Corticotropinoma as a Component of Carney Complex.

Known germline gene abnormalities cause one-fifth of the pituitary adenomas in children and adolescents, but, in contrast with other pituitary tumor types, the genetic causes of corticotropinomas are largely unknown. In this study, we report a case of Cushing disease (CD) due to a loss-of-function mutation in PRKAR1A, providing evidence for association of this gene with a corticotropinoma. A 15-year-old male presenting with hypercortisolemia was diagnosed with CD. Remission was achieved after surgical resection of a corticotropin (ACTH)-producing pituitary microadenoma, but recurrence 3 years later prompted reoperation and radiotherapy. Five years after the original diagnosis, the patient developed ACTH-independent Cushing syndrome, and a diagnosis of primary pigmented nodular adrenocortical disease was confirmed. A PRKAR1A mutation (c.671delG, p.G225Afs*16) was detected in a germline DNA sample from the patient, which displayed loss of heterozygosity in the corticotropinoma. No other germline or somatic mutations of interest were found. As corticotropinomas are not a known component of Carney complex (CNC), we performed loss of heterozygosity and messenger RNA stability studies in the patient's tissues, and analyzed the effect of Prkar1a silencing on AtT-20/D16v-F2 mouse corticotropinoma cells. No PRKAR1A defects were found among 97 other pediatric CD patients studied. Our clinical case and experimental data support a role for PRKAR1A in the pathogenesis of a corticotroph cell tumor. This is a molecularly confirmed report of a corticotropinoma presenting in association with CNC. We conclude that germline PRKAR1A mutations are a novel, albeit apparently infrequent, cause of CD

Drug-free holidays: Compliance, tolerability, and acceptability of a 3-day atovaquone/proguanil schedule for pretravel malaria chemoprophylaxis in australian travelers

Background Poor compliance with chemoprophylaxis is a major contributing factor to the risk of malaria in travelers. Pre-travel chemoprophylaxis may improve compliance by enabling “drug-free holidays.” The standard treatment dose of atovaquone/proguanil (250 mg/100 mg, 4 tablets/day for 3 days) provides protection against malaria for at least 4 weeks, and could therefore potentially be used for pre-travel chemoprophylaxis. In this study, we assessed the compliance, tolerability, and acceptability of the 3-day atovaquone/proguanil schedule for malarial chemoprophylaxis. Methods Two hundred thirty-three participants were recruited from 4 specialized travel medicine clinics in Australia. Adults traveling to malaria-endemic areas with low/medium risk for ≤4 weeks were enrolled and prescribed the 3-day schedule of atovaquone/proguanil, completed at least 1 day before departure. Questionnaires were used to collect data on demographics, travel destination, medication compliance, side effects, and reasons for choosing the 3-day schedule. Results Overall, 97.7% of participants complied with the 3-day schedule. Although side effects were reported in 43.3% of the participants, these were well tolerated, and mainly occurred during the first and second days. None of the participants developed malaria. The main reasons for choosing the 3-day schedule over standard chemoprophylaxis options were that it was easier to remember (72.1%), required taking fewer tablets (54.0%), and to help scientific research (54.0%). Conclusions The 3-day atovaquone/proguanil schedule had an impressively high compliance rate, and was well tolerated and accepted by travelers. Further studies are required to assess the effectiveness of this schedule for chemoprophylaxis in travelers.Financial support. C. L. L. was supported by a fellowship from the Australian National Health and Medical Research Council (grant number 1109035). This study was conducted as part of everyday clinical practice, and participants or their employers paid for the medications.Scopu

Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease.

The CABLES1 cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene

The Morpho-kinematic Architecture of Super Star Clusters in the Center of NGC 253

The center of the nearby galaxy NGC 253 hosts a population of more than a dozen super star clusters (SSCs) that are still in the process of forming. The majority of the star formation of the burst is concentrated in these SSCs, and the starburst is powering a multiphase outflow from the galaxy. In this work, we measure the 350 GHz dust continuum emission toward the center of NGC 253 at 47 mas (0.8 pc) resolution using data from the Atacama Large Millimeter/submillimeter Array. We report the detection of 350 GHz (dust) continuum emission in the outflow for the first time, associated with the prominent South-West streamer. In this feature, the dust emission has a width of approximate to 8 pc, is located at the outer edge of the CO emission, and corresponds to a molecular gas mass of similar to(8-17)x10(6) M (circle dot). In the starburst nucleus, we measure the resolved radial profiles, sizes, and molecular gas masses of the SSCs. Compared to previous work at the somewhat lower spatial resolution, the SSCs here break apart into smaller substructures with radii 0.4-0.7 pc. In projection, the SSCs, dust, and dense molecular gas appear to be arranged as a thin, almost linear, structure roughly 155 pc in length. The morphology and kinematics of this structure can be well explained as gas following x (2) orbits at the center of a barred potential. We constrain the morpho-kinematic arrangement of the SSCs themselves, finding that an elliptical, angular-momentum-conserving ring is a good description of both the morphology and kinematics of the SSCs

ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP

Aberrant activation of the PI3K/mTOR pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves as is the case for any cancer cell-targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38. Inhibition of p38 relieved proliferation arrest and allowed upregulation of MYC and YAP through stabilization of CREB. These data provide new insights into cellular signaling mechanisms that influence resistance to PI3K/mTOR inhibitors. Furthermore, they suggest that therapies that inactivate YAP or MYC or augment p38 activity could enhance the efficacy of PI3K/mTOR inhibitors.National Institutes of Health (U.S.) (Grant R01CA103866)National Institutes of Health (U.S.) (Grant AI47389

Availability of Advance Care Planning Documentation for Older Emergency Department Patients: A Cross-Sectional Study

Introduction: Increasing advance care planning (ACP) among older adults is a national priority. Documentation of ACP in the electronic health record (EHR) is particularly important during emergency care

The Molecular Outflow in NGC 253 at a Resolution of Two Parsecs

We present 0.'' 15 (similar to 2.5 pc) resolution ALMA CO(3-2) observations of the starbursting center in NGC 253. Together with archival ALMA CO(1-0) and CO(2-1) data, we decompose the emission into disk and nondisk components. We find similar to 7%-16% of the CO luminosity to be associated with the nondisk component (1.2-4.2 x 10(7) K km s(-1) pc(2)). The total molecular gas mass in the center of NGC 253 is similar to 3.6 x 10(8) M-circle dot with similar to 0.5 x 10(8) M-circle dot (similar to 15%) in the nondisk component. These measurements are consistent across independent mass estimates through three CO transitions. The high-resolution CO(3-2) observations allow us to identify the molecular outflow within the nondisk gas. Using a starburst conversion factor, we estimate the deprojected molecular mass outflow rate, kinetic energy, and momentum in the starburst of NGC 253. The deprojected molecular mass outflow rate is in the range of similar to 14-39 M-circle dot yr(-1) with an uncertainty of 0.4 dex. The large spread arises due to different interpretations of the kinematics of the observed gas while the errors are due to unknown geometry. The majority of this outflow rate is contributed by distinct outflows perpendicular to the disk, with a significant contribution by diffuse molecular gas. This results in a mass-loading factor eta = (M) over dot(out)/(M) over dot(SFR) in the range eta similar to 8-20 for gas ejected out to similar to 300 pc. We find the kinetic energy of the outflow to be similar to 2.5-4.5 x 10(54) erg and a typical error of similar to 0.8 dex, which is similar to 0.1% of the total or similar to 8% of the kinetic energy supplied by the starburst. The outflow momentum is 4.8-8.7 x 10(8) M-circle dot km s(-1) (similar to 0.5 dex error) or similar to 2.5%-4% of the kinetic momentum released into the ISM by the feedback. The unknown outflow geometry and launching sites are the primary sources of uncertainty in this study.Peer reviewe

Behavior problems and prevalence of asthma symptoms among Brazilian children.

OBJECTIVE: Asthma is the most common chronic disease in childhood and has been designated a public health problem due to the increase in its prevalence in recent decades, the amount of health service expenditure it absorbs and an absence of consensus about its etiology. The relationships among psychosocial factors and the occurrence, symptomatology, and severity of asthma have recently been considered. There is still controversy about the association between asthma and a child's mental health, since the pathways through which this relationship is established are complex and not well researched. This study aims to investigate whether behavior problems are associated with the prevalence of asthma symptoms in a large urban center in Latin America. METHODS: It is a cross-section study of 869 children between 6 and 12 years old, residents of Salvador, Brazil. The International Study of Allergy and Asthma in Childhood (ISAAC) instrument was used to evaluate prevalence of asthma symptoms. The Child Behavior Checklist (CBCL) was employed to evaluate behavioral problems. RESULTS: 19.26% (n=212) of the children presented symptoms of asthma. 35% were classified as having clinical behavioral problems. Poisson's robust regression model demonstrated a statistically significant association between the presence of behavioral problems and asthma symptoms occurrence (PR: 1.43; 95% CI: 1.10-1.85). CONCLUSION: These results suggest an association between behavioral problems and pediatric asthma, and support the inclusion of mental health care in the provision of services for asthma morbidity

Forming Super Star Clusters in the Central Starburst of NGC 253

NGC 253 hosts the nearest nuclear starburst. Previous observations show a region rich in molecular gas, with dense clouds associated with recent star formation. We used the Atacama Large Submillimeter/Millimeter Array (ALMA) to image the 350 GHz dust continuum and molecular line emission from this region at 2 pc resolution. Our observations reveal similar to 14 bright, compact (similar to 2-3 pc FWHM) knots of dust emission. Most of these sources are likely to be forming super star clusters (SSCs) based on their inferred dynamical and gas masses, association with 36 GHz radio continuum emission, and coincidence with line emission tracing dense, excited gas. One source coincides with a known SSC, but the rest remain invisible in Hubble near-infrared (IR) imaging. Our observations imply that gas still constitutes a large fraction of the overall mass in these sources. Their high brightness temperature at 350 GHz also implies a large optical depth near the peak of the IR spectral energy distribution. As a result, these sources may have large IR photospheres, and the IR radiation force likely exceeds L/c. Still, their moderate observed velocity dispersions suggest that feedback from radiation, winds, and supernovae are not yet disrupting most sources. This mode of star formation appears to produce a large fraction of stars in the burst. We argue for a scenario in which this phase lasts similar to 1 Myr, after which the clusters shed their natal cocoons but continue to produce ionizing photons. The strong feedback that drives the observed cold gas and X-ray outflows likely occurs after the clusters emerge from this early phase.Peer reviewe