Lateral transorbital canthopexy using a silicone tube in patients with paralytic ectropion.

PURPOSE: We describe the efficacy of lateral transorbital canthopexy using a silicone tube in managing severe paralytic ectropion. METHODS: Patients with paralytic ectropion involving at least two-third of lower eyelid length and scleral exposure of 3 mm or more were considered. A silicone prosthetic was inserted during canthopexy. RESULTS: Lateral transorbital canthopexy using a silicone tube was performed on 10 eyelids in nine patients. All patients had corneal surface abnormalities. Scleral exposure resolved completely in three cases. At 8-month follow-up, residual scleral exposure of 1 mm and 2 mm persisted in n = 6 and n = 1 cases, respectively. CONCLUSIONS: Lateral transorbital canthopexy using a silicone tube is an effective therapeutic option for paralytic ectropion, facilitating both functional and cosmetic results that proved durable over time.

HNF4a transcription is a target of trichloroethylene toxicity in the embryonic mouse heart.

In exploration of congenital heart defects produced by TCE, Hepatocyte Nuclear Factor 4 alpha (HNF4a) transcriptional activity was identified as a central component. TCE exposure altered gene transcription in the chick heart in a non-monotonic pattern where only low dose exposure inhibited transcription by HNF4a. As the chick embryo is non-placental, we examine here HNF4a as a target of TCE in developing mouse embryos. Benfluorex and Bi6015, published agonist and antagonist, respectively, of HNF4a were compared to low dose TCE exposure. Pregnant mice were exposed to 10 ppb (76 nM) TCE, 5 µM Benfluorex, 5 µM Bi6015, or a combination of Bi6015 and TCE in drinking water. Litters (E12) were collected during a sensitive window in heart development. Embryonic hearts were collected, pooled for extraction of RNA and marker expression was examined by quantitative PCR. Multiple markers, previously identified as sensitive to TCE exposure in chicks or as published targets of HNF4a transcription were significantly affected by Benfluorex, Bi6015 and TCE. Activity of TCE and both HNF4a-specific reagents on transcription argues that HNF4a is a component of TCE cardiotoxicity and likely a proximal target of low dose exposure during development. The effectiveness of these reagents after delivery in maternal drinking water suggests that neither maternal metabolism, nor placental transport is protective of exposure.

Exploring the risks accompanying child-bearing in aboriginal society on Gran Canaria (Canary Islands, 13th-15th cal. CE): death of a pregnant woman during her third trimester.

In the pre-Hispanic necropolis of Juan Primo, northwest Gran Canaria (Canary Islands, Spain) a grave was found containing a 20-25 year-old woman with a foetus in her abdominal region, whose age at death was estimated at 33-35 weeks of gestation. The purpose of this study is to discuss the possible cause of death of the woman and foetus. Skeletons of both individuals were well preserved, permitting a good record of the bones found in the burial, which is compatible with a pregnancy at preterm. The age of the foetus and the position of the left upper limb raise the possibility that their death was the result of a difficult birth (dystocia). However, a number of alternative disorders can be put forward to explain this death in the third trimester of pregnancy, such as eclampsia and abruption placentae. In this case, pertinent ethnohistorical and osteoarchaeological information about the ancient canaries allows us to assess some of the stressors that would increase their maternal mortality. The lack of similar evidence in archaeological contexts makes this an important finding, providing a likely case of obstetric problems and their impact on pre-industrial societies.

Trichloroethylene perturbs HNF4a expression and activity in the developing chick heart.

Exposure to trichloroethylene (TCE) is linked to formation of congenital heart defects in humans and animals. Prior interactome analysis identified the transcription factor, Hepatocyte Nuclear Factor 4 alpha (HNF4a), as a potential target of TCE exposure. As a role for HNF4a is unknown in the heart, we examined developing avian hearts for HNF4a expression and for sensitivity to TCE and the HNF4a agonist, Benfluorex. In vitro analysis using a HNF4a reporter construct showed both TCE and HFN4a to be antagonists of HNF4a-mediated transcription at the concentrations tested. HNF4a mRNA is expressed transiently in the embryonic heart during valve formation and cardiac development. Embryos were examined for altered gene expression in the presence of TCE or Benfluorex. TCE altered expression of selected mRNAs including HNF4a, TRAF6 and CYP2C45. There was a transition between inhibition and induction of marker gene expression in embryos as TCE concentration increased. Benfluorex was largely inhibitory to selected markers. Echocardiography of exposed embryos showed reduced cardiac function with both TCE and Benfluorex. Cardiac contraction was reduced by 29% and 23%, respectively at 10 ppb. The effects of TCE and Benfluorex on autocrine regulation of HNF4a, selected markers and cardiac function argue for a functional interaction of TCE and HNF4a. Further, the dose-sensitive shift between inhibition and induction of marker expression may explain the nonmonotonic-like dose response observed with TCE exposure in the heart.

Cardiac Regeneration in the Human Left Ventricle After CorMatrix Implantation.

CorMatrix is an organic extracellular matrix (ECM) derived from porcine small intestine submucosa and is used for pericardial closure and cardiac tissue repair. During explantation of a HeartMate II (Thoratec Corp, Pleasanton, CA) left ventricular assist device (LVAD) because of infection, CorMatrix was used to repair the left ventricular apex and aorta. Three months later, a HeartWare HVAD (HeartWare International, Inc, Framingham, MA) was implanted for recurrent heart failure. Excised apical CorMatrix samples showed cardiac tissue remodeling with viable cardiomyoblasts similar to native myocardium. Excised CorMatrix from the aorta showed organization of collagen and elastin similar to native aortic tissue.

Inhibition of Ciliogenesis Promotes Hedgehog Signaling, Tumorigenesis, and Metastasis in Breast Cancer.

Primary cilia are chemosensors that play a dual role to either activate or repress Hedgehog signaling, depending on presence or absence of ligand, respectively. While inhibition of ciliogenesis has been shown to be characteristic of breast cancers, the functional consequence is unknown. Here, for the first time, inhibition of ciliogenesis led to earlier tumor formation, faster tumor growth rate, higher grade tumor formation, and increased metastasis in the polyoma middle T (PyMT) mouse model of breast cancer. In in vitro model systems, inhibition of ciliogenesis resulted in increased expression of Hedgehog-target genes through a mechanism involving loss of the repressor form of the GLI transcription factor (GLIR) and activation of Hedgehog target gene expression through cross-talk with TGF-alpha (TGFA) signaling. Bioinformatics analysis revealed that increased Hedgehog signaling is frequently associated with increased TGFA; signaling in patients with triple-negative breast cancers (TNBC), a particularly aggressive breast cancer subtype. These results identify a previously unrecognized role for inhibition of ciliogenesis in breast cancer progression. This study identifies inhibition of ciliogenesis as an important event for activation of Hedgehog signaling and progression of breast cancer to a more aggressive, metastatic disease.Implications: These findings change the way we understand how cancer cells turn on a critical signaling pathways and a provide rationale for developing novel therapeutic approaches to target noncanonical Hedgehog signaling for the treatment of breast cancer. Mol Cancer Res; 15(10); 1421-30. ©2017 AACR.

Chest compression depth and survival in out-of-hospital cardiac arrest.

AIM: Outcomes from out-of-hospital cardiac arrest (OHCA) may improve if rescuers perform chest compressions (CCs) deeper than the previous recommendation of 38-51mm and consistent with the 2010 AHA Guideline recommendation of at least 51mm. The aim of this study was to assess the relationship between CC depth and OHCA survival. METHODS: Prospective analysis of CC depth and outcomes in consecutive adult OHCA of presumed cardiac etiology from two EMS agencies participating in comprehensive CPR quality improvement initiatives. ANALYSIS: Multivariable logistic regression to calculate adjusted odds ratios (aORs) for survival to hospital discharge and favorable functional outcome. RESULTS: Among 593 OHCAs, 136 patients (22.9%) achieved return of spontaneous circulation, 63 patients (10.6%) survived and 50 had favorable functional outcome (8.4%). Mean CC depth was 49.8±11.0mm and mean CC rate was 113.9±18.1CCmin(-1). Mean depth was significantly deeper in survivors (53.6mm, 95% CI: 50.5-56.7) than non-survivors (48.8mm, 95% CI: 47.6-50.0). Each 5mm increase in mean CC depth significantly increased the odds of survival and survival with favorable functional outcome: aORs were 1.29 (95% CI 1.00-1.65) and 1.30 (95% CI 1.00-1.70) respectively. CONCLUSION: Deeper chest compressions were associated with improved survival and functional outcome following OHCA. Our results suggest that adhering to the 2010 AHA Guideline-recommended depth of at least 51mm could improve outcomes for victims of OHCA.

Whole blood gene expression profiles in insulin resistant Latinos with the metabolic syndrome.

Although insulin resistance in skeletal muscle is well-characterized, the role of circulating whole blood in the metabolic syndrome phenotype is not well understood. We set out to test the hypothesis that genes involved in inflammation, insulin signaling and mitochondrial function would be altered in expression in the whole blood of individuals with metabolic syndrome. We further wanted to examine whether similar relationships that we have found previously in skeletal muscle exist in peripheral whole blood cells. All subjects (n=184) were Latino descent from the Arizona Insulin Resistance registry. Subjects were classified based on the metabolic syndrome phenotype according to the National Cholesterol Education Program's Adult Treatment Panel III. Of the 184 Latino subjects in the study, 74 were classified with the metabolic syndrome and 110 were without. Whole blood gene expression profiling was performed using the Agilent 4x44K Whole Human Genome Microarray. Whole blood microarray analysis identified 1,432 probes that were altered in expression ≥ 1.2 fold and P<0.05 after Benjamini-Hochberg in the metabolic syndrome subjects. KEGG pathway analysis revealed significant enrichment for pathways including ribosome, oxidative phosphorylation and MAPK signaling (all Benjamini-Hochberg P<0.05). Whole blood mRNA expression changes observed in the microarray data were confirmed by quantitative RT-PCR. Transcription factor binding motif enrichment analysis revealed E2F1, ELK1, NF-kappaB, STAT1 and STAT3 significantly enriched after Bonferroni correction (all P<0.05). The results of the present study demonstrate that whole blood is a useful tissue for studying the metabolic syndrome and its underlying insulin resistance although the relationship between blood and skeletal muscle differs.

Increased redox-sensitive green fluorescent protein reduction potential in the endoplasmic reticulum following glutathione-mediated dimerization.

As the endoplasmic reticulum (ER) is the compartment where disulfide bridges in secreted and cell surface proteins are formed, the disturbance of its redox state has profound consequences, yet regulation of ER redox potential remains poorly understood. To monitor the ER redox state in live cells, several fluorescence-based sensors have been developed. However, these sensors have yielded results that are inconsistent with each other and with earlier non-fluorescence-based studies. One particular green fluorescent protein (GFP)-based redox sensor, roGFP1-iL, could detect oxidizing changes in the ER despite having a reduction potential significantly lower than that previously reported for the ER. We have confirmed these observations and determined the mechanisms by which roGFP1-iL detects oxidizing changes. First, glutathione mediates the formation of disulfide-bonded roGFP1-iL dimers with an intermediate excitation fluorescence spectrum resembling a mixture of oxidized and reduced monomers. Second, glutathione facilitates dimerization of roGFP1-iL, which shifted the equilibrium from oxidized monomers to dimers, thereby increasing the molecule's reduction potential compared with that of a dithiol redox buffer. We conclude that the glutathione redox couple in the ER significantly increased the reduction potential of roGFP1-iL in vivo by facilitating its dimerization while preserving its ratiometric nature, which makes it suitable for monitoring oxidizing and reducing changes in the ER with a high degree of reliability in real time. The ability of roGFP1-iL to detect both oxidizing and reducing changes in ER and its dynamic response in glutathione redox buffer between approximately -190 and -130 mV in vitro suggests a range of ER redox potentials consistent with those determined by earlier approaches that did not involve fluorescent sensors.

Ethnicity and elevated liver transaminases among newly diagnosed children with type 2 diabetes.

BACKGROUND: To examine the influence of ethnicity on liver transaminases among adolescents with type 2 diabetes mellitus (T2DM). METHODS: A retrospective medical chart review of 57 (30 males and 27 females) newly diagnosed patients with T2DM. Ethnicity was determined by self-report and height, weight, body mass index (BMI) and glycosylated hemoglobin (HbA1c) were obtained using standard clinical procedures. Fasting levels of alanine aminotransaminase (ALT) and aspartate aminotransferase (AST) were collected prior to the initiation of any therapy. RESULTS: Age, gender, height, weight, BMI, and HbA1c did not differ between ethnic groups. Compared to African-Americans, Hispanics had significantly higher ALT (23.9 ± 3.4 vs. 107.8 ± 20.3, p=0.002) and AST (17.7 ± 2.5 vs. 71.1 ± 15.7, p<0.001) and were significantly more likely to have ALT values above the upper limit of normal (20% vs. 71%, p=0.005) and twice the upper limit of normal (0% vs. 39%, p=0.05) as well as AST values above the upper limit of normal (0% vs. 53%, p=0.002). No differences in ALT or AST were found between Hispanics and non-Hispanic whites or between African-Americans and non-Hispanic whites. CONCLUSIONS: These preliminary findings suggest that Hispanic children with T2DM may be at higher risk for developing non-alcoholic fatty liver disease and indicate that a comprehensive hepatic evaluation is warranted in this population. Future studies that incorporate more precise and proximal measures of liver health are warranted in this population.

Extracellular conversion of adiponectin hexamers into trimers.

Adiponectin is an adipocyte-secreted hormone that exists as trimers, hexamers and larger species collectively referred to as HMW (high-molecular-weight) adiponectin. Whether hexamers or HMW adiponectin serve as precursors for trimers outside the circulation is currently unknown. Here, we demonstrate that adiponectin trimers can be generated from larger oligomers secreted from primary rat adipose cells or differentiated 3T3-L1 adipocytes. Purified hexameric, but not HMW, adiponectin converted into trimers in conditioned media separated from 3T3-L1 adipocytes or, more efficiently, when enclosed in the dialysis membrane in the presence of adipocytes. Several lines of evidence indicate that the conversion is mediated by an extracellular redox system. First, N-terminal epitope-tagged hexamers converted into trimers without proteolytic removal of the tag. Secondly, appearance of trimers was associated with conversion of disulfide-bonded dimers into monomers. Thirdly, thiol-reactive agents inhibited conversion into trimers. Consistent with a redox-based mechanism, purified hexamers reductively converted into trimers in defined glutathione redox buffer with reduction potential typically found in the extracellular environment while the HMW adiponectin remained stable. In addition, conversion of hexamers into trimers was enhanced by NADPH, but not by NADP+. Collectively, these data strongly suggest the presence of an extracellular redox system capable of converting adiponectin oligomers.

Mitigation of isolation-associated adipocyte interleukin-6 secretion following rapid dissociation of adipose tissue.

Primary adipocyte isolation by collagenase digestion is a widely used technique to study metabolic regulation and insulin action in adipocytes. However, induction of a proinflammatory response characterized by enhanced secretion of interleukin (IL)-6 has been tightly linked to the isolation process itself. To test the hypothesis that the shaking mechanical force exerted on adipocytes stimulates inflammation during isolation, rat primary adipocytes were prepared by collagenase digestion in orbital shaking incubators maintained at varying speeds. Contrary to expectation, the isolation-induced release of IL-6 was attenuated by increasing the rotational speed of digestion and the concentration of collagenase, both of which resulted in rapid dissociation of adipocytes from the vasculature. In addition, the attenuation of IL-6 secretion was associated with decreased phosphorylation of the stress-related p38 mitogen-activated protein kinase (p38 MAPK) and preserved insulin action. The data suggest that optimization of parameters including, but not limited to, mincing technique, time of digestion, and collagenase concentration will make it possible to isolate primary adipocytes without activation of a proinflammatory response leading to elevated secretion of IL-6.

Role of redox environment on the oligomerization of higher molecular weight adiponectin.

BACKGROUND: Adiponectin is an adipocyte-secreted hormone with insulin-sensitizing and anti-inflammatory actions. The assembly of trimeric, hexameric, and higher molecular weight (HMW) species of adiponectin is a topic of significant interest because physiological actions of adiponectin are oligomer-specific. In addition, adiponectin assembly is an example of oxidative oligomerization of multi-subunit protein complexes in endoplasmic reticulum (ER). RESULTS: We previously reported that trimers assemble into HMW adiponectin via intermediates stabilized by disulfide bonds, and complete oxidation of available cysteines locks adiponectin in hexameric conformation. In this study, we examined the effects of redox environment on the rate of oligomer formation and the distribution of oligomers. Reassembly of adiponectin under oxidizing conditions accelerated disulfide bonding but favored formation of hexamers over the HMW species. Increased ratios of HMW to hexameric adiponectin could be achieved rapidly under oxidizing conditions by promoting disulfide rearrangement. CONCLUSIONS: Based upon these observations, we propose oxidative assembly of multi-subunit adiponectin complexes in a defined and stable redox environment is favored under oxidizing conditions coupled with high rates of disulfide rearrangement.

Development of a fermented goats' milk containing Lactobacillus rhamnosus: in vivo study of health benefits.

BACKGROUND: Lactobacillus rhamnosus CRL1505, a strain of goats' milk origin, is able to stimulate mucosal immunity and protect immunocompetent mice from intestinal and respiratory infections. RESULTS: In this work we developed and characterized a fermented goats' milk containing L. rhamnosus CRL1505, and we demonstrated in a model of immunosuppression in mice that the final dairy product preserves the immunomodulatory properties of the strain. L. rhamnosus CRL1505 survived the manufacturing process of fermented milk and maintained a viability of 10(6) cfu g(-1) during storage. The fermented goats' milk was accepted by 90.48% of the panelists and was considered as having an acid taste and pleasant aroma. We also demonstrated that the developed product, used as a supplement during the repletion of immunocompromised malnourished mice, was effective in accelerating the recovery of clinical parameters altered by malnutrition and to induce increased resistance against intestinal and respiratory infections. CONCLUSION: Goats' milk fermented with L. rhamnosus CRL1505 could be manufactured as an alternative probiotic dairy product since this new food has the ability to stimulate the common mucosal immune system and to improve defenses against respiratory and intestinal infections.

Sarcoma de vena cava inferior / Sarcoma of the vena cava inferior

Se presentó un caso infrecuente de una paciente con tumor abdominal y gran circulación colateral superficial tipo cava-cava, el ultrasonido abdominal, el ecocardiograma trans-torácico y transesofágico y la tomografía axial computarizada identificaron un tumor de la vena cava inferior. La citología aspirativa con aguja fina de la lesión confirmó que se trataba de un sarcoma fusopleomórfico de alto grado de malignidad primario de la vena cava inferior

Authors present an infrequent case of a female patient with abdominal tumor a great superficial collateral circulation type cava-cava, the abdominal ultrasound, the transthoracic and transesophageal echocardiogram and the computerized axial tomography (CAT) identified a tumor of the vena cava inferior. The fine-needle aspiration cytology of lesion confirmed the presence of primary fusopleomorphous sarcoma of high degree of malignancy of vena cava inferior

Sarcoma de vena cava inferior / Sarcoma of the vena cava inferior

Se presentó un caso infrecuente de una paciente con tumor abdominal y gran circulación colateral superficial tipo cava-cava, el ultrasonido abdominal, el ecocardiograma trans-torácico y transesofágico y la tomografía axial computarizada identificaron un tumor de la vena cava inferior. La citología aspirativa con aguja fina de la lesión confirmó que se trataba de un sarcoma fusopleomórfico de alto grado de malignidad primario de la vena cava inferior(AU)

Authors present an infrequent case of a female patient with abdominal tumor a great superficial collateral circulation type cava-cava, the abdominal ultrasound, the transthoracic and transesophageal echocardiogram and the computerized axial tomography (CAT) identified a tumor of the vena cava inferior. The fine-needle aspiration cytology of lesion confirmed the presence of primary fusopleomorphous sarcoma of high degree of malignancy of vena cava inferior(AU)

Nódulo de la hermana María José" en tumor de ovario gigante / \"Sister María José\" nodule in giant ovary tumor

Se presenta el caso de una paciente con un gran tumor abdominal y nódulo umbilical. La citología aspirativa con aguja fina confirmó la presencia de lesión metastásica por adenocarcinoma con ßreas papilares de alto grado, lo que unido a la clínica y al resto de las investigaciones permitió establecer que se trataba de una neoplasia de ovario con metástasis en hígado, bazo y ganglios. Concluimos que ante el hallazgo clínico de un ganglio umbilical es necesario tomar muestra para estudio histológico, lo que facilita el diagnóstico y la conducta terapéutica

This is the case of a patient presenting with a large abdominal tumor and umbilical nodule. The fine-needle aspiration cytology confirmed the presence of a metastatic lesion due to adenocarcinoma with a high degree papillary areas and it joined to clinics and remainder researches allowed to establish the presence of ovarian neoplasm in liver, spleen and ganglia. We concluded that in the face of a clinical finding of an umbilical ganglion, it is necessary to take a sample for histological study allowing the diagnosis and the therapeutical behavior

Nódulo de la hermana María José" en tumor de ovario gigante / "Sister María José" nodule in giant ovary tumor

Se presenta el caso de una paciente con un gran tumor abdominal y nódulo umbilical. La citología aspirativa con aguja fina confirmó la presencia de lesión metastásica por adenocarcinoma con ßreas papilares de alto grado, lo que unido a la clínica y al resto de las investigaciones permitió establecer que se trataba de una neoplasia de ovario con metástasis en hígado, bazo y ganglios. Concluimos que ante el hallazgo clínico de un ganglio umbilical es necesario tomar muestra para estudio histológico, lo que facilita el diagnóstico y la conducta terapéutica(AU)

This is the case of a patient presenting with a large abdominal tumor and umbilical nodule. The fine-needle aspiration cytology confirmed the presence of a metastatic lesion due to adenocarcinoma with a high degree papillary areas and it joined to clinics and remainder researches allowed to establish the presence of ovarian neoplasm in liver, spleen and ganglia. We concluded that in the face of a clinical finding of an umbilical ganglion, it is necessary to take a sample for histological study allowing the diagnosis and the therapeutical behavior(AU)

Disulfide-dependent self-assembly of adiponectin octadecamers from trimers and presence of stable octadecameric adiponectin lacking disulfide bonds in vitro.

Adiponectin is a circulating insulin-sensitizing hormone that homooligomerizes into trimers, hexamers, and higher molecular weight (HMW) species. Low levels of circulating HMW adiponectin appear to increase the risk for insulin resistance. Currently, assembly of adiponectin oligomers and, consequently, mechanisms responsible for decreased HMW adiponectin in insulin resistance are not well understood. In the work reported here, we analyzed the reassembly of the most abundant HMW adiponectin species, the octadecamer, following its collapse to smaller oligomers in vitro. Purified bovine serum adiponectin octadecamer was treated with reducing agents at pH 5 to obtain trimers. These reduced trimers partially and spontaneously reassembled into octadecamers upon oxidative formation of disulfide bonds. Disulfide bonds appear to occupy a greater role in the process of oligomerization than in the structural stabilization of mature octadecamer. Stable octadecamers lacking virtually all disulfide bonds could be observed in abundance using native gel electrophoresis, dynamic light scattering, and collision-induced dissociation nanoelectrospray ionization mass spectrometry. These findings indicate that while disulfide bonds help to maintain the mature octadecameric adiponectin structure, their more important function is to stabilize intermediates during the assembly of octadecamer. Adiponectin oligomerization must proceed through intermediates that are at least partially reduced. Accordingly, fully oxidized adiponectin hexamers failed to reassemble into octadecamers at a rate comparable to that of reduced trimers. As the findings from the present study are based on in vitro experiments, their in vivo relevance remains unclear. Nevertheless, they describe a redox environment-dependent model of adiponectin oligomerization that can be tested using cell-based approaches.

Pseudoquiste esplénico gigante / Giant splenic pseudocyst

Se reportó una paciente asintomática a la que incidentalmente se le descubrió la presencia de esplenomegalia por tumoración de aspecto quístico del bazo; se le realizó esplenectomía e histológicamente se correspondió con un peudoquiste esplénico. Se concluyó que en el diagnóstico diferencial de una esplenomegalia hay que plantearse las lesiones quísticas y pseudoquísticas del bazo. La esplenectomía parcial o total es una opción terapéutica eficaz y permite la diferenciación entre quiste y pseudoquiste esplénico.

This is the case of a female asymptomatic patient, in whom incidentally authors discovered the presence of splenomegalia from splenic cystic tumor; a splenectomy was carried out that from the histological point if view corresponding to a splenic pseudocyst. We conclude that in differential diagnosis of a splenomegalia, we must to consider splenic cystic and pseudocystic lesions. Partial or total splenomegalia is a efficacious therapeutical option allowing differentiation between cyst and splenic pseudocyst.