Fatal pulmonary embolism in hospitalized patients. Clinical diagnosis versus pathological confirmation

OBJECTIVE - To assess the incidence of fatal pulmonary embolism (FPE), the accuracy of clinical diagnosis, and the profile of patients who suffered an FPE in a tertiary University Hospital. METHODS - Analysis of the records of 3,890 autopsies performed at the Department of General Pathology from January 1980 to December 1990. RESULTS - Among the 3,980 autopsies, 109 were cases of clinically suspected FPE; of these, 28 cases of FPE were confirmed. FPE accounted for 114 deaths, with clinical suspicion in 28 cases. The incidence of FPE was 2.86%. No difference in sex distribution was noted. Patients in the 6th decade of life were most affected. The following conditions were more commonly related to FPE: neoplasias (20%) and heart failure (18.5%). The conditions most commonly misdiagnosed as FPE were pulmonary edema (16%), pneumonia (15%) and myocardial infarction (10%). The clinical diagnosis of FPE showed a sensitivity of 25.6%, a specificity of 97.9%, and an accuracy of 95.6%. CONCLUSION - The diagnosis of pulmonary embolism made on clinical grounds still has considerable limitations.

Clinical and pathological assessment of 82 patients with cardiovascular diseases undergoing autopsy at the Hospital das Clínicas of the Faculdade de Medicina de Botucatu from 1988 to 1993

OBJECTIVE: To evaluated the clinical diagnostic, efficiency for basic death causes in patients dying of circulatory disease and de relative frequency of those diseases. METHODS: Analysis of medical record data of 82 patients, ages from 16 to 84 years old (68 over 40 years old), whose died of circulatory disease and had undergone necropsy in the period from 1988 to 1993 years in the University Hospital of Medicine Faculty of Botucatu-UNESP, Br. RESULTS: The functional class of patients were III or IV, in 78%, and 81.7% needed urgent hospitalization. By the clinical judgment the death were by ischemic heart disease in 32 (21 acute myocardial infarction), Chagas'disease in 12, valvopathy in 11, cardiomyopathy in 7, heart failure with no specification of cardiopathy in 11 and other causes in 9. At the necropsy the death cause was ischemic heart disease in 34 patients, valvopathy in 10, Chagas'disease in 10, cardiomyopathy in 5, and heart failure with no specification of cardiopathy in 2.The concordance taxes were in thhe same order: 94,6%, 90,0%, 83.3%, 71.4% and 28.5%. CONCLUSION: There was a great efficiency of clinical diagnosis for death cause in a general university hospital. The ischemic heart disease were the main causes of death.

Analysis of the Prevalence of Ventricular Late Potentials in the Late Phase of Myocardial Infarction Based on the Site of Infarction

OBJECTIVE: The initial site of myocardial infarction (MI) may influence the prevalence of ventricular late potentials (VLP), high-frequency signals, due to the time course of ventricular activation. The prevalence of VLP in a period of more than 2 years after acute MI was assessed focusing on the initially injured wall . METHODS: The prevalence of VLP in a late phase after MI (median of 924 days) in anterior/antero-septal and inferior/infero-dorsal wall lesion was analyzed using signal-averaged electrocardiogram in time domain. The diagnostic performance of the filters employed for analysis on was tested at high-pass cut-off frequencies of 25 Hz, 40 Hz and 80 Hz. RESULTS: The duration of the ventricular activation and its terminal portion were larger in inferior than anterior infarction, at high-pass cut-off frequencies of 40 Hz and 80 Hz. In patients with ventricular tachycardia, these differences were more remarked. The prevalence of ventricular late potentials was three times greater in inferior than anterior infarction. CONCLUSION: Late after myocardial infarction, the prevalence and the duration of ventricular late potentials are greater in lesions of inferior/infero-dorsal than anterior/antero-septal wall confirming their temporal process, reflecting their high-frequency content.

Interacciones inmuno-endócrinas: participación de tlr-4 y citoquinas pro-inflamatorias en la regulación de la proliferación de células lactotropas. Immuno-endocrine interactions: Contribution of tlr-4 and pro-inflammatory cytokines in the regulation of lactotroph cell proliferation.

El presente proyecto tiene como objetivo estudiar, a nivel celular y molecular, los mecanismos inmuno-endócrinos que participan en la proliferación de células lactotropas normales y tumorales frente a procesos inflamatorios inducidos experimentalmente. Una particular atención se pondrá al evaluar la contribución de IL-6 como citoquina intrahipofisaria durante el desarrollo tumoral y su rol como señal paracrina/autocrina en la senescencia hipofisaria. Debido a que agentes inflamatorios y anti-inflamatorios pueden inducir alteraciones en el crecimiento y la función hipofisaria, no se descartaría que, en el curso de una inflamación, como la inducida por el lipopolisacárido bacteriano LPS, puedan ocurrir modificaciones en el índice proliferativo de las células lactotropas y/o en la secreción de su producto hormonal, la prolactina. Dado el auge en las investigaciones referidas al campo de la modulación inmuno-endócrina, es que planteamos investigar la participación de TLR4, componente crucial del complejo proteico que inicia la señal LPS, en hipófisis normales y tumorales inducidas por estrógeno así como también en la línea celular somatolactotrópica GH3B6. Dentro de las vías de transducción de señales involucradas se determinará la participación de MAPK-ERK1/2 y de PI3K asi como la contribución de NF-kB en la regulación del crecimiento celular inducido por IL-6/LPS mediante el uso de inhibidores específicos. La microscopía electrónica y confocal, resultarán de fundamental importancia para valorar los procesos de translocación nuclear de NF-kB como así también para definir la localización ultraestructural de los mediadores mencionados. Además, se valorará el mecanismo de senescencia celular hipofisaria mediante parámetros morfológicos, bioquímicos y ultraestructurales durante el desarrollo de prolactinomas inducidos experimentalmente. Finalmente dilucidar las posibles vías de transducción de señales que se desencadenan frente a estímulos inflamatorios/proliferativos podría explicar algunos aspectos moleculares sobre la función de control del ciclo celular y las limitaciones de crecimiento en adenomas hipofisarios que subyacen en la falta de progresión de estos tumores a la malignidad. The aim of the present project is to study the immuno-endocrine mechanisms involved in the proliferation of normal and tumoral lactotrophs experimentally induced by inflammatory factors. Also, the contribution of IL-6 as a paracrine / autocrine signal in the pituitary senescence will be assessed along tumor development induced by estrogen treatment. Considering that both, inflammatory and anti-inflammatory agents can modify the pituitary function, it is possible that in the course of inflammation, as induced by bacterial lipopolysaccharide LPS, some alteration may occur in the proliferative index of lactotrophs and / or in the PRL secretion. Our main objective is to investigate the cellular and molecular mechanisms involved by the activation of TLR4, a crucial component of the protein complex initiated by LPS, in normal and pathological pituitaries induced by estrogen as well as in the GH3B6 cell line. The participation of MAPK-ERK1 / 2 and PI3K signaling pathway and the contribution of NF-kB in the proliferative responses triggered by IL-6/LPS will be analyzed by using specific inhibitors. Confocal microscopy analysis is essential to assess the process of nuclear translocation of NF-kB as well as the use of electron microscopy to define the ultrastructural localization of the above mentioned mediators. In addition, the mechanisms of pituitary cell senescence will be evaluated through morphological, biochemical and ultrastructural approaches during the development of experimental prolactinomas. Finally, the elucidation of possible signal transduction pathways which are triggered by inflammatory / proliferative stimuli, would explain some molecular aspects of cell cycle control and limitations in pituitary tumor growth that underlie the lack of progress in these pituitary tumors to malignancy.

Acoustic emission analysis of the effect of a 2D wedge shaped blade on the compact bone cutting process

Surgeons may use a number of cutting instruments such as osteotomes and chisels to cut bone during an operative procedure. The initial loading of cortical bone during the cutting process results in the formation of microcracks in the vicinity of the cutting zone with main crack propagation to failure occuring with continued loading. When a material cracks, energy is emitted in the form of Acoustic Emission (AE) signals that spread in all directions, therefore, AE transducers can be used to monitor the occurrence and development of microcracking and crack propagation in cortical bone. In this research, number of AE signals (hits) and related parameters including amplitude, duration and absolute energy (abs-energy) were recorded during the indentation cutting process by a wedge blade on cortical bone specimens. The cutting force was also measured to correlate between load-displacement curves and the output from the AE sensor. The results from experiments show AE signals increase substantially during the loading just prior to fracture between 90% and 100% of maximum fracture load. Furthermore, an amplitude threshold value of 64dB (with approximate abs-energy of 1500 aJ) was established to saparate AE signals associated with microcracking (41 – 64dB) from fracture related signals (65 – 98dB). The results also demonstrated that the complete fracture event which had the highest duration value can be distinguished from other growing macrocracks which did not lead to catastrophic fracture. It was observed that the main crack initiation may be detected by capturing a high amplitude signal at a mean load value of 87% of maximum load and unsteady crack propagation may occur just prior to final fracture event at a mean load value of 96% of maximum load. The author concludes that the AE method is useful in understanding the crack initiation and fracture during the indentation cutting process.

Ultra high performance supercritical fluid chromatography coupled with tandem mass spectrometry for screening of doping agents. II: Analysis of biological samples.

The potential and applicability of UHPSFC-MS/MS for anti-doping screening in urine samples were tested for the first time. For this purpose, a group of 110 doping agents with diverse physicochemical properties was analyzed using two separation techniques, namely UHPLC-MS/MS and UHPSFC-MS/MS in both ESI+ and ESI- modes. The two approaches were compared in terms of selectivity, sensitivity, linearity and matrix effects. As expected, very diverse retentions and selectivities were obtained in UHPLC and UHPSFC, proving a good complementarity of these analytical strategies. In both conditions, acceptable peak shapes and MS detection capabilities were obtained within 7min analysis time, enabling the application of these two methods for screening purposes. Method sensitivity was found comparable for 46% of tested compounds, while higher sensitivity was observed for 21% of tested compounds in UHPLC-MS/MS and for 32% in UHPSFC-MS/MS. The latter demonstrated a lower susceptibility to matrix effects, which were mostly observed as signal suppression. In the case of UHPLC-MS/MS, more serious matrix effects were observed, leading typically to signal enhancement and the matrix effect was also concentration dependent, i.e., more significant matrix effects occurred at the lowest concentrations.

Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis.

RATIONALE: Lung injury leads to pulmonary inflammation and fibrosis through myeloid differentiation primary response gene 88 (MyD88) and the IL-1 receptor 1 (IL-1R1) signaling pathway. The molecular mechanisms by which lung injury triggers IL-1beta production, inflammation, and fibrosis remain poorly understood. OBJECTIVES: To determine if lung injury depends on the NALP3 inflammasome and if bleomycin (BLM)-induced lung injury triggers local production of uric acid, thereby activating the NALP3 inflammasome in the lung. Methods: Inflammation upon BLM administration was evaluated in vivo in inflammasome-deficient mice. Pulmonary uric acid accumulation, inflammation, and fibrosis were analyzed in mice treated with the inhibitor of uric acid synthesis or with uricase, which degrades uric acid. MEASUREMENTS AND MAIN RESULTS: Lung injury depends on the NALP3 inflammasome, which is triggered by uric acid locally produced in the lung upon BLM-induced DNA damage and degradation. Reduction of uric acid levels using the inhibitor of uric acid synthesis allopurinol or uricase leads to a decrease in BLM-induced IL-1beta production, lung inflammation, repair, and fibrosis. Local administration of exogenous uric acid crystals recapitulates lung inflammation and repair, which depend on the NALP3 inflammasome, MyD88, and IL-1R1 pathways and Toll-like receptor (TLR)2 and TLR4 for optimal inflammation but are independent of the IL-18 receptor. CONCLUSIONS: Uric acid released from injured cells constitutes a major endogenous danger signal that activates the NALP3 inflammasome, leading to IL-1beta production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1beta production and chronic inflammatory lung pathology.

Does Semantic Context Benefit Speech Understanding through "Top-Down" Processes? Evidence from Time-resolved Sparse fMRI.

When speech is degraded, word report is higher for semantically coherent sentences (e.g., her new skirt was made of denim) than for anomalous sentences (e.g., her good slope was done in carrot). Such increased intelligibility is often described as resulting from "top-down" processes, reflecting an assumption that higher-level (semantic) neural processes support lower-level (perceptual) mechanisms. We used time-resolved sparse fMRI to test for top-down neural mechanisms, measuring activity while participants heard coherent and anomalous sentences presented in speech envelope/spectrum noise at varying signal-to-noise ratios (SNR). The timing of BOLD responses to more intelligible speech provides evidence of hierarchical organization, with earlier responses in peri-auditory regions of the posterior superior temporal gyrus than in more distant temporal and frontal regions. Despite Sentence content × SNR interactions in the superior temporal gyrus, prefrontal regions respond after auditory/perceptual regions. Although we cannot rule out top-down effects, this pattern is more compatible with a purely feedforward or bottom-up account, in which the results of lower-level perceptual processing are passed to inferior frontal regions. Behavioral and neural evidence that sentence content influences perception of degraded speech does not necessarily imply "top-down" neural processes.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻&supl;³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Comparative Analysis by Polymerase Chain Reaction Amplified Minicircles of Kinetoplast DNA of a Stable Strain of Trypanosoma cruzi from São Felipe, Bahia, its Clones and Subclones: Possibility of Predominance of a Principal Clone in this Area

Molecular characterization of one stable strain of Trypanosoma cruzi, the 21 SF, representative of the pattern of strains isolated from the endemic area of São Felipe, State of Bahia, Brazil, maintained for 15 years in laboratory by serial passages in mice and classified as biodeme Type II and zymodeme 2 has been investigated. The kinetoplast DNA (kDNA) of parental strain, 5 clones and 14 subclones were analyzed. Schizodeme was established by comparative study of the fragments obtained from digestion of the 330-bp fragments amplified by polymerase chain reaction (PCR) from the variable regions of the minicicles, and digested by restriction endonucleases Rsa I and Hinf I. Our results show a high percentual of similarity between the restriction fragment lenght polymorphism (RFLP) for the parental strain and its clones and among these individual clones and their subclones at a level of 80 to 100%.This homology indicates a predominance of the same "principal clone" in the 21SF strain and confirms the homogeneity previously observed at biological and isozymic analysis. These results suggest the possibility that the T. cruzi strains with similar biological and isoenzymic patterns, circulating in this endemic area, are representative of one dominant clone. The presence of "principal clones" could be responsible for a predominant tropism of the parasites for specific organs and tissues and this could contribute to the pattern of clinico-pathological manifestations of Chagas's disease in one geographical area.

MR spectroscopy of the human brain with enhanced signal intensity at ultrashort echo times on a clinical platform at 3T and 7T.

Recently, the spin-echo full-intensity acquired localized (SPECIAL) spectroscopy technique was proposed to unite the advantages of short TEs on the order of milliseconds (ms) with full sensitivity and applied to in vivo rat brain. In the present study, SPECIAL was adapted and optimized for use on a clinical platform at 3T and 7T by combining interleaved water suppression (WS) and outer volume saturation (OVS), optimized sequence timing, and improved shimming using FASTMAP. High-quality single voxel spectra of human brain were acquired at TEs below or equal to 6 ms on a clinical 3T and 7T system for six volunteers. Narrow linewidths (6.6 +/- 0.6 Hz at 3T and 12.1 +/- 1.0 Hz at 7T for water) and the high signal-to-noise ratio (SNR) of the artifact-free spectra enabled the quantification of a neurochemical profile consisting of 18 metabolites with Cramér-Rao lower bounds (CRLBs) below 20% at both field strengths. The enhanced sensitivity and increased spectral resolution at 7T compared to 3T allowed a two-fold reduction in scan time, an increased precision of quantification for 12 metabolites, and the additional quantification of lactate with CRLB below 20%. Improved sensitivity at 7T was also demonstrated by a 1.7-fold increase in average SNR (= peak height/root mean square [RMS]-of-noise) per unit-time.

A modular approach for integrative analysis of large-scale gene-expression and drug-response data

High-throughput technologies are now used to generate more than one type of data from the same biological samples. To properly integrate such data, we propose using co-modules, which describe coherent patterns across paired data sets, and conceive several modular methods for their identification. We first test these methods using in silico data, demonstrating that the integrative scheme of our Ping-Pong Algorithm uncovers drug-gene associations more accurately when considering noisy or complex data. Second, we provide an extensive comparative study using the gene-expression and drug-response data from the NCI-60 cell lines. Using information from the DrugBank and the Connectivity Map databases we show that the Ping-Pong Algorithm predicts drug-gene associations significantly better than other methods. Co-modules provide insights into possible mechanisms of action for a wide range of drugs and suggest new targets for therapy

Developmental and pathological lymphangiogenesis: from models to human disease.

The lymphatic vascular system, the body's second vascular system present in vertebrates, has emerged in recent years as a crucial player in normal and pathological processes. It participates in the maintenance of normal tissue fluid balance, the immune functions of cellular and antigen trafficking and absorption of fatty acids and lipid-soluble vitamins in the gut. Recent scientific discoveries have highlighted the role of lymphatic system in a number of pathologic conditions, including lymphedema, inflammatory diseases, and tumor metastasis. Development of genetically modified animal models, identification of lymphatic endothelial specific markers and regulators coupled with technological advances such as high-resolution imaging and genome-wide approaches have been instrumental in understanding the major steps controlling growth and remodeling of lymphatic vessels. This review highlights the recent insights and developments in the field of lymphatic vascular biology.

Echolocation calls of the bats of Trinidad, West Indies: is guild membership reflected in echolocation signal design?

Time-expanded echolocation calls were recorded from 29 species of Neotropical bats in lowland moist tropical forest in Trinidad, West Indies with three aims (I) to describe the echolocation calls of the members of a diverse Neotropical bat community, especially members of the family Phyllostomidae, whose calls are not well documented (2) to investigate whether multivariate analysis of calls allows species and foraging guilds to be identified and (3) to evaluate the use of bat detectors in surveying the phyllostomids of Neotropical forests. The calls of 12 species of the family Phyllostomidae are described here for the first time and a total of 29 species, belonging to five families (Emballonuridae, Mormoopidae, Phyllostomidae, Molossidae and Vespertilionidae) were recorded Quadratic discriminant function analysis (DFA) was used to obtain classification rates for each one of 11 individual species and for six guilds (based on diet, foraging mode and habitat) comprising 26 species Overall classification rates were low compared to similar studies conducted in the Palaeotropics We suggest that this may be due to a combination of ecological plasticity for certain species and a loose relationship between echolocation call shape, fine-grained resource partitioning and resource acquisition in phyllostomids

Pathological Reorganization of NMDA Receptors Subunits and Postsynaptic Protein PSD-95 Distribution in Alzheimer's Disease.

In Alzheimer's disease (AD), synaptic alterations play a major role and are often correlated with cognitive changes. In order to better understand synaptic modifications, we compared alterations in NMDA receptors and postsynaptic protein PSD-95 expression in the entorhinal cortex (EC) and frontal cortex (FC; area 9) of AD and control brains. We combined immunohistochemical and image analysis methods to quantify on consecutive sections the distribution of PSD-95 and NMDA receptors GluN1, GluN2A and GluN2B in EC and FC from 25 AD and control cases. The density of stained receptors was analyzed using multivariate statistical methods to assess the effect of neurodegeneration. In both regions, the number of neuronal profiles immunostained for GluN1 receptors subunit and PSD-95 protein was significantly increased in AD compared to controls (3-6 fold), while the number of neuronal profiles stained for GluN2A and GluN2B receptors subunits was on the contrary decreased (3-4 fold). The increase in marked neuronal profiles was more prominent in a cortical band corresponding to layers 3 to 5 with large pyramidal cells. Neurons positive for GluN1 or PSD-95 staining were often found in the same localization on consecutive sections and they were also reactive for the anti-tau antibody AD2, indicating a neurodegenerative process. Differences in the density of immunoreactive puncta representing neuropile were not statistically significant. Altogether these data indicate that GluN1 and PSD-95 accumulate in the neuronal perikarya, but this is not the case for GluN2A and GluN2B, while the neuropile compartment is less subject to modifications. Thus, important variations in the pattern of distribution of the NMDA receptors subunits and PSD-95 represent a marker in AD and by impairing the neuronal network, contribute to functional deterioration.