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Numerical geodynamo simulations capture several features of the spatial and temporal geomagnetic field variability on historical and Holocene timescales. However, a recent analysis questioned the a...

BackgroundMortality attributable to coronavirus disease-19 (COVID-19) 2 infection occurs mainly through the development of viral pneumonia-induced acute respiratory distress syndrome (ARDS).Research QuestionThe objective of the study is to delineate the clinical profile, predictors of disease progression, and 30-day mortality from ARDS using the Veterans Affairs Corporate Data Warehouse.Study Design and MethodsAnalysis of a historical cohort of 7,816 hospitalized patients with confirmed COVID-19 infection between January 1, 2020, and August 1, 2020. Main outcomes were progression to ARDS and 30-day mortality from ARDS, respectively.ResultsThe cohort was comprised predominantly of men (94.5%) with a median age of 69 years (interquartile range [IQR] 60-74 years). 2,184 (28%) were admitted to the intensive care unit and 643 (29.4%) were diagnosed with ARDS. The median Charlson Index was 3 (IQR 1-5). Independent predictors of progression to ARDS were body mass index (BMI)≥ 40 kg/m2, diabetes, lymphocyte counts450 U/L, ferritin >862 ng/ml, C-reactive protein >11 mg/dL, and D-dimer >1.5 ug/ml. In contrast, the use of an anticoagulant lowered the risk of developing ARDS (OR 0.66 [95% CI 0.49-0.89]. Crude 30-day mortality rate from ARDS was 41% (95% CI 38%-45%). Risk of death from ARDS was significantly higher in those who developed acute renal failure and septic shock. Use of an anticoagulant was associated with two-fold reduction in mortality. Survival benefit was observed in patients who received corticosteroids and/or remdesivir but there was no advantage of combination therapy over either agent alone.ConclusionsAmong those hospitalized for COVID-19, nearly one in ten progressed to ARDS. Septic shock, and acute renal failure are the leading causes of death in these patients. Treatment with either remdesivir and corticosteroids reduced the risk of mortality from ARDS. All hospitalized patients with COVID-19 should be placed at a minimum on prophylactic doses of anticoagulation.

A defining characteristic of the recent geomagnetic field is its dominant axial dipole which provides its navigational utility and dictates the shape of the magnetosphere. Going back through time, much less is known about the degree of axial dipole dominance. Here we use a substantial and diverse set of 3D numerical dynamo simulations and recent observation-based field models to derive a power law relationship between the angular dispersion of virtual geomagnetic poles at the equator and the median axial dipole dominance measured at Earth’s surface. Applying this relation to published estimates of equatorial angular dispersion implies that geomagnetic axial dipole dominance averaged over 107–109 years has remained moderately high and stable through large parts of geological time. This provides an observational constraint to future studies of the geodynamo and palaeomagnetosphere. It also provides some reassurance as to the reliability of palaeogeographical reconstructions provided by palaeomagnetism., This study describes how the geomagnetic axial dipole dominance of Earth’s magnetic field remained stable through large parts of the geological time. Since other characteristics of the geomagnetic field have changed substantially on the same timescales, this new observation provides a challenge for future core modeling studies.

A commonly used family of statistical magnetic field models is based on a giant Gaussian process (GGP), which assumes each Gauss coefficient can be realized from an independent normal distribution. GGP models are capable of generating suites of plausible Gauss coefficients, allowing for palaeomagnetic data to be tested against the expected distribution arising from a time‐averaged geomagnetic field. However, existing GGP models do not simultaneously reproduce the distribution of field strength and palaeosecular variation estimates reported for the past 10 million years and tend to underpredict virtual geomagnetic pole (VGP) dispersion at high latitudes unless trade‐offs are made to the fit at lower latitudes. Here we introduce a new family of GGP models, BB18 and BB18.Z3 (the latter includes non‐zero‐mean zonal terms for spherical harmonic degrees 2 and 3). Our models are distinct from prior GGP models by simultaneously treating the axial dipole variance separately from higher degree terms, applying an odd‐even variance structure, and incorporating a covariance between certain Gauss coefficients. Covariance between Gauss coefficients, a property both expected from dynamo theory and observed in numerical dynamo simulations, has not previously been included in GGP models. Introducing covariance between certain Gauss coefficients inferred from an ensemble of “Earth‐like” dynamo simulations and predicted by theory yields a reduced misfit to VGP dispersion, allowing for GGP models which generate improved reproductions of the distribution of field strengths and palaeosecular variation observed for the last 10 million years.

Long-term temporal variations of the magnetic field (timescales >10 Myr), characterized from paleomagnetic data, have been hypothesized to reflect the evolution of Earth's deep interior and couplings between the core and mantle. By tying observed changes in the paleomagnetic record to mechanisms predicted from numerical geodynamo simulations, we have a unique tool for assessing changes in the deep interior back in time. However, numerical simulations are not run in an Earth-like parameter regime and assessing how well they reproduce the geomagnetic field is difficult. Criteria have been proposed to determine the level of spatial and temporal agreement between simulations and observations spanning historical and Holocene timescales, but no such criteria exist for longer timescales. Here we present a new set of five criteria (Quality of Paleomagnetic Modeling criteria, Q PM ) that assess the degree of semblance between a simulated dynamo and the temporal and spatial variations of the long-term (∼10 Myr) paleomagnetic field. These criteria measure inclination anomaly, virtual geomagnetic pole dispersion at the equator, latitudinal variation in virtual geomagnetic pole dispersion, normalized width of virtual dipole moment distribution, and dipole field reversals. We have assessed 46 geodynamo simulations using the Q PM criteria. The simulations have each been run for the equivalent of at least ∼300 kyr, span reversing and non-reversing regimes, and include either homogeneous or heterogeneous heat flux boundary conditions. We find that none of our simulations reproduce all salient aspects of the long-term paleomagnetic field behavior for the past 10 Myr. Nevertheless, our simulations bracket Earth values, suggesting that an Earth-like simulation is feasible within the available computationally accessible parameter space. This new set of criteria can inform future simulations that aim to reproduce all aspects of Earth's long-term magnetic field behavior.

This prospective study aimed to evaluate whether 18F-FDG-PET/CT performed before, during and after neoadjuvant chemo-radiotherapy (CRT) could predict histopathological response in patients with locally advanced cervical cancer (LACC) treated with CRT followed by radical surgery. Between October 2010 and June 2014, 88 patients with LACC were enrolled. For each patient, three 18F-FDG-PET/CT scans (baseline, early and final) were acquired and evaluated by qualitative and quantitative analysis. Maximum standardized uptake value (SUVmax), SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured as absolute values and their percentage variation (delta) (early vs. baseline and final vs. baseline). The role of 18F-FDG-PET/CT in predicting lymph node (LN) residual disease was evaluated by qualitative analysis only. Histopathology was the reference standard. At histopathology, 40 patients had complete response (CR, pR0), 48 had partial response (PR: 21 microscopic [pR1] and 27 macroscopic [pR2]). At baseline, SUVmax and SUVmean were significantly higher in pR0 than in pR1–pR2 patients. At early evaluation, MTV and TLG were significantly higher in pR1–pR2 than in pR0 patients. At final evaluation, SUVmax, SUVmean and TLG were significantly higher in pR1–pR2 than in pR0 patients. Delta SUV parameters and delta TLG were significantly lower in PR group both during and after CRT. Delta MTV was significantly lower in patients with PR in the early phase only. In receiver operating characteristic (ROC) curve analysis, baseline SUVmean, early delta TLG, and final delta SUVmax better discriminated PR, providing 83.3%, 67.6% and 85% positive predictive value (PPV) and 60.3%, 90% and 70.8% negative predictive value (NPV), respectively. For LN assessment, high NPV was observed at early and final 18F-FDG-PET/CT (93.5% and 92.3%, respectively). In LACC patients treated with CRT followed by surgery, early variations in metabolic parameters effectively discriminate histopathological PR of the primary tumor, suggesting the potential role of 18F-FDG-PET/CT in early personalized treatment. The high NPV of early and final PET/CT could enable “tailored surgery” by avoiding lymphadenectomy in selected patients.

We investigate numerically the flow of an electrically conducting fluid in a rapidly rotating spherical shell where the inner boundary spins slightly faster than the outer one. The magnetic field evolves self-consistently from an initial dipolar configuration of weak amplitude, and a toroidal field is produced by winding this poloidal field through the internal differential rotation. First, we characterize the axisymmetric field solutions obtained at long times when the Lorentz force is negligible and the flow follows the steady, purely hydrodynamical solution. We then examine the stability of these solutions, focusing on the regime of large magnetic Reynolds numbers where the field is dominantly toroidal. When the ratio of the azimuthal Alfven frequency to the rotation frequency exceeds a certain value, a nonaxisymmetric instability develops. We show that the instability properties are compatible with those expected for the magnetorotational instability. Finally, we compare the instability properties with predictions obtained from a local linear stability analysis. The linear analysis agrees well with the numerical simulation results, except in a number of cases where the discrepancies are attributed to shearing effects on the unstable modes.

Conditionally expressed progesterone receptor isoforms PRA and PRB enhance breast cancer cell migration through interaction with focal adhesion kinase (FAK) and differential regulation of FAK phosphorylation and turnover. PRB-stimulated migration is reduced by progestins, which is prevented by PR antagonists or agonist-bound PRA., Progesterone receptor (PR) and progestins affect mammary tumorigenesis; however, the relative contributions of PR isoforms A and B (PRA and PRB, respectively) in cancer cell migration remains elusive. By using a bi-inducible MDA-MB-231 breast cancer cell line expressing PRA and/or PRB, we analyzed the effect of conditional PR isoform expression. Surprisingly, unliganded PRB but not PRA strongly enhanced cell migration as compared with PR(–) cells. 17,21-Dimethyl-19-norpregna-4,9-dien-3,20-dione (R5020) progestin limited this effect and was counteracted by the antagonist 11β-(4-dimethyl­amino)­phenyl-17β-hydroxy-17-(1-propynyl)­estra-4,9-dien-3-one (RU486). Of importance, PRA coexpression potentiated PRB-mediated migration, whereas PRA alone was ineffective. PR isoforms differentially regulated expressions of major players of cell migration, such as urokinase plasminogen activator (uPA), its inhibitor plasminogen activator inhibitor type 1, uPA receptor (uPAR), and β1-integrin, which affect focal adhesion kinase (FAK) signaling. Moreover, unliganded PRB but not PRA enhanced FAK Tyr397 phosphorylation and colocalized with activated FAK in cell protrusions. Because PRB, as well as PRA, coimmunoprecipitated with FAK, both isoforms can interact with FAK complexes, depending on their respective nucleocytoplasmic trafficking. In addition, FAK degradation was coupled to R5020-dependent turnovers of PRA and PRB. Such an effect of PRB/PRA expression on FAK signaling might thus affect adhesion/motility, underscoring the implication of PR isoforms in breast cancer invasiveness and metastatic evolution with underlying therapeutic outcomes.

Aim The aims of the present study were: (i) to evaluate the focal incidental colorectal uptake of (18)F-fluorodeoxyglucose ([(18)F]FDG) and to correlate it with colonoscopy and histological findings; (ii) to evaluate the relationship between the presence/absence of neoplastic disease and clinical data and the anatomical site of [(18)F]FDG uptake; and (iii) to compare our results with those reported for incidental colorectal uptake of [(18)F]FDG in the literature and those obtained from various screening programmes for colorectal cancer. Method The database of 6000 patients referred for [(18)F]FDG positron emission tomography/computed tomography (PET-CT) to our centre was retrospectively reviewed for incidental colorectal uptake of [(18)F]FDG. Patients with focal uptake were selected and the aetiology of PET findings was verified with a subsequent colonoscopy and histopathological analysis when available. Results Incidental colorectal uptake of [(18)F]FDG was seen in 144 (2.4%) patients, of whom 64 (1.1%) had focal uptake; 48 out of these 64 patients underwent colonoscopy, which showed malignant tumours in 12 (25%), premalignant lesions in 19 (40%), non-neoplastic lesions in six (12%) and lesions not confirmed by colonoscopy in 11 (23%). Our data agreed with previously published data. Statistical analysis did not show any significant relationship between the presence/absence of neoplastic disease and patient sex or age, type of primary disease and anatomical site of [(18)F]FDG uptake. Comparing our data with various screening programmes, a significant difference was found only with series in which colonoscopy was performed in patients at high risk for colorectal cancer. Conclusion Focal incidental colorectal uptake of [(18)F]FDG is observed in about 1% of PET/CT studies and carries a high risk of neoplastic disease. A PET-CT report should suggest colonoscopy when abnormal findings are reported.

The Sun and the Earth possess dipolar magnetic fields that exhibit polarity reversals. Recent works, based on numerical simulations and laboratory experiments, found similar dynamical behaviours. We present results of a statistical analysis of a numerical simulation based on a generalized two–disk dynamo model. From a first investigation, we found that the dynamics of the system is controlled by the variations of the ratio of the torques and we observed different dynamical regimes characterized either by bursts or reversals, which can be periodic or random, of the magnetic field.

© 2015 Elsevier Ltd. Objective: A double-blind, randomized controlled trial showed that low-dose glucocorticoid therapy in pediatric ARDS patients is feasible and may improve both ventilation and oxygenation indices in these patients. However, the molecular mechanisms underlying potential changes in outcomes remain unclear. Based on these clinical findings, this study was designed to examine the effects of intravenous methylprednisolone on circulating inflammatory biomarkers in pediatric ARDS patients. Design: Double-blind, placebo-controlled randomized trial with blood collection on study entry and day 7. Setting: Tertiary care children's hospital. Patients: Children (0-18. years) with ARDS undergoing mechanical ventilation. Interventions: 35 children were randomized within 72. h of mechanical ventilation. The glucocorticoid group received methylprednisolone 2. mg/kg loading dose followed by 1. mg/kg/day continuous infusion from days 1 to 7. Both groups were ventilated following the ARDSnet recommendations. WBC and differential cell counts, plasma cytokines and CRP levels, and coagulation parameters were analyzed on days 0 and 7. Results: At study entry, the placebo group had higher IL-15 and basophil levels. On day 7, in comparison to study entry, the placebo group had lower IL-1α, IFN-γ and IL-10 levels. The glucocorticoid group had lower INF-α, IL-6, IL-10, MCP-1, G-CSF and GM-CSF levels, and higher IL-17α levels on day 7 in comparison to study entry. Total and differential cell counts remained unchanged within the placebo group between days 0 and 7, whereas in the glucocorticoid group total WBC and platelets counts were increased on day 7. Pearson's correlation studies within the placebo and glucocorticoid groups revealed positive and negative correlations between cytokine levels, cell counts, coagulation parameters and relevant clinical parameters of disease severity identified in our previous study. Multiple regression models identified several cytokines as predictors for alterations in clinical parameters of disease severity. Conclusion: This pilot study shows the feasibility of simultaneously measuring multiple inflammatory cytokines, cell counts and coagulation parameters in pediatric ARDS patients. We report statistical models that may be useful for future, larger trials to predict ARDS severity and outcomes.

IGF system expression has been largely explored in the bovine follicular wall whereas it remains poorly studied in the COC. Using semi-quantitative RT-PCR and Western blot analysis, we have investigated spatial and temporal expression of IGF-1, IGFR-1, IGFBP-2, IGFBP-4, as well as gonadotropin receptors in bovine COC during oocyte maturation. In addition, we have compared changes in the IGF system and FSHR expression during in vitro maturation in TCM199 alone or in the presence of 10 ng/ml of EGF. The transcripts for IGFR-1 and IGFBP-2 were detected in cumulus and germinal cells whereas IGF-1, IGFBP-4 and FSHR mRNA were restricted to cumulus cells. Topography of the IGF system and gonadotropin receptor expression within COC were unaffected by the maturation step. In contrast, levels of IGFBP-2 and FSHR expression decreased (P < 0.05) in matured COC. Under defined culture conditions, IGFBP-2 and FSHR mRNA expression remained at a high level in TCM199 alone and were significantly reduced (P < 0.05) in the presence of 10 ng/ml EGF after a 24 h period of in vitro maturation. In conclusion, our results demonstrate a cell-specific pattern of IGF system member gene expression within bovine COC suggesting interaction between the somatic and germinal compartments. In addition, synchronized changes in the pattern of COC IGFBP-2 and FSHR expression during oocyte maturation suggest possible synergistic actions between IGF-1 and FSH.

99mTc-tetrofosmin seems to show a prolonged thyroid retention when compared with 99m Tc-sestamibi; this may explain its poorer performance in the dual-phase parathyroid scintigraphy. In order to verify objectively whether and to what extent 99m Tc-sestamibi and 99m Tc-tetrofosmin uptake and retention differ in the thyroid gland, we performed a head-to-head comparison between the tracers in 86 euthyroid subjects enrolled in five centres. Data were compared with those of 99m Tc-pertechnetate obtained from the same subjects. For comparison purposes, quantitative data from the salivary glands were also obtained. 99m Tc-sestamibi showed a higher early thyroid uptake (2.26±0.52 vs. 2.01±0.49, respectively; P

Field reversals are the most spectacular events in the geomagnetic history but remain little understood. Here we explore the dipole behaviour in particularly long numerical dynamo simulations to reveal statistically significant conditions required for reversals and excursions to happen. We find that changes in the axial dipole moment behaviour are crucial while the equatorial dipole moment plays a negligible role. For small Rayleigh numbers, the axial dipole always remains strong and stable and obeys a clearly Gaussian probability distribution. Only when the Rayleigh number is increased sufficiently the axial dipole can reverse and its distribution becomes decisively non-Gaussian. Increased likelihoods around zero indicate a pronounced lingering in a new low dipole moment state. Reversals and excursions can only happen when axial dipole fluctuations are large enough to drive the system from the high dipole moment state assumed during stable polarity epochs into the low dipole moment state. Since it is just a matter of chance which polarity is amplified during dipole recovery, reversals and grand excursions, i.e. excursions during which the dipole assumes reverse polarity, are equally likely. While the overall reversal behaviour seems Earth-like, a closer comparison to palaeomagnetic findings suggests that the simulated events last too long and that grand excursions are too rare. For a particularly large Ekman number we find a second but less Earth-like type of reversals where the total field decays and recovers after a certain time.

The spatio-temporal dynamics of the solar magnetic field has been investigated by using NSO/Kitt Peak synoptic magnetic maps covering ~28 yr. For each heliographic latitude the field has been analyzed through the Empirical Mode Decomposition, in order to investigate the time evolution of the various characteristic oscillating frequencies. Preliminary results are discussed.

A new cell line was derived from primary culture of rat choroid plexus (RCP) by immortalization with the TSOri minus adenovirus. The selected clone expressed vasopressin V1a receptors at a density of 64,000 sites per cell, and a K(d) of 7.2 nM. Addition of vasopressin to the RCP cells induced a transient calcium peak comparable to V1a receptor signalling in different expression systems. This [Ca(2+)](i) increase was dose-dependent with an EC(50) of 22 nM vasopressin. Similar [Ca(2+)](i) increase was elicited by addition of serotonin, angiotensin II, endothelin-1, and bradykinin. Heterologous desensitization of V1a receptor was observed in RCP cells exposed to the phorbol ester PMA or following stimulation of other receptors coupled to the phosphoinositide pathway. Positive immunolabelling with Factor VIII, Flt1 and CD 34 antibodies suggests that this new RCP cell line originated from endothelial cells of rat choroid plexus.

Few articles on neuroimaging techniques in the study of central and peripheral olfactory pathways are present in the literature. By Single Photon Emission Computed Tomography (SPECT), cortical perfusion increment after sensorial stimulation can be evaluated objectively. In the present research, 10 healthy adults underwent SPECT by CER.TO.96 cerebral tomograph, before and after olfactory stimulation with lavender-water. A variable degree of cortical activation was detected in all patients. Cyrus rectus (+24.5%), orbito-frontal cortex (right +26.6%, left +25.6%), and superior temporal (right +9.9%, left +5.5%) cortical areas were always activated. A slight perfusion increase was present in middle temporal (right +3.2%, left +2.1%) and parieto-occipital (right +0.4%, left +2%) regions. Five patients affected by posttraumatic anosmia were also investigated: they showed a perfusion increment markedly inferior to 0.5% in every olfactory area. SPECT is a rather diffused, easily performed technique which yields objective semi-quantitative information on brain perfusion. Hence, it can be regarded as a promising contribution in the fields of smell neurophysiology, clinical olfactometry, and medicolegal queries.

Study objectives Scintigraphic prediction of the residual pulmonary function following a lobectomy is not widely employed; its accuracy is poorly known. This study aims at determining the accuracy and the clinical value of the scintigraphic prediction of postlobectomy residual function. Patients and interventions In this study, 41 patients with bronchial carcinoma underwent a perfusion lung scintigraphy before lobectomy; the functional contribution of each single lobe was computed by an indirect method proposed by Wernly et al; the results of the scintigraphic prediction were compared with those of the pulmonary function tests performed 1 month after surgery. Measurements and results The linear regression analyses of predicted and observed values of FVC and FEV 1 showed significant correlations (R 2 =0.607 and 0.749, respectively); however, an evident scatter of data was obtained, as quantified by the values of imprecision (20.70% and 18.11%, respectively) and global inaccuracy (25.50% and 22.90%, respectively). The estimates of both FVC and FEV 1 were significantly better in right lung lobectomies than in left lung lobectomies (mean imprecision and global inaccuracy: 15.43% and 14.94% for the right lung, and 27.27% and 29.00% for the left lung). Conclusions The scintigraphic prediction of postlobectomy residual function is easily implemented by the method herein employed; it has a greater margin of uncertainty than that of pneumonectomy, especially for left lobectomies; however, the use of some safety thresholds for predicted values of FEV 1 (1.2 L for upper lobectomies and 1 L for lower lobectomies) guarantees a safe clinical use of the test.

The aim of this study was to attempt to specify the nature of the signal modifications observed in MRI in the supraspinatus tendon apart from any pathology of the shoulder, and due, according to certain authors, to an artefact associated with MRI. Five macroscopically normal supraspinatus tendons were removed from 4 young subjects (14-28 years), 30 min after cardiac arrest, with the authorization of the ethical committee. These tendons were examined by MRI in the frontal oblique plane along the axis of the muscle with a surface coil of 4 cm diameter, using a T2-weighted spin-echo sequence, and then studied histologically using the same plane of section. 22 control subjects (18-24 years) were examined by MRI with the same T2-weighted spin echo sequence. All the tendons examined possessed a dark signal with zones of intermediate signal on the first echo of the sequence. There was a complete correlation between the MRI appearances of the 5 tendons and their histologic description. Three histologic appearances were described : fibrillary degeneration, fibrous dystrophy, and eosinophil transformation of the tendinous collagen. All the tendons examined in healthy volunteers exhibited heterogenic images at the first echo, in the second echo the hyposignal was uniform and obvious. The good correlation obtained suggests that modifications of the tendon signal from the supraspinatus m. are not related to an artefact described in MRI, but are linked with premature degeneration of this tendon, probably associated with the severity of the mechanical constraints to which it is subject.

The entire prostate of a 10 year old boy was cut with a microtome in to 4300 serial slices. The nerves were stained using a monoclonal antibody called anti PS 100. All information was recorded using a computer reconstruction programme. The prostatic nerve supply is very abundant. The nerve fibers of the cranial prostate (central zone) follow a pathway parallel to the anterior surface of the seminal vesicles going towards the caudal prostate. The periurethral zone is widely innervated by nerves arising from the periphery. The caudal prostate also contains many nerve fibers of variable size. We identified many nerve fibers along the anterior surface of the seminal vesicles and surrounding the lateral aspect of the prostatic capsule. They penetrate the capsule and the whole circumference of the caudal prostate. The prostatic capsule is covered by numerous nerve fibers and ganglia, which form a true periprostatic nerve network. The urethra is supplied by numerous thick fibers of more than 30 microns in diameter.

BACKGROUND: We previously demonstrated in a small pilot study that oral medroxyprogesterone acetate and percutaneous testosterone (OMP/PT) induce reversible spermatogenesis suppression. The aims of this study were to determine the rate of spermatogenetic inhibition and recovery and to obtain preliminary data on efficacy for a larger population under OMP/PT. METHODS: A total of 35 healthy men with normal spermiograms requesting male hormonal contraception were treated with OMP (20 mg/day) and PT (50-125 mg/day) for periods up to 18 months. Couples were included in a contraceptive efficacy phase after a value of

The impact of early exposure to endocrine disruptor mixtures on mammary gland development is poorly known. Here, we identify the effects of a conception to weaning exposure of rats to the phytoestrogen genistein (G) and/or the antiandrogen vinclozolin (V) at 1 mg/kg-d, alone or in association. Using several approaches, we found that G- and GV-exposed rats displayed significantly greater epithelial branching and proliferation, wider terminal end buds than controls at PND35, as well as ductal hyperplasia and periductal fibrosis. Focal branching defects were present in V-exposed rats. An increased ER and AR expression was observed in G- and CV- as compared to V-exposed rats at PND35. Surprisingly, a significant number of CV- and to a lesser extent. V-exposed animals displayed abnormal hyperplasic alveolar structures at PND50. Thus, gestational and lactational exposure to low doses of genistein plus vinclozolin may seriously affect peripubertal development of the rat mammary gland.

International audience; Aldosterone effects are mediated by the mineralocorticoid receptor (MR), a transcription factor highly expressed in the distal nephron. Given that MR expression level constitutes a key element controlling hormone responsiveness, there is much interest in elucidating the molecular mechanisms governing MR expression. To investigate whether hyper- or hypotonicity could affect MR abundance, we established by targeted oncogenesis a novel immortalized cortical collecting duct (CCD) cell line and examined the impact of osmotic stress on MR expression. KC3AC1 cells form domes, exhibit a high transepithelial resistance, express 11beta-hydroxysteroid dehydrogenase 2 and functional endogenous MR, which mediates aldosterone-stimulated Na(+) reabsorption through the epithelial sodium channel activation. MR expression is tightly regulated by osmotic stress. Hypertonic conditions induce expression of tonicity-responsive enhancer binding protein, an osmoregulatory transcription factor capable of binding tonicity-responsive enhancer response elements located in MR regulatory sequences. Surprisingly, hypertonicity leads to a severe reduction in MR transcript and protein levels. This is accompanied by a concomitant tonicity-induced expression of Tis11b, a mRNA-destabilizing protein that, by binding to the AU-rich sequences of the 3'-untranslated region of MR mRNA, may favor hypertonicity-dependent degradation of labile MR transcripts. In sharp contrast, hypotonicity causes a strong increase in MR transcript and protein levels. Collectively, we demonstrate for the first time that optimal adaptation of CCD cells to changes in extracellular fluid composition is accompanied by drastic modification in MR abundance via transcriptional and posttranscriptional mechanisms. Osmotic stress-regulated MR expression may represent an important molecular determinant for cell-specific MR action, most notably in renal failure, hypertension, or mineralocorticoid resistance.

We have observed typical cytomegalovirus cytopathology associated with multifocal inflammatory and necrotic lesions of peripheral nerve in biopsy specimens from 4 patients who developed a rapidly progressive, multifocal neuropathy late in the course of human immunodeficiency virus infection. The inflammatory infiltrates, which contained numerous polymorphonuclear cells, were associated with mixed, axonal, and demyelinative lesions of nerve fibers. One of these patients improved on treatment with DHPG (9-[2-hydroxy-l(hydroxymethyl) ethoxymethyl] guanine) and remains stable after 18 months. The other 3 died soon after the onset of the neuropathy. In another patient with acquired immunodeficiency syndrome, who developed a severe, predominantly motor neuropathy of the lower limbs, the nerve biopsy did not reveal cytomegalovirus inclusions, but the neurological deficit improved on treatment with DHPG. The patient died from cachexia 2 months later; numerous cytomegalovirus lesions were found in the spinal cord at the time of postmortem examination. The multifocal necrotic endoneurial nerve lesions with polymorphonuclear cell infiltration we describe may help identify cytomegalovirus neuropathy when characteristic inclusions are not present in the biopsy specimen.

The induction of vascular endothelial growth factor (VEGF) expression by 17β-estradiol (E2) in many target cells, including epithelial cells, fibroblasts and smooth muscle cells, suggests a role for this hormone in the modulation of angiogenesis and vascular permeability. We have already described a cyclic increase in Flk-1/KDR-expressing capillaries in the human endometrium during the proliferative and mid-secretory phases, strongly suggestive of an E2 effect on Flk-1/KDR expression in the endometrial capillaries. However, it is unclear whether these processes are due to a direct effect of E2 on endothelial cells. Using immunohistochemistry, we report an increase in Flk-1/KDR expression in endometrial capillaries of ovariectomized mice treated with E2, or both E2 and progesterone. This process is mediated through estrogen receptor (ER) activation. In vitro experiments using quantitative RT-PCR analysis demonstrate that Flk-1/KDR expression was not regulated by E2 in human endothelial cells from the microcirculation (HMEC-1) or macrocirculation (HUVEC), even in endothelial cells overexpressing ERα or ERβ after ER-mediated adenovirus infection. In contrast, Flk-1/KDR expression was up-regulated by VEGF itself, in a time- and dose-dependent manner, with the maximal response at 10 ng/ml. Thus, we suggest that E2 up-regulates Flk-1/KDR expression in vivo in endothelial cells mainly through the modulation of VEGF by a paracrine mechanism. It is currently unknown whether or not the endothelial origin might account for differences in the E2-modulation of VEGF receptor expression, particularly in relation to the vascular bed of sex steroid-responsive tissues.

A 35-year-old woman who had hyperparathyroidism (increased serum levels of calcium and parathormone) and normal neck US scan, underwent standard Tl-201/ Tc-99m pertechnetate parathyroid scintigraphy with the addition of early and delayed imaging with Tc-99m tetrofosmin. A rounded area of increased uptake of Tl-201 and Tc-99m tetrofosmin, located in the upper left mediastinum, was detectable on raw and Tc-99m subtracted images, which represented an ectopic parathyroid adenoma that was surgically removed and histologically confirmed as an intrathymic parathyroid adenoma. Adenoma detectability was much better with Tc-99m tetrofosmin than with Tl-201 as shown by the higher tumor to background ratio. Such favorable imaging characteristics suggest that Tc-99m tetrofosmin may have the potential to act as a suitable agent for parathyroid scintigraphy.

The presence of thrombi on a permanent pacemaker lead is a rare complication of pacing. The reported cases relate to axillary subclavian vein thrombosis or the onset of thrombi at different sites on the permanent pacemaker lead [1–3]. Clinically, thromboembolic complications related to permanent cardiac pacing may affect the upper arm, axillary, subclavian or jugular veins, right atrium, and pulmonary circulation [4,5].

Atrial fibrillation (AF) is a common arrhythmia: its incidence increases markedly with age and it is frequently associated with heart failure (HF) [1]. In patients with HF the incidence of AF is estimated at between 20% and 40%.HF gives rise to electrophysiologic and hemodynamic changes in atrial tissue that favor the onset and maintenance of atrial fibrillation: sympathetic tone, increased pressure, wall-stretching, and mitral regurgitation. On the other hand, the onset of AF in patients with HF often leads to a marked worsening of the clinical condition of these patients: loss of atrial systole, high and irregular ventricular rate, mitral regurgitation, low coronary and cerebral flow, and so on.

OBJECTIVE: To compare noninvasive positive pressure ventilation (NPPV) vs. invasive mechanical ventilation in AIDS patients with Pneumocystis carinii pneumonia (PCP)-related acute respiratory failure (ARF). DESIGN: A single-center, prospective, case-control trial. SETTING: An ICU of a private tertiary hospital specialized in infectious disease. PATIENTS: Forty-eight AIDS patients with severe PCP-related ARF needing mechanical ventilation. INTERVENTIONS: Twenty-four patients treated with NPPV by a facial mask strictly matched with 24 patients treated with invasive ventilation by endotracheal intubation. RESULTS: Use of NPPV avoided intubation in 67% of patients, and avoidance of intubation was associated with improved survival (100% vs. 38%; P=0.003). NPPV-treated patients required fewer invasive devices ( P

The recent discovery of a new isoform of estrogen receptor (ER) beta has prompted the reexamination of estrogen action on target organs. Here, we describe the endometrial expression of human ERbeta and compare its distribution with that of ERalpha in the endometrial functional zone. Using immunocytochemistry with well characterized polyclonal antibodies against ERbeta, we have detected specific ERbeta expression in all endometrial compartments (glandular, stromal, and vascular); the specificity of the immunostaining is confirmed by lack of staining of the uterine sections with anti-ERbeta antibodies previously incubated with peptide preparation. The highest levels of ERbeta expression are observed in epithelial cells during the periovulatory period (days 14 and 15), as well as in stromal cells and cells of the vascular wall in the late-secretory phase; both smooth muscle cells and endothelial cells express ERbeta, as deduced from immunocytochemistry and RT-PCR analysis. ERbeta staining is usually low compared with that of ERalpha, except at days 24-26. The presence of ERbeta in decidualized stromal cells is deduced from immunocytochemistry using antismooth alpha-actin and anti-ERbeta antibodies or from RT-PCR analysis of ERbeta and insulin-like growth factor-BP transcripts in the same cells; the presence of ERbeta-positive stromal cells located close to vascular smooth muscle cells during this period suggests some specific role of this receptor during decidualization. ERalpha is also present in the cells of the endometrial vascular wall, in addition to the nuclei of glandular epithelial and stromal cells. Vascular ERalpha expression is highest during the periovulatory period, suggesting a regulation by estradiol, and a role in vascular function. Moreover, different variations of ERbeta and ERalpha in arterioles might have implications for the modulation of vascular function, possibly of vascular tone, during the menstrual cycle. Finally, these data suggest that ERbeta may have important roles in endometrial function, in addition to the well known role of ERalpha in endometrial proliferation and differentiation.

The regulation of the thyroid gland by TSH is mediated by a heterotrimeric G protein-coupled receptor. Nonthyroid effects of TSH have been reported, and expression of its receptor has been described in adipocytes and lymphocytes. We have previously reported the existence of specific and saturable binding sites of TSH and specific TSH effects in primary cultured rat brain astroglial cells. We now report expression of the TSH receptor gene in these cells; the coding sequence of the corresponding complementary DNA is identical to that previously established in thyroid. Using specific antisense RNA probe, expression of this gene was detected in some isolated or clustered glial fibrillary acidic protein-positive primary cultured cells by in situ hybridization. With this technique, we further detected TSH receptor messenger RNA (mRNA) expression in rat brain cryoslices in both neuronal cells and astrocytes. Its presence predominated in neuron-rich areas (pyriform and postcingulate cortex, hippocampus, and hypothalamic nuclei) and was mostly colocalized with neuron-specific enolase. In astrocytes, this mRNA was detected in the ependymal cell layer and the subependymal zone, and several isolated cells were also found in the brain parenchyma. We also detected TSH receptor mRNA and protein in primary cultured human astrocytes. The protein was detected as well in both rat and human brain cryoslices. Together, these findings clearly demonstrate the expression of the TSH receptor gene in the brain in both neuronal cells and astrocytes.

Angiogenesis is fundamental for human endometrial development and differentiation necessary for implantation. These vascular changes are thought to be mediated by the vascular endothelial growth factor (VEGF), whose specific receptors have not been examined in detail thus far. We conducted the present study to determine, by immunocytochemistry and computerized image analysis of the functionalis, the expression and modulation of the receptors Flk-1/KDR and Flt-1, which mediate VEGF effects on endothelial mitogenicity, chemotaxis, and capillary permeability. VEGF receptors are expressed mainly in endometrial endothelial cells, with variations of intensity and number of stained capillaries related to the phase of the cycle. The number of capillaries immunostained for Flk-1/KDR was maximal in the proliferative phase (ratio Flk-1/CD34: 1), twice as high as the number of Flt-1-expressing capillaries (ratio Flt-1/CD34: 0.47). The staining intensity for Flk-1 decreased during the late proliferative and early secretory phases, to increase again in the midsecretory period. The number of Flt-1-labeled capillaries was about 2-fold higher in the secretory than in the proliferative phase; however, the proportion of Flt-1-positive cells did not change, owing to the associated increase in vascular density that characterizes progression of the functionalis from the proliferative to the secretory stage. The staining intensity for Flt-1 was higher during the late proliferative and secretory phases (especially in the midsecretory phase) and the premenstrual period. In contrast, the proportion of capillaries expressing Flk-1/KDR decreased in the secretory phase (ratio Flk-1/Von Willebrand factor: 0.55). Enhanced expression of Flk-1/KDR, and of Flt-1, on narrow capillary strands at the beginning of and during the proliferative phase may account for the rapid capillary growth associated with endometrial regeneration following menstrual shedding. The high coexpression of Flk-1/KDR and Flt-1 observed on capillaries during the midsecretory period correlates with an increase of endometrial microvascular density and of permeability characteristic of this phase of the cycle, which is a prerequisite for implantation. Finally, strong expression of Flt-1, but not Flk-1/KDR, was observed on dilated capillaries during the premenstrual period and the late proliferative phase, suggesting preferential association of Flt-1 with nonproliferating capillaries at those times; activation of this receptor by VEGF could be involved in premenstrual vascular hyperpermeability, edema, and extravasation of leukocytes. In addition to the endothelial localization, we found that epithelial cells expressed Flt-1 and Flk-1/KDR. We conclude that Flt-1 and Flk-1/KDR in the functionalis are modulated in parallel or independently according to the phase of the cycle, and that these changes are responsible for VEGF actions on endometrial vascular growth and permeability. The molecular mechanisms concerning these regulations will require further investigation.

Portal hypertensive gastropathy (PHG) is frequently found among patients with hepatic cirrhosis and at present the only way to detect and follow PHG is via endoscopy.To assess gastric and intestinal permeability and investigate its relationship to endoscopic findings and indices of portal hypertension and hepatic function.Thirty-one non-diabetic patients with hepatic cirrhosis and PHG (PHG+) were studied and compared with 17 cirrhotic patients without PHG (PHG-). All patients underwent endoscopy for the assessment of PHG and Helicobacter pylori status, ultrasound determination of the diameters of spleen and portal vein, and, subsequently, an oral load of sucrose, lactulose, and mannitol. Sugar concentrations were determined in 6-h urine specimens and expressed as a percentage of the orally administered dose or as lactulose/mannitol ratio.The urinary sucrose excretion was significantly elevated in patients with PHG compared to those without (PHG+, 0.20% +/- 0.03; PHG-, 0.07% +/- 0.01; P0.001). No difference was found for the small intestinal probes lactulose and mannitol. Gastric sucrose permeability correlated positively with the endoscopic lesion score (P0.001), but not with other parameters of portal hypertension or hepatic function. H. pylori status did not influence gastric permeability. The sensitivity of this test reached 100% for PHG scores2.Gastric permeability to sucrose is increased in patients with PHG, independently of the presence of H. pylori. Sucrose permeability may be useful for the follow-up of patients with PHG.

Matrix metalloproteinases (MMPs) are zinc-requiring enzymes that can degrade components of the extracellular matrix and that are implicated in tissue remodeling. Their role in the onset of menstruation in vivo has been proven; however, the expression and functions of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in vascular structures are poorly understood. We determined by immunocytochemistry, using characterized monoclonal antibodies, the distribution of MMPs and of their inhibitors TIMP-1 and TIMP-2 in the endometrium during the menstrual cycle. MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 had differing distributions and patterns of expression. In addition to the localization of MMP-9 in the epithelium and of MMP-2, MMP-3, and MMP-1 in the stromal tissue, these MMPs were detected in the vascular structures. MMP-2 (72-kDa gelatinase) and tissue inhibitors TIMP-1 and TIMP-2 were detectable in vessels throughout the cycle. In contrast, MMP-3 (stromelysin-1) was detected only in late-secretory and menstrual endometrial vessels, while MMP-9 (92-kDa gelatinase) was detected in spiral arteries during the secretory phase and in vascular structures during the midfollicular and menstrual phases. The expression of MMP-2 and MMP-9 in endometrial vessels during the proliferative and secretory periods suggests their relationship to vascular growth and angiogenesis. The pronounced expression of MMP-3 (stromelysin-1) in the vessels situated in the superficial endometrial layer during menses suggests that this metalloproteinase initiates damage in the vascular wall during menstrual breakdown. The finding of an intense expression of TIMP-1 and TIMP-2 in the vessels delineating necrotic from non-necrotic areas during menses also suggests that they could limit tissue damage, allowing regeneration of the endometrium after menses. These data indicate that, in addition to expression in epithelial cells and stromal tissue, MMPs are expressed in endometrial vascular cells in a cycle-specific pattern, consistent with regulation by steroid hormones and with specific roles in the vascular remodeling processes occurring in the endometrium during the cycle.

The aim of the study was to quantitatively compare the scintigraphic images of the thyroid and abnormal parathyroid glands obtained with technetium-99m tetrofosmin and thallium-201 in patients with hyperparathyroidism. Forty-six patients with hyperparathyroidism underwent (201)Tl (74 MBq), (99m)Tc-pertechnetate (74 MBq) and (99m)Tc-tetrofosmin (555-740 MBq) scintigraphy in a single session. Image analysis included the computation of the thyroid/background ratio in the whole study population and the parathyroid/background ratio, parathyroid/thyroid ratio and diagnostic sensitivity in 17 patients who underwent parathyroid surgery. The pertechnetate subtraction technique was used. (201)Tl and (99m)Tc-tetrofosmin showed a similar thyroid/background ratio (1.79+/-0.41 and 1.81+/-0. 47, respectively, P=NS); however, (99m)Tc-tetrofosmin showed a higher parathyroid/background ratio than (201)Tl (2.06+/-0.54 vs 1. 79+/- 0.50, P=0.007). Despite the superior quality of (99m)Tc-tetrofosmin images, both tracers showed identical sensitivity in detecting enlarged parathyroid glands in patients with primary hyperparathyroidism (89%) and in those with secondary hyperparathyroidism (50%).

This experiment was conducted to determine why follicles luteinize faster in the Meishan breed than in the Large White breed of pig. Follicles were recovered during the late follicular phase from ovaries of both breeds before and after administration of hCG given to mimic the LH surge. First, the patterns of cholesterol transporters (high and low density lipoproteins: HDL and LDL) were compared. Cholesterol transporters detected in follicular fluid consisted of HDL only. Similar amounts of Apolipoprotein A-I were found in all samples. There was no obvious breed effect on minor lipoproteins found in the HDL-rich fraction, and this pattern was altered similarly by hCG in the two breeds. The LDL-rich samples of serum from both breeds contained similar amounts of protein. Second, three steroidogenic enzymes, adrenodoxin, 17 alpha-hydroxylase-lyase (P450(17) alpha) and 3 beta-hydroxysteroid-dehydrogenase (3 beta-HSD) were detected by immunohistochemistry and quantified by image analysis on sections of the two largest follicles. Before hCG treatment, theca interna cells demonstrated immunoreactivities for adrenodoxin (strong), P450(17) alpha and 3 beta-HSD (very strong), whereas granulosa cells displayed immunoreactivities for adrenodoxin only. After hCG treatment, the localization of the enzymes was unchanged but the staining intensity of adrenodoxin on granulosa cells and 3 beta-HSD on theca cells increased (P0.01 and P0.05, respectively). Breed effects were detected for the amounts of adrenodoxin in theca cells (MeishanLarge White; P0.05) and of 17 alpha-hydroxylase (Large WhiteMeishan, P0.01). Breed x treatment interactions were never detected. Finally, gelatinases, plasminogen activator, plasminogen activator inhibitor, tissue inhibitors of metalloproteases (TIMP-1 and TIMP-2) were visualized by direct or reverse zymography or western blotting. Whatever the stage relative to LH administration, follicular fluid from Large White gilts contained more TIMP-1, and TIMP-2 (P0.02 and P0.01, respectively). No breed effect was detected for the amounts of gelatinases and plasminogen activator inhibitor 1. However, for these parameters, a significant breed x time interaction was obvious, as the Meishan follicles had a greater response to hCG (P0.01). Since proteolysis plays a key role in the bioavailability of growth factors such as insulin-like growth factor 1, fibroblast growth factor and transforming growth factor beta, which have the ability to alter gonadotrophin-induced progesterone production in pigs, the differences observed in its control in the present study may explain, at least in part, the different patterns of luteinization observed in Meishan and Large White follicles.

Background Previous studies have suggested that an abnormal cardiac adrenergic tone may have a pathophysiological role in syndrome X (effort angina, positive exercise testing, angiographically normal coronary arteries). Methods and Results To evaluate cardiac adrenergic nerve function, we performed [ 123 I]metaiodobenzylguanidine (MIBG) myocardial scintigraphy in 12 patients with syndrome X and 10 control subjects. Cardiac MIBG uptake was assessed by the heart/mediastinum (H/M) ratio and by an MIBG uptake defect score (higher values=lower uptake). In syndrome X patients, we also correlated MIBG scintigraphic findings with stress myocardial perfusion as assessed by 201 Tl scintigraphy. An inferior MIBG defect was observed in only 1 control subject, whereas 9 patients ( P P =.03) and MIBG uptake defect score higher (35±31 versus 4±2, P =.003) in syndrome X patients. Reversible stress thallium perfusion defects were found in 62% of patients with MIBG defects but in no patient with normal MIBG uptake. MIBG defects persisted unchanged in 7 patients at a 5±3-month follow-up study. Conclusions In this study, obvious defects in global and/or regional cardiac MIBG uptake, indicating an abnormal cardiac adrenergic nerve function, were detected in 75% of patients with syndrome X. These findings strongly support the cardiac origin of chest pain in syndrome X, although the mechanisms and the pathophysiological meaning of the abnormal cardiac MIBG uptake in these patients deserve further investigation.

We report the case of an infant who presented at birth with a hypoplastic phallus associated with hypospadias. Low testosterone production, normal serum levels of steroid precursors, and increased LH in response to LH-releasing hormone supported a defect in Leydig cell differentiation or function. Conventional microscopic study of the testes showed fibroblastic cells in the interstitium. However immunocytochemical analysis using anti-LH receptor and anti-P450c17 antibodies demonstrated that about one third of these cells were Leydig cells or precursors of Leydig cells. No histological feature could distinguish the latter cells from fibroblasts. A homozygous substitution of cysteine 133 for arginine was found in the extracellular domain of the receptor. This is the first naturally occurring missense mutation found in the extracellular domain of the LH receptor. COS-7 cells transfected with the mutant receptor exhibited a marked impairment of hCG binding, whereas some cAMP production could be observed at high hCG concentrations. We propose that the partial impairment of LH receptor function, as reflected by the presence of Leydig cells, was responsible for the incomplete male pseudohermaphroditism observed in our patient.

Recent studies have suggested that human choriogonadotropin (hCG), in addition to its function in regulating steroidogenesis, may also play a role as a growth factor. Immunocytochemistry using two different monoclonal antibodies (LHR29 and LHR1055) raised against the human luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor allowed us to detect this receptor in breast cancer cell lines (T47D, MCF7, and ZR75) in individual cancer biopsies and in benign breast lesions. The receptor was also present in epithelial cells of normal human and sow breast. In the latter, its concentration increased after ovulation. The presence of LH/hCG receptor mRNA was confirmed by reverse transcription-PCR using primers extending over exons 2-4, 5-11, and 9-11. The proportion of LH/hCG-receptor positive cells and the intensity of the immunolabeling varied in individual biopsies, but there was no obvious correlation with the histological type of the cancer. These results are compatible with previous studies suggesting that during pregnancy, hCG is involved in the differentiation of breast glandular epithelium and that this hormone may play an inhibitory role in mammary carcinogenesis and in the growth of breast tumors.

The aim of the present work was to evaluate whether oro-pharyngeal-esophageal scintigraphy could be used in the dynamic study of the various phases of deglutition and to determine whether it could be applied in otorhinolaryngological practice along with videofluoroscopy and videoendoscopy. The patients were divided into four different groups according to clinical features and the scintigraphic data were analyzed on this basis. Emphasis is placed on the ease of this technique, its tolerability and the low level of radiation. It is pointed out that scintigraphy is quite useful in determinating the exact percentage of the bolus inhaled into the trachealbronchial branch and in measuring the transit time of the various phases of deglutition in detail. In patients affected by upper airway-digestive tract neoplasms it is, therefore, possible to make a semiquantitative evaluation of the results of surgery. Moreover, with this method the results of any rehabilitation can be measured as well as the onset of compensation mechanisms.