Myddosome clustering in IL-1 receptor signaling regulates the formation of an NF-kB activating signalosome.

IL-1 receptor (IL-1R) signaling can activate thresholded invariant outputs and proportional outputs that scale with the amount of stimulation. Both responses require the Myddosome, a multiprotein complex. The Myddosome is required for polyubiquitin chain formation and NF-kB signaling. However, how these signals are spatially and temporally regulated to drive switch-like and proportional outcomes is not understood. During IL-1R signaling, Myddosomes dynamically reorganize into multi-Myddosome clusters at the cell membrane. Blockade of clustering using nanoscale extracellular barriers reduces NF-kB activation. Myddosomes function as scaffolds that assemble an NF-kB signalosome consisting of E3-ubiquitin ligases TRAF6 and LUBAC, K63/M1-linked polyubiquitin chains, phospho-IKK, and phospho-p65. This signalosome preferentially assembles at regions of high Myddosome density, which enhances the recruitment of TRAF6 and LUBAC. Extracellular barriers that restrict Myddosome clustering perturbed the recruitment of both ligases. We find that LUBAC was especially sensitive to clustering with 10-fold lower recruitment to single Myddosomes than clustered Myddosomes. These data reveal that the clustering behavior of Myddosomes provides a basis for digital and analog IL-1R signaling.

Type 1 diabetes and subcutaneous insulin resistance syndrome treated with pancreas transplantation.

We present a case of subcutaneous insulin resistance syndrome, a rare entity, consisting of subcutaneous and intramuscular insulin resistance, with normal or almost normal sensitivity to insulin when administered intravenously. Its cause is unknown and its treatment is challenging. Our patient required a pancreas transplant.

Presentamos un caso de síndrome de resistencia subcutánea a la insulina, entidad infrecuente, que consiste en resistencia a la insulina por vía subcutánea e intramuscular, con sensibilidad normal o casi normal a la insulina cuando se aplica por vía intravenosa. Se desconoce su causa y su tratamiento es un desafío. Nuestra paciente requirió trasplante de páncreas.

Type 1 diabetes and subcutaneous insulin resistance syndrome treated with pancreas transplantation / Diabetes tipo 1 y síndrome de resistencia subcutánea a la insulina tratada con trasplante de páncreas

Abstract We present a case of subcutaneous insulin resistance syndrome, a rare entity, consisting of subcutaneous and intramuscular insulin resistance, with normal or almost normal sensitivity to insulin when administered intravenously. Its cause is unknown and its treatment is challenging. Our patient required a pancreas transplant.

Resumen Presentamos un caso de síndrome de resistencia subcutánea a la insulina, entidad in frecuente, que consiste en resistencia a la insulina por vía subcutánea e intramuscular, con sensibilidad normal o casi normal a la insulina cuando se aplica por vía intravenosa. Se desconoce su causa y su tratamiento es un desafío. Nuestra paciente requirió trasplante de páncreas.

MyD88 oligomer size functions as a physical threshold to trigger IL1R Myddosome signaling.

A recurring feature of innate immune receptor signaling is the self-assembly of signaling proteins into oligomeric complexes. The Myddosome is an oligomeric complex that is required to transmit inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for how Myddosome proteins self-assemble and regulate intracellular signaling remains poorly understood. Here, we developed a novel assay to analyze the spatiotemporal dynamics of IL1R and Myddosome signaling in live cells. We found that MyD88 oligomerization is inducible and initially reversible. Moreover, the formation of larger, stable oligomers consisting of more than four MyD88s triggers the sequential recruitment of IRAK4 and IRAK1. Notably, genetic knockout of IRAK4 enhanced MyD88 oligomerization, indicating that IRAK4 controls MyD88 oligomer size and growth. MyD88 oligomer size thus functions as a physical threshold to trigger downstream signaling. These results provide a mechanistic basis for how protein oligomerization might function in cell signaling pathways.

Thymoma Causing Bilateral Upper Extremity Deep Vein Thrombosis.

A 38-year-old African American male presented with progressive pain, swelling, numbness, and warmth of the left upper extremity ten days before admission. A chest computerized tomography scan showed a large 8.3 cm × 6.1 cm x 9.9 cm anterior mediastinal mass with compression of the left brachiocephalic vein and superior vena cava. A venous doppler showed multiple occlusive venous thrombi in bilateral upper extremities, including the bilateral internal jugular and subclavian veins, as well as the left subclavian, axillary, cephalic, brachial and median cubital veins. Further laboratory workup came positive for acetylcholine receptor binding antibody suggesting myasthenia gravis, but the patient was asymptomatic for myasthenia gravis. A percutaneous core CT guided biopsy pathology resulted in a predominant T-cell population CD5 positive with few B cells; the immunophenotypic features suggested Type B2 thymoma. To the best of our knowledge, this case is the only reported thymoma presenting with bilateral deep vein thrombosis of the upper extremities. The deep vein thrombosis therapy was enoxaparin 1mg/kg subcutaneously every 12 hours and dexamethasone 4mg intravenously every 4 hours as an anti-inflammatory drug for thymoma related compression of the mediastinum. The patient was referred to a tertiary oncological medical center for a total thymectomy, chemotherapy, and adjuvant radiotherapy.

Lessons about the reliability of congenital syphilis and vertical HIV transmission data learned from case reviews in Uruguay: a cross-sectional study.

BACKGROUND: In Uruguay it is mandatory to review all cases of positive HIV or reactive syphilis tests in pregnancy and peripartum. We compared the rates of mother-to-child transmission of syphilis and HIV detected by case reviews to those obtained from the usual surveillance system and described the characteristic of vertical transmission cases. METHODS: This is a cross-sectional study performed with secondary data obtained from official government sources, for all the country cases of maternal to child transmission of HIV and syphilis from 2012 to 2017, with descriptive analyses. For congenital syphilis analyses, the following pregnancy characteristics were investigated: number of antenatal checks, gestational age at pregnancy diagnosis, gestational age at syphilis test and diagnosis, adequate treatment, and treatment of partners. Sociodemographic characteristics included type of health care (public/private), maternal age, distribution of ethnic minorities, maximum educational attainment, presence of partner, planned pregnancy, drug and alcohol use, domestic violence, previous maternal diagnosis of syphilis, and previous children with congenital syphilis. RESULTS: Coverage of syphilis case reviews increased from 82% in 2014 to 97.4% in 2017. For HIV, this coverage reached 100% in 2017 and elimination of mother to child transmission was achieved. A marked decline in congenital syphilis was noted in the public health care sector, especially in the capital Montevideo, whereas the private sector has remained below the elimination target. Variables related with congenital syphilis in exposed children were late pregnancy diagnosis, < 5 antenatal checks, delayed diagnosis of gestational syphilis, lower rate of correct treatment for gestational syphilis, untreated partner, low maternal schooling, unplanned pregnancy, history of syphilis, and having other children with syphilis. CONCLUSION: The use of case reviews provided knowledge regarding the accurate number of mother-to-child transmission cases and the evolution of elimination of mother to child transmission in the country. The results suggest that rates must be adjusted, providing an opportunity to improve the reliability of surveillance data, and point the need to address specific gaps in order to improve the quality of care during pregnancy, delivery, and the neonatal period.

Rickettsia typhi infection presenting as severe ARDS.

Murine typhus, also known as endemic typhus, is a disease resulting from an infection caused by the gram-negative bacillus Rickettsia typhi. Murine typhus is identified worldwide, predominantly in tropical and subtropical geographic locations. Transmission occurs through direct inoculation by an arthropod vector, most commonly the rat flea, Xenopsylla cheopis. rickettsial infections are notorious for disseminated infections throughout the endothelial cells. The increase in permeability is an immediate consequence and has the potential of leading to non-cardiogenic pulmonary edema, otherwise known as acute respiratory distress syndrome (ARDS). Clinical manifestations are non-specific and initially mimic typical viral etiologies, obscuring early diagnosis. As a result, clinicians often do not include rickettsial infections in their differential diagnoses. Definitive diagnosis is based on clinical recognition, epidemiologic awareness, and serological testing. Here we present a confirmed case of murine typhus in a young non-immunocompromised patient who developed ARDS one week from the initial onset of symptoms.

Cryptococcus laurentii meningitis in a non-HIV patient.

Cryptococcus species (other than Cryptococcus neoformans) have been labeled as saprophytic and nonpathogenic in immunocompetent individuals in the past. In recent years, infections caused by non-neoformans Cryptococcus species have been recognized. Cryptococcus laurentii is known to be a rare human pathogen. In this case report, we present a 59-year-old man who did not have HIV infection with meningoencephalitis caused by Cryptococcus laurentii. No significant underlying immunosuppressive disorder was found. The only identifiable risk factors were that the patient was a farmer with previous exposure to pigeon droppings. Here, we describe what we believe to be the fifth reported case of meningitis caused by Cryptococcus laurentii.

Análisis de las cesáreas en Uruguay por tipo de centro hospitalario / An analysis of caesarean sections in Uruguay by type of hospital

Objetivo: Analizar comparativamente la incidencia de las cesáreas en los subsistemas de salud de Uruguay y en relación con los estándares de la Organización Mundial de la Salud (OMS) considerando las características médico-obstétricas de los partos, en especial la clasificación de Robson. Método: Se emplean 190.847 nacimientos registrados en el Sistema Informático Perinatal de Uruguay entre 2009 y 2014 por tipo de subsector sanitario. Mediante modeloslogitse analiza la probabilidad de cesárea considerando la clasificación de Robson, otros factores de riesgo y las características de las madres. Se comparan las tasas de cesárea predichas por los distintos subsectores sanitarios para una población común. Asimismo, se contraponen las tasas de cesáreas observadas en cada subsistema con las que, hipotéticamente, se encontrarían si los hospitales siguiesen las pautas de la muestra de hospitales de referencia de la OMS. Resultados: El subsector privado, en términos generales, presenta una incidencia de cesáreas mucho más elevada que el público, incluso después de considerar las características médico-obstétricas de los nacimientos. Las tasas de cesáreas en Uruguay están más de un 75% por encima del valor que cabría esperar de acuerdo con el modelo de la OMS. Conclusiones: La incidencia de cesáreas en Uruguay es muy alta respecto a los estándares definidos por la OMS, en especial en el subsector privado. Este hecho no se explica por las características clínicas de los nacimientos

Objective: To analyse on a comparative basis the incidence of caesarean sections among the different health care systems in Uruguay and with respect to the World Health Organization's (WHO) standards, taking into account the medical-obstetric characteristics of the births, particularly, the Robson classification. Methods: We examine 190,847 births registered by the Perinatal Information System in Uruguay between 2009 and 2014 by type of health care system. Usinglogitmodels, we analyse the probability of caesarean section taking into account the Robson classification, other risk factors and the mothers’ characteristics. We compared the caesarean rates predicted by the different subsystems for a common population. Furthermore, we contrast the caesarean rates observed in each subsystem with the rates that resulted if the Uruguayan hospitals followed the guidelines of the sample of WHO reference hospitals. Results: Private health systems in Uruguay exhibit a much higher incidence of caesarean sections than public ones, even after considering the medical-obstetric characteristics of the births. Caesarean rates are more than 75% higher than those observed if the WHO standards are applied. Conclusions: Uruguay has a very high incidence of caesarean sections with respect to WHO standards, particularly, in the private sector. This fact is unrelated to the clinical characteristics of the births

Nontyphoidal Salmonella purulent pericarditis presenting with pericardial tamponade in a patient on infliximab therapy.

Infection with nontyphoidal Salmonella is traditionally characterized by intestinal manifestations. However, extra-intestinal infections are known to occur, with purulent pericarditis associated with cardiac tamponade being rare. This case report is of a 57-year-old male with Crohn's disease initiated on infliximab therapy two months prior to presentation. He presented with recurrent chest pain and a single occurrence of fever. A Computed Tomography (CT) scan of the chest revealed a pericardial effusion. An echocardiogram confirmed the presence of the fluid with tamponade physiology, requiring immediate surgical decompression. The pericardial fluid culture grew Salmonella enterica, despite the patient having only a single episode of fever, disproportionate to the severity of the infection. Conceivably, the lack of systemic symptoms may be attributed to recent infliximab therapy. Upon conducting a literature review, immunosuppressive factors seem to play a significant role in nontyphoid Salmonella enterica pericardial effusion presenting with cardiac tamponade.

[An analysis of caesarean sections in Uruguay by type of hospital]. / Análisis de las cesáreas en Uruguay por tipo de centro hospitalario.

OBJECTIVE: To analyse on a comparative basis the incidence of caesarean sections among the different health care systems in Uruguay and with respect to the World Health Organization's (WHO) standards, taking into account the medical-obstetric characteristics of the births, particularly, the Robson classification. METHODS: We examine 190,847 births registered by the Perinatal Information System in Uruguay between 2009 and 2014 by type of health care system. Using logit models, we analyse the probability of caesarean section taking into account the Robson classification, other risk factors and the mothers' characteristics. We compared the caesarean rates predicted by the different subsystems for a common population. Furthermore, we contrast the caesarean rates observed in each subsystem with the rates that resulted if the Uruguayan hospitals followed the guidelines of the sample of WHO reference hospitals. RESULTS: Private health systems in Uruguay exhibit a much higher incidence of caesarean sections than public ones, even after considering the medical-obstetric characteristics of the births. Caesarean rates are more than 75% higher than those observed if the WHO standards are applied. CONCLUSIONS: Uruguay has a very high incidence of caesarean sections with respect to WHO standards, particularly, in the private sector. This fact is unrelated to the clinical characteristics of the births.

Takotsubo Myocardiopathy and Hyperthyroidism: A Case Report and Literature Review.

BACKGROUND Takotsubo cardiomyopathy (TM), also called stress myocardiopathy or transient left ventricular apical ballooning syndrome, is characterized by acute left ventricular dysfunction with reversible wall motion abnormalities. TM resembles acute coronary syndrome (ACS) in the absence of coronary artery disease (CAD). In several reports, TM has been described in association with hyperthyroidism, suggesting the potential role of thyrotoxicosis in the pathophysiology. CASE REPORT We present the case of a 34-year-old man with TM associated with hyperthyroidism caused by Graves' disease. In this case, TM was also preceded by an emotional trigger. The diagnosis of TM was based on clinical manifestations, electrocardiographic and echocardiographic abnormalities, and the absence of coronary artery disease (CAD) in the angiography. A diagnosis of hyperthyroidism was made based on hormonal and antibody measurements. The patient had a favorable outcome, and the cardiac and thyroid disorders resolved. CONCLUSIONS Our case illustrates that thyroid disease, mainly hyperthyroidism, should be considered in patients with TM with or without previous emotional triggers. As in our patient, the outcome in TM is usually favorable, with reversibility of cardiac abnormalities.

The role of medical abortion in the implementation of the law on voluntary termination of pregnancy in Uruguay.

OBJECTIVE: To evaluate the implementation of the law that liberalizes voluntary abortion in Uruguay and enables health services to offer these services to the population. METHODS: The legal and regulatory provisions are described and the national data-provided by the Ministry of Public Health's National Information System (SINADI)-on the number of voluntary terminations of pregnancy, the abortion method (medical or surgical), and whether it was performed as an outpatient or inpatient are analyzed. To determine complications, the number of maternal deaths and admissions to intensive care units for pregnant women was used. The study period ran from December 1, 2012, to December 31, 2014. RESULTS: A total of 15 996 abortions were performed during the study period; only 1.2% were surgical and 98.8% were medical. Of the latter, only 3.4% required hospitalization. Less than half of the pregnancies were terminated up to 9weeks of gestation and 54% were at 10 to 12weeks in a sample from the Pereira Rossell Hospital. CONCLUSION: The rapid nationwide rollout of voluntary termination of pregnancy services to all women was possible to a large degree thanks to the availability and broad acceptance of medical abortion, facilitated by the prior experience in applying the risk and harm reduction strategy.

The role of medical abortion in the implementation of the law on voluntary termination of pregnancy in Uruguay.

OBJECTIVE: To evaluate the implementation of the law that liberalizes voluntary abortion in Uruguay and enables health services to offer these services to the population. METHODS: The legal and regulatory provisions are described and the national data-provided by the Ministry of Public Health's National Information System (SINADI)-on the number of voluntary terminations of pregnancy, the abortion method (medical or surgical), and whether it was performed as an outpatient or inpatient are analyzed. To determine complications, the number of maternal deaths and admissions to intensive care units for pregnant women was used. The study period ran from December 1, 2012, to December 31, 2014. RESULTS: A total of 15 996 abortions were performed during the study period; only 1.2% were surgical and 98.8% were medical. Of the latter, only 3.4% required hospitalization. Less than half of the pregnancies were terminated up to 9 weeks of gestation and 54% were at 10 to 12 weeks in a sample from the Pereira Rossell Hospital. CONCLUSION: The rapid nationwide rollout of voluntary termination of pregnancy services to all women was possible to a large degree thanks to the availability and broad acceptance of medical abortion, facilitated by the prior experience in applying the risk and harm reduction strategy.

Copper tolerance of Saccharomyces cerevisiae nonsense-mediated mRNA decay mutants.

The eukaryotic nonsense-mediated mRNA (NMD) is a specialized pathway that leads to the recognition and rapid degradation of mRNAs with premature termination codons, and importantly some natural mRNAs as well. Natural mRNAs with atypically long 3'-untranslated regions (UTRs) are degraded by NMD in Saccharomyces cerevisiae. A number of S. cerevisiae mRNAs undergo alternative 3'-end processing producing mRNA isoforms that differ in their 3'-UTR lengths. Some of these alternatively 3'-end processed mRNA isoforms have atypically long 3'-UTRs and would be likely targets for NMD-mediated degradation. Here, we investigated the role NMD plays in the regulation of expression of CTR2, which encodes a vacuolar membrane copper transporter. CTR2 pre-mRNA undergoes alternative 3'-end processing to produce two mRNA isoforms with 300-nt and 2-kb 3'-UTRs. We show that both CTR2 mRNA isoforms are differentially regulated by NMD. The regulation of CTR2 mRNA by NMD has physiological consequences, since nmd mutants are more tolerant to toxic levels of copper relative to wild-type yeast cells and the copper tolerance of nmd mutants is dependent on the presence of CTR2.