leads to a balanced bidirectional exchange, termination of export by physiologically irreversible hydrolysis of the Ran-bound GTP leads to unidirectional transport. We present a concise mathematical model that predicts protein distributions and kinetic rates for receptor-mediated nuclear export, which further exhibit an unexpected pseudolinear relation one to the other. Predictions of the model are verified with permeabilized and live cell measurements.

The pursuit of stability in halide perovskites: the monovalent cation and the key for surface and bulk self-healing.

We find significant differences between degradation and healing at the surface or in the bulk for each of the different APbBr3 single crystals (A = CH3NH3+, methylammonium (MA); HC(NH2)2+, formamidinium (FA); and cesium, Cs+). Using 1- and 2-photon microscopy and photobleaching we conclude that kinetics dominate the surface and thermodynamics the bulk stability. Fluorescence-lifetime imaging microscopy, as well as results from several other methods, relate the (damaged) state of the halide perovskite (HaP) after photobleaching to its modified optical and electronic properties. The A cation type strongly influences both the kinetics and the thermodynamics of recovery and degradation: FA heals best the bulk material with faster self-healing; Cs+ protects the surface best, being the least volatile of the A cations and possibly through O-passivation; MA passivates defects via methylamine from photo-dissociation, which binds to Pb2+. DFT simulations provide insight into the passivating role of MA, and also indicate the importance of the Br3- defect as well as predicts its stability. The occurrence and rate of self-healing are suggested to explain the low effective defect density in the HaPs and through this, their excellent performance. These results rationalize the use of mixed A-cation materials for optimizing both solar cell stability and overall performance of HaP-based devices, and provide a basis for designing new HaP variants.

Caldesmon inhibits nonmuscle cell contractility and interferes with the formation of focal adhesions.

Caldesmon is known to inhibit the ATPase activity of actomyosin in a Ca(2+)-calmodulin-regulated manner. Although a nonmuscle isoform of caldesmon is widely expressed, its functional role has not yet been elucidated. We studied the effects of nonmuscle caldesmon on cellular contractility, actin cytoskeletal organization, and the formation of focal adhesions in fibroblasts. Transient transfection of nonmuscle caldesmon prevents myosin II-dependent cell contractility and induces a decrease in the number and size of tyrosine-phosphorylated focal adhesions. Expression of caldesmon interferes with Rho A-V14-mediated formation of focal adhesions and stress fibers as well as with formation of focal adhesions induced by microtubule disruption. This inhibitory effect depends on the actin- and myosin-binding regions of caldesmon, because a truncated variant lacking both of these regions is inactive. The effects of caldesmon are blocked by the ionophore A23187, thapsigargin, and membrane depolarization, presumably because of the ability of Ca(2+)-calmodulin or Ca(2+)-S100 proteins to antagonize the inhibitory function of caldesmon on actomyosin contraction. These results indicate a role for nonmuscle caldesmon in the physiological regulation of actomyosin contractility and adhesion-dependent signaling and further demonstrate the involvement of contractility in focal adhesion formation.

[Social inequalities in health and public health: from research to policies]. / Inégalités sociales de santé et santé publique: des recherches aux politiques.

This paper analyses the main results and prospects concerning research and studies about social inequalities in health in France. Research orientations, which may contribute usefully to defining health and social policies in this field and favour their development are then proposed. Health policy content and implementation placing high priority on the problem of social inequalities in health are discussed.

Molecular requirements for the effect of neuregulin on cell spreading, motility and colony organization.

Neuregulin can trigger morphogenetic signals in cells both in vivo and in culture through the activation of receptors from the ErbB family. We have ectopically expressed various ErbB-receptors in 32D myeloid cells lacking endogenous ErbB-proteins, and in CHO cells, which express only ErbB-2. We show here that activation of ErbB-3/ErbB-2 heterodimeric receptors triggers PI3-kinase-dependent lamellipodia formation and spreading, while individual ErbB-receptor homodimers as well as ErbB-3/ErbB-1 heterodimers are much less effective. CHO cells expressing ErB-3/ErbB-2 together with N-cadherin, an adhesion receptor, form epithelioid colonies. Neuregulin activates cell motility leading to transition of these colonies into ring-shaped multicellular arrays, similar to those induced by neuregulin in epithelial cells of different types (Chausovsky et al., 1998). This process requires both PI3-kinase and MAP kinase kinase activity and depends on coordinated changes in the actin- and microtubule-based cytoskeleton. Transactivation of ErbB-2 is not sufficient for the activation of cell motility and ring formation, and the C-terminal domain of ErbB-3 bearing the docking sites for the p85 subunit of PI3-kinase is essential for these morphogenetic effects. Thus, ErbB-3 in conjunction with ErbB-2 mediates, via its C-terminal domain, cytoskeletal and adhesion alterations which activate cell spreading and motility, leading to the formation of complex structures such as multicellular rings. Oncogene (2000) 19, 878 - 888.

Microtubule involvement in regulating cell contractility and adhesion-dependent signalling: a possible mechanism for polarization of cell motility.

The dynamic shape of an isolated cell results from an interplay between protrusion, adhesion and contraction activities. These are most closely associated with the actin cytoskeleton. In many cell types, microtubules have been shown to be involved in the development of morphological polarity required for directional migration. This suggests a role for the microtubule system in regulating both the actin cytoskeleton and the formation of cell-substrate adhesions. The most prominent role of microtubules in the cell is in transport of vesicles and organelles. Disruption of the microtubules, on the other hand, leads to a significant increase in actomyosin-driven contractility. This suggests the involvement of microtubules in the control of forces produced by the cell against the points at which it contacts the substrate or extracellular matrix. We show that microtubule disruption also activates an adhesion-dependent signal transduction cascade and promotes the formation of focal adhesions and associated actin microfilament bundles. Using overexpression of caldesmon, a regulatory protein which inhibits the interaction between actin and myosin, we show that these effects of microtubule disruption depend on the activation of contractility. Formation of focal adhesions induced by the small GTPase Rho is also blocked by the caldesmon inhibition of contractility. We infer that there is a step in the adhesion-dependent signalling pathway that requires mechanical tension applied to cell-substrate contacts. Although the experimental data are based on complete microtubule disruption, we suggest that a similar effect occurs locally following depolymerization of individual microtubules. We speculate that the interplay among microtubule dynamics, actomyosin contractility and adhesion-dependent signalling can produce a mechanism for the determination of cell polarity and direction of migration. In essence, microtubule depolymerization would create a local increase in contractile force, testing and promoting the maturation of nearby cell-substrate adhesions.

Precision of automatic measurements of pigmented skin lesion parameters with a MelaFind(TM) multispectral digital dermoscope.

The purpose of this study was to assess the precision of automatic computerized measurement of parameters that may be useful in the differentiation of malignant melanoma from benign pigmented skin lesions, and also to determine the feasibility of quantitative monitoring of skin lesions over time. Ten independent sequences of images were acquired with a MelaFind multispectral digital dermoscope for each of 12 benign or malignant pigmented skin lesions. The sequences of images were processed automatically to provide 10 independent measurements of the various parameters for each lesion. Parameters included lesion area, greatest 'diameter', perimeter, reflectance and asymmetry. The precision of each parameter determination was computed from the mean and standard deviation of the 10 measurements of that parameter. The relative errors in determining the lesion area, 'diameter' and perimeter were found to be 6%, 3% and 4%, respectively. Other lesion parameters that are used in differentiating melanomas from benign skin lesions were also analysed as a function of wavelength. In the blue band (about 430 nm) the relative error was about 7% for the mean lesion reflectance and about 7% for the asymmetry parameter. These results demonstrate the feasibility of using MelaFind for objective quantitative monitoring of changes in pigmented skin lesions over time. As suggested by some studies, such information is useful in the early detection of malignant melanoma. The results show that parameters obtained automatically from MelaFind images are sufficiently precise to allow pertinent parameters to be used to classify pigmented skin lesions.

Wavelet representations for monitoring changes in teeth imaged with digital imaging fiber-optic transillumination.

Digital imaging fiber-optic transillumination (DI-FOTI) is a novel method to detect and monitor dental caries, using light, a charge-coupled device (CCD) camera, and computer-controlled image acquisition. The advantages of DIFOTI over radiography include: no ionizing radiation, no film, real-time diagnosis, and higher sensitivity in detection of early lesions not apparent to X-ray, as demonstrated in vitro. Here, we present a method of processing DIFOTI images, acquired at different times, for monitoring changes. Of central importance to this application is pattern matching of image frames that is invariant to translation and rotation of a tooth, relative to the field of view of the imaging camera, and that is robust to changes in illumination source intensity. Our method employs: 1) wavelet modulus maxima representations for segmentation of teeth images; 2) first and second moments of gray level representations of DIFOTI images in the spatial domain, to estimate tooth location and orientation; and 3) multiresolution wavelet magnitude representations for quantitative monitoring. Even with illumination source intensity variation, it is demonstrated in vitro that such wavelet representations can facilitate detection of simulated clinical changes in light transmission that cannot be detected in the spatial domain.

SNR in photocounting images of rough objects in partially coherent light.

Image irradiance distributions from objects illuminated with partially coherent, quasi-monochromatic light, viewed against a spatially uniform background and received with a photosensitive detector are analyzed. A general expression for the SNR at the detector output is obtained as a function of the coherence of the illuminating light, the object surface roughness, the width of the telescope point spread function, and the aperture and integration time of the detector. The expression is evaluated for several limiting cases of coherence of illumination and of object surface roughness.

Estimation of image centroid, size, and orientation with laser radar.

Angular tracking of targets with monopulse laser radar can be performed by tracking the centroid of the image. The image irradiance distribution is sensed with an array of noncoherent photocounting detectors and the counts processed to provide estimates of the image centroid, size, and orientation. The mean and variance of the centroid and second moment are obtained for optically rough and smooth extended targets, as functions of coherence, target extent, resolution, and integration time. The limits on accuracy imposed by shot noise from the image and background irradiances and by laser speckle are discussed.

Annular apertures for angular tracking.

The estimation of the angular position of a target based on its image is considered when the image is formed with a telescope possessing an annular pupil and is sensed with a four-quadrant noncoherent detector. The Cramér-Rao lower bound on the estimation error is calculated as a function of the linear obscuration ratio for unresolved targets in the shot-noise limit. The ratio influences the error both via the shape of the telescope point spread function (PSF) and via the SNR. The error increase associated with the PSF becomes significant for greater, similar 0.5.

Enhanced diffusion in active intracellular transport.

We show that within a living eukaryotic cell, mean square displacement of an engulfed microsphere shows enhanced diffusion scaling as t(3/2) at short times, with a clear crossover to subdiffusive or ordinary diffusion scaling at longer times. The motion, observed nearby the nucleus, is due to interactions with microtubule-associated motor proteins rather than thermal Brownian motion. We propose that time-dependent friction introduced by the intracellular polymer networks leads to sub-ballistic motion, analogous to subdiffusion observed in passive networks of semiflexible biopolymers.