Convolutional Neural Networks for Chagas' Parasite Detection in Histopathological Images.

Chagas disease is a widely spreaded illness caused by the parasite Trypanosoma cruzi (T. cruzi). Most cases go unnoticed until the accumulated myocardial damage affect the patient. The endomyocardium biopsy is a tool to evaluate sustained myocardial damage, but analyzing histopathological images takes a lot of time and its prone to human error, given its subjective nature. The following work presents a deep learning method to detect T. cruzi amastigotes on histopathological images taken from a endomyocardium biopsy during an experimental murine model. A U-Net convolutional neural network architecture was implemented and trained from the ground up. An accuracy of 99.19% and Jaccard index of 49.43% were achieved. The obtained results suggest that the proposed approach can be useful for amastigotes detection in histopathological images.Clinical relevance- The proposed method can be incorporated as automatic detection tool of amastigotes nests, it can be useful for the Chagas disease analysis and diagnosis.

Association of RMND1/CCDC170-ESR1 single nucleotide polymorphisms with hip fracture and osteoporosis in postmenopausal women.

OBJECTIVE: This study aimed to investigate the association of seven single nucleotide polymorphisms (SNPs) on the RMND1, CCDC170, and ESR1 genes with osteoporosis or hip fracture in a postmenopausal Mexican population. METHODS: We included a group of 400 postmenopausal women from the Health Workers Cohort Study from the Mexican Institute of Social Security. As a replication sample, we recruited 423 postmenopausal women from the National Institute of Rehabilitation. Demographic data were collected through a structured questionnaire. Bone mineral density was assessed using dual X-ray absorptiometry. Individuals were classified as normal, osteopenia, osteoporosis, and fracture, according to World Health Organization criteria. Genotyping was performed using predesigned TaqMan Probes. Linear regression analysis was used to investigate association. RESULTS: All of the analyzed SNPs showed association with at least one of the phenotypes of the study groups. In addition, we observed a region with linkage disequilibrium within the ESR1 gene in all groups. CONCLUSION: This study shows that an association of the SNPs can exist with osteopenia, osteoporosis, or fragility fracture. Our results agree with data published elsewhere, supporting the potential of these loci for the identification of the population at risk. However, additional studies are required to determine the extent of this association for other geographic regions of Mexico.

Electrical velocimetry for non-invasive monitoring of the closure of the ductus arteriosus in preterm infants.

Closure of a patent ductus arteriosus (PDA) in preterm infants modifies cardiac output and induces adaptive changes in the hemodynamic situation. The present study aims to analyze those changes, through a non-invasive cardiac output monitor based on blood electrical velocimetry, in preterm babies. A prospective observational study of preterm infants with a gestational age of less than 28 weeks, and a hemodynamic significant PDA, requires intravenous ibuprofen or surgical closure. All patients were monitored with electrical velocimetry before treatment and through the following 72 h. Two groups were defined, ibuprofen and surgical closure. Variations of cardiac output were analyzed from the basal situation and at 1, 8, 24, 48, and 72 h on each group. During a 12-month period, 18 patients were studied. The median gestational age in the ibuprofen group (12/18) was 26+5 weeks (25+5-27+3) with a median birth weight of 875 (670-1010) g. The cardiac output index (CI) value was 0.29 l/kg/min (0.24-0.34). Among the patients with confirmed ductus closure (50%), a significant CI decrease was shown (0.24 vs 0.29 l/kg/min; P 0.03) after 72 h (three ibuprofen doses). A statistically significant decrease in systolic volume (SVI) was found: 1.62 vs 1.88 ml/kg, P 0.03 with a decrease in contractility (ICON), 85 vs 140, P 0.02. The gestational age in the surgical group (6/18) was 25+2 weeks (24-26+3) with a median weight of 745 (660-820) g. All patients in this group showed a decrease in the immediate postoperative CI (1 h after surgery) 0.24 vs 0.30 l/kg/min, P 0.05, and a significant decrease in contractility (ICON 77 vs 147, P 0.03). In addition, a no statistically significant decrease in SVI (1.54 vs 1.83 ml/kg, P 0.06), as well as an increase in systemic vascular resistance (10,615 vs 8797 dyn/cm2, P 0.08), were detected. This deterioration was transient without significant differences in the remaining periods of time evaluated. CONCLUSION: The surgical closure of the PDA in preterm infants causes a transient deterioration of cardiac function linked to a documented decrease in the left ventricular output. The hemodynamic changes detected after pharmacological PDA closure are similar but those patients present a better clinical tolerance to changes in the cardiac output. What is Known: • Surgical ductus closure generates acute hemodynamic changes in cardiac output and left ventricular function. What is New: • The hemodynamic changes detected after pharmacological ductus closure are similar to those found in the surgical closure. Electrical velocimetry can detect those changes.

Using very high frequencies with very low lung volumes during high-frequency oscillatory ventilation to protect the immature lung. A pilot study.

OBJECTIVE: High-frequency oscillatory ventilation (HFOV) has been described as a rescue therapy in severe respiratory distress syndrome (RDS) with a potential protective effect in immature lungs. In recent times, HFOV combined with the use of volume guarantee (VG) strategy has demonstrated an independent effect of the frequency on tidal volume to increase carbon-dioxide (CO2) elimination. The aim of this study was to demonstrate the feasibility of using the lowest tidal volume on HFOV+VG to prevent lung damage, maintaining a constant CO2 elimination by increasing the frequency. STUDY DESIGN: Newborn infants with RDS on HFOV were prospectively included. After adequate and stable ventilation using a standard HFOV strategy, the tidal volume was fixed using VG and decreased while the frequency was increased to the highest possible to maintain a constant CO2 elimination. Pre- and post-PCO2, delta pressure and tidal volume obtained in each situation were compared. RESULT: Twenty-three newborn infants were included. It was possible to increase the frequency while decreasing the tidal volume in all patients, maintaining a similar CO2 elimination, with a tendency to a lower mean PCO2 after reaching the highest frequency. High-frequency tidal volume was significantly lower, 2.20 ml kg(-1) before vs 1.59 ml kg(-1) at the highest frequency. CONCLUSION: It is possible to use lower delivered tidal volumes during HFOV combined with VG and higher frequencies with adequate ventilation to allow minimizing lung injury.

Resistance index measured by Doppler ultrasound as a predictor of graft function after kidney transplantation.

INTRODUCTION: Doppler ultrasound (US) has become the primary imaging technique for the evaluation of renal transplants. It provides information about the intrarenal resistance index (RI). A high RI is seen in every form of graft dysfunction. In this article, we review the utility of sonography, particularly the intrarenal RI measured early after renal transplant, as a predictor of acute and chronic clinical outcome in patients. RESULTS: RI is a valuable marker to determine graft function and related vascular complications. It reveals a strong correlation with serum creatinine levels measured days after transplant. Its elevation is typical for acute tubular necrosis and can be used to predict its duration. An RI >1 (absent end-diastolic flow) seen in the first weeks after transplant is associated with impaired renal graft recovery. In addition, it is an early predictor of chronic allograft nephropathy (even correlated with biopsy results), which will allow a change in therapy. CONCLUSIONS: RI measured serially in the early period after kidney transplantation is a valuable marker for determining renal graft function. It is also useful for demonstrating various types of graft dysfunction; however, it cannot differentiate between them. In recent studies, extrarenal factors in kidney transplantation (eg, recipient's age) may significantly influence RI in the recipient, demonstrating that RI depends on the vascular characteristics of the recipient and not on the graft itself.

La ecografía Doppler en la detección de invasión vesical en la placenta percreta: nuestra experiencia / Doppler ultrasound in the detection of bladder invasion in the percrete placenta: our experience

Objetivo: Demostrar la utilidad de la ecografía Doppler en la detección de la invasión vesical en el percretismo placentario. Materiales y métodos: Se evaluó por ecografía, desde noviembre de 2011 hasta mayo de 2013, a 21 pacientes de entre 20 y 44 anos que tenían diagnóstico quirúrgico e histopatológico de acretismo placentario (AP). Se consideró invasión vesical a la presencia de estructuras vasculares parietales en la evaluación Doppler color, mientras que se estableció como probable invasión a la presencia de otros hallazgos ecográficos sin senal Doppler. Resultados: De las 21 pacientes con acretismo placentario, 7 presentaron afectación vesical en el examen histopatológico: 5 tuvieron diagnóstico e informe ecográfico de invasión vesical (por la detección de estructuras vasculares en la evaluación Doppler color) y en las 2 restantes se planteó una probable afectación. De las 14 pacientes sin afectación vesical en el resultado histopatológico, hubo 7 con informes normales en la ecografía y 7 con resultados probables. Conclusión: La ecografía Doppler es un método muy útil para la detección de la invasión vesical en el percretismo placentario. Esta se observa con una vascularización parietal positiva en el Doppler color.

Purpose: To demonstrate the usefulness of Doppler ultrasound in the detection of bladder invasion in cases of placenta percreta. Materials and methods: Twenty-one patients, aged 20-44 years old, with surgery and histopathological diagnosis of placenta accreta were tested with ultrasound between November 2011 and May 2013. We considered bladder invasion the presence of hypervascularity detected with Doppler ultrasound, and probable invasion the presence of signs in gray-scale ultrasound, without Doppler color. Results: From the 21 patients included in the study with placenta accreta, 7 had bladder invasion in the histopathological study. Out of these seven, five had been reported to have bladder invasion because of the presence of hypervascularity detected with Doppler ultrasound, and the 2 remaining were reported as probably affected. Regarding the other 14, 7 were reported as normal in the ultrasound, and 7 as probable. Conclusion: Doppler ultrasound is a very reliable method to detect bladder invasion in placenta percreta, seen as hipervascularity of the uterine-bladder interface in the Doppler color exam.

La ecografía Doppler en la detección de invasión vesical en la placenta percreta: nuestra experiencia

Objetivo: Demostrar la utilidad de la ecografía Doppler en la detección de la invasión vesical en el percretismo placentario. Materiales y métodos: Se evaluó por ecografía, desde noviembre de 2011 hasta mayo de 2013, a 21 pacientes de entre 20 y 44 anos que tenían diagnóstico quirúrgico e histopatológico de acretismo placentario (AP). Se consideró invasión vesical a la presencia de estructuras vasculares parietales en la evaluación Doppler color, mientras que se estableció como probable invasión a la presencia de otros hallazgos ecográficos sin senal Doppler. Resultados: De las 21 pacientes con acretismo placentario, 7 presentaron afectación vesical en el examen histopatológico: 5 tuvieron diagnóstico e informe ecográfico de invasión vesical (por la detección de estructuras vasculares en la evaluación Doppler color) y en las 2 restantes se planteó una probable afectación. De las 14 pacientes sin afectación vesical en el resultado histopatológico, hubo 7 con informes normales en la ecografía y 7 con resultados probables. Conclusión: La ecografía Doppler es un método muy útil para la detección de la invasión vesical en el percretismo placentario. Esta se observa con una vascularización parietal positiva en el Doppler color.(AU)

Purpose: To demonstrate the usefulness of Doppler ultrasound in the detection of bladder invasion in cases of placenta percreta. Materials and methods: Twenty-one patients, aged 20-44 years old, with surgery and histopathological diagnosis of placenta accreta were tested with ultrasound between November 2011 and May 2013. We considered bladder invasion the presence of hypervascularity detected with Doppler ultrasound, and probable invasion the presence of signs in gray-scale ultrasound, without Doppler color. Results: From the 21 patients included in the study with placenta accreta, 7 had bladder invasion in the histopathological study. Out of these seven, five had been reported to have bladder invasion because of the presence of hypervascularity detected with Doppler ultrasound, and the 2 remaining were reported as probably affected. Regarding the other 14, 7 were reported as normal in the ultrasound, and 7 as probable. Conclusion: Doppler ultrasound is a very reliable method to detect bladder invasion in placenta percreta, seen as hipervascularity of the uterine-bladder interface in the Doppler color exam.(AU)

Síndrome de apnea-hipopnea obstructiva del sueño asociado a malformación de Arnold-Chiari tipo II. Beneficios de la intervención neuroquirúrgica / Obstructive sleep apnea-hypopnea syndrome associated with type II arnold-chiari malformation. Benefits of neurosurgical intervention

No disponible

Significance of cytomegalovirus prophylaxis strategies and development of cancer in kidney transplant recipients.

Cytomegalovirus (CMV) infection is one of the most common complications among kidney transplant recipients; two approaches preventing this complication are currently available: universal prophylaxis (UP) and pre-emptive therapy (PT). Despite some differences, similar effectiveness and safety have been proven in several studies for both strategies. However, Spinner et al compared both treatments in 115 renal transplant recipients showing deaths were more likely to occur in patients who received UP. Most of these deaths (2/4 cases) occurred because malignancies developed. This finding is paradoxical because CMV is considered a potentially oncogenic virus and, therefore, UP (a longer therapy compared with the PT) should not be linked with the emergence of a greater number of tumors. New evidence suggests that changes in host immune response triggered by CMV infection may have a mitigating effect on the development of tumors. It is now known CMV infection produces a clonal expansion of gamma delta T lymphocytes which can elicit an aggressive response against neoplastic cells. Currently, UP is the therapy most frequently used in Colombian transplant centers; however, doses administered vary depending on several clinical and laboratory factors. There are no clinical cohorts treated with PT. Reviewing the impact of different length dosing schemes is important for creating an immune response affecting malignancy development in kidney transplant recipients.

Gene regulation by BCL3 in a cervical cancer cell line.

BCL3 is a putative proto-oncogene deregulated in haematopoieitic and solid tumours. It has been suggested that its oncogenic effects could be mediated, at least in part, by inducing proliferation and inhibiting cell death. To provide more insight into the mediators of these effects, we used an unbiased approach to analyse the mRNA expression changes after knocking-down BCL3 using specific shRNAs. One hundred eighty genes were up-regulated and sixtynine genes were down-regulated after knocking down BCL3. Function analyses showed enrichment in genes associated with cellular growth and proliferation, cell death and gene expression. We found that STAT3, an important oncogene in human cancer, was the central node of one of the most significant networks. We validated STAT3 as a bona fide target of BCL3 by additional interference RNA and in silico analyses of previously reported lymphoma patients.

Piomiositis primaria en un niño: difícil diagnóstico inicial. A propósito de un caso y revisión de la bibliografía / Primary pyomyositis in a child: difficult initial diagnosis. Report of a case and a review of the literature

La piomiositis es una infección bacteriana profunda del músculo esquelético, que muestra predilección por los grandes grupos musculares. Esta entidad clínica, frecuente en países de clima tropical, en nuestro medio tiene escasa incidencia. La falta de conciencia de la enfermedad y la presentación insidiosa de los síntomas hacen que a menudo se demore su diagnóstico. Ante un niño con fiebre sin foco aparente, debe considerarsela piomiositis como posible causa, teniendo gran importancia antecedentes como la vacunación previa, debido a que la lesión muscular puede condicionar la infección local tras una bacteriemia. En estas páginas presentamos un caso de piomiositis de glúteo mayor en un paciente de 15 meses de edad que cursó con bacteriemia por Staphylococcus aureus y planteó dificultades en el diagnóstico inicial (AU)

Pyomyositis is a deep bacterial infection of skeletal muscle, which has a predilection for large muscle groups. This clinicalentity is frequently detected in tropical countries, but is not common in our region. Due to a lack of awareness of the disease and the insidious presentation of the clinical symptoms, the final diagnosis is often delayed. Pyomyositis should be considered in every febrile child with no apparent origin. It is very important to take into account the previous history of the patient, including vaccinations. A vaccine can be the origin of muscle injury, which could result in infection due to bacteremia. We present a case of pyomyositis of the gluteus maximus in a 15-month-old child with Staphylococcus aureus bacteremia, and discuss the difficulties encountered in the initial diagnosis (AU)

Decrease of cyclin D1 in the human lung adenocarcinoma cell line A-427 by 7-hydroxycoumarin.

Coumarin in vivo has antitumor activity in various types of cancer. In vitro, coumarin and 7-hydroxycoumarin, its major biotransformation product in humans, inhibit the proliferation of several human tumor cell lines. The molecular mechanisms of these effects are unknown. To gain information about these mechanisms, we studied the effects of coumarin and 7-hydroxycoumarin in the human lung adenocarcinoma cell line A-427 on the inhibition of: (i) cell proliferation; (ii) cell cycle progression; and (iii) expression of cyclins D1, E and A. The inhibitory concentrations 50 (IC(50)) of both compounds were estimated by cytostatic assays of tetrazolium (MTT) reduction. The effects on cell cycle progression were assayed with propidium iodide and BrdU using DNA histograms and multiparametric flow cytometry. The percentages of cells expressing cyclins D1, E, and A were estimated by means of bivariate flow cytometry using propidium iodide, and FITC-conjugated monoclonal antibodies for each cyclin. The IC(50) (+/-S.E.M. n=3) of 7-hydroxycoumarin and coumarin at 72 h exposure, were 100+/-4.8 and 257+/-8.8 microg/ml, respectively. 7-Hydroxycoumarin at the concentration of 160 microg/ml (1 mM), inhibited the G(1)/S transition of the cell cycle, an action consistent with the cytostatic effect. No significant decreases of cyclins E and A were observed. In contrast, cyclin D1 significantly decreased, which appears to indicate an action of 7-hydroxycoumarin in early events of phase G(1). However, messenger RNA of cyclin D1, assayed by RT-PCR, did not change. This suggests a posttranscriptional effect. The effects of coumarin were not significant. Cyclin D1 is overexpressed in many types of cancer, and its inhibition has been proposed as a pharmacological and therapeutic target for novel antitumor agents. Knowledge of the decrease of cyclin D1 by 7-hydroxycoumarin may lead to its use in cancer therapy, as well as to the development of more active compounds.

Interaction of new PNA-based molecules with TAR RNA of HIV-1: molecular modelling and biological evaluation.

During the HIV-1 replication process, interactions between the RNA sequence, named TAR RNA, and the viral protein, Tat, permit a fast and efficient transcription of viral DNA into RNA. Based on the NMR structure of TAR RNA from the PDB, two Peptidic Nucleic Analog- (PNA) based molecules were designed by molecular modelling, the first one targeting G32 U31 and the second targeting U31 C30 free loop bases. Before designing the molecules, the flexibility of the TAR RNA was evaluated by molecular dynamics (MD). The molecules studied are composed of three domains: an arginine, a linker, and two PNA bases. First, molecules were designed and the linker length was optimized to fit the TAR RNA; second, a MD simulation on the TAR RNA molecule complex was performed to validate the molecular structure. Optimal molecules were synthesized and tested on infected cells. The experimental results support the choices made in the design of the molecules.

Synthesis and biological activities of new carbaacyclonucleosides and 1'-oxaacyclonucleosides related to clitocine.

We describe the synthesis of two series of acyclonucleosides:carbaacyclonucleosides and 1'-oxaacyclonucleosides which possess the same aglycone as clitocine 3 which is a natural nucleoside exhibiting interesting biological properties. These compounds have been obtained by condensation of 4-aminobutanol or 3-silyloxypropoxyamine with 4,6-dichloro-5-nitropyrimidine. Structural modifications have been made on the heterocyclic base and the side chain to enhance their potential activity. All these compounds have been tested against different viruses: HIV-1, HSV-1, HSV-2, CMV, VZV, EBV. The carbaacyclonucleoside 10 was associated with an anti-EBV activity (EC50 = 0.86 microg/mL).

Synthesis and antiviral activity of ethidium-arginine conjugates directed against the TAR RNA of HIV-1.

The regulatory protein Tat is essential for viral gene expression and replication of the human immunodeficiency virus type 1 (HIV-1). Tat transactivates the HIV-1 long terminal repeat (LTR) via its binding to the transactivation responsive element (TAR) and increases the viral transcription. Studies have shown that the binding of arginine and arginine derivatives induces a conformational change of the TAR RNA at the Tat-binding site. The unpaired A17 residue delimits a small cavity which constitutes a receptor site for small molecules, especially for ethidium bromide. These binding characteristics have prompted us to design a series of ethidium-arginine conjugates capable of interacting with the TAR RNA. Here we report the synthesis of six ethidium derivatives equipped with arginine side chains. These molecules were biologically evaluated, and two compounds (17 and 20) exhibited in vitro anti-HIV-1 activity at micromolar concentration, without toxicity (up to 100 microM concentration). Melting temperature studies indicated that the most active molecule (20) bound strongly to TAR in vitro. RNase protection experiments agreed with the molecular modeling studies which suggested that the ethidium moiety of 20 was inserted next to the A17 residue while the arginine side chain occupied the pyrimidine bulge.

[Integrins and integrin-associated molecules: targets for the development of antimetastatic therapies]. / Integrinas y moléculas asociadas a integrinas: blancos para el desarrollo de terapias antimetastásicas.

Integrins are receptors that mediate cell adhesion and the formation of signaling complex. Changes in the expression of integrins are required during the following steps in the generation of metastases: a) angiogenesis; b) detachment from the primary tumor; c) tumor cell-platelet interaction; d) adhesion to vascular endothelium and e) proliferation. There is a correlation between invasive capability and changes in the expression of some proteins that are clustered in focal adhesion sites, as FAK, CD82, CD9 or CD63. Both, integrin blocking (using antibodies or RGD containing peptides), as well as induced changes in the expression of integrin-associated molecules, are able to inhibit formation of metastases. Discovery and characterization of molecules that regulate the adhesive capability of tumor cells, will lead to development of antimetastasic therapies. In the search of tumor dissemination inhibitors, integrins and some integrin-associated molecules are important pharmacological targets.

Cytostatic activity of coumarin metabolites and derivatives in the B16-F10 murine melanoma cell line.

Coumarin has antitumour effects in vivo and cytostatic effects in vitro. Its half-life in humans is short (1-1.5 h) and the monohydroxylated biotransformation products have significantly longer half-lives. One or several of these products may thus be responsible for the antitumoral effects. We have assayed the in vitro cytostatic activity of five monohydroxylated coumarins (3-, 4-, 6-, 7- and 8-monohydroxycoumarin), their acetates and methyl-ethers. Murine melanoma cells (cell line B16-F10) and murine fibroblasts (B82) were exposed to the test compounds at concentrations between 10 and 160 microg/ml. The cytostatic effects were estimated by reduction of the tetrazolium dye MTT. In the melanoma cells, some of the compounds inhibited growth after exposure for 1 day. In contrast, coumarin inhibited growth to a smaller extent, and only after exposure for 3 days. The most active compounds (3-acetoxycoumarin, 4-methoxycoumarin and 6-hydroxycoumarin), as well as coumarin, were also assayed in murine fibroblasts. The cytostatic effects of 4-methoxycoumarin and 6-hydroxycoumarin were less pronounced in fibroblasts than in melanoma cells. Our observations suggest that these compounds may have a greater therapeutic margin.