Evaluation of a Curricular Addition to Assist Medical Students in Specialty Selection.

Early hands-on experience with surgical procedures may help medical students make better-informed choices if considering a surgical specialty. Here, we evaluate a curricular addition in surgical anatomy, formally exposing second-year students to different surgical subspecialties. Students met with surgeons for 7 weeks (one afternoon per week) and practiced surgical procedures on human cadavers with supervision. About a quarter of the participants reported a change in their top choice of specialty upon completing the course, and about half of the students reported changes in their second and third choices. At the time of graduation, 85% of those surveyed reported participation in the course impacted their final choice of specialty. These results demonstrate such a course helped medical students select a specialty during early training.

Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy.

CONTEXT: Leptin alters bone and mineral metabolism in rodents, but this has not been verified in humans. PATIENTS with congenital generalized lipodystrophy (CGL) have low leptin due to deficient adipose mass and serve as models of leptin deficiency and replacement. OBJECTIVE: To study the effects of recombinant human methionyl leptin (metreleptin) on bone mineral content (BMC) and mineral metabolism. DESIGN AND SETTING: An open-label nonrandomized study at the National Institutes of Health. PATIENTS: Thirty-one patients with CGL (ages 4.3 to 46.7 y). INTERVENTION: Metreleptin (0.06 to 0.24 mg/kg/d) for 6 months to 11 years. OUTCOME MEASURES: BMC was assessed by dual-energy x-ray absorptiometry. SD scores (SDS) for BMC were calculated based on height, race, sex, and age using population normative data. Calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at baseline and follow-up. RESULTS: At baseline, patients demonstrated significantly increased total body less head BMC (mean SDS, 1.8 ± 0.7), height (mean SDS, 1.3 ± 1.3), and lean mass index, defined as lean body mass per height squared (mean SDS, 1.5 ± 0.83), vs population normative data. No change in total body less head BMC was observed after metreleptin. Lean mass index decreased with metreleptin. Serum calcium decreased with metreleptin, but remained within normal limits. No changes were seen in phosphorus, PTH, or vitamin D. CONCLUSIONS: In contrast to rodent models, CGL patients have increased BMC in the leptin-deficient state, which does not change with leptin replacement. The high BMC in these patients is partially explained by high lean mass and tall stature.

Refocusing Mussel Watch on contaminants of emerging concern (CECs): the California pilot study (2009-10).

To expand the utility of the Mussel Watch Program, local, regional and state agencies in California partnered with NOAA to design a pilot study that targeted contaminants of emerging concern (CECs). Native mussels (Mytilus spp.) from 68 stations, stratified by land use and discharge scenario, were collected in 2009-10 and analyzed for 167 individual pharmaceuticals, industrial and commercial chemicals and current use pesticides. Passive sampling devices (PSDs) and caged Mytilus were co-deployed to expand the list of CECs, and to assess the ability of PSDs to mimic bioaccumulation by Mytilus. A performance-based quality assurance/quality control (QA/QC) approach was developed to ensure a high degree of data quality, consistency and comparability. Data management and analysis were streamlined and standardized using automated software tools. This pioneering study will help shape future monitoring efforts in California's coastal ecosystems, while serving as a model for monitoring CECs within the region and across the nation.

Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma.

UNLABELLED: Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2). We employed 50 human CCA samples (25 intrahepatic and 25 extrahepatic CCA) as well as human KMCH-1, Mz-CHA-1, and HUCCT-1 CCA cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. In human samples, polo-like kinase (PLK)1/2/3-immunoreactive cancer cells were present in the preponderance of intra- and extrahepatic CCA specimens. Inhibition of Hh signaling by cyclopamine reduced PLK2, but not PLK1 or PLK3, messenger RNA and protein expression in vehicle-treated and sonic Hh-treated CCA cells, confirming our previous microarray study. PLK2 regulation by Hh signaling appears to be direct, because the Hh transcription factors, glioma-associated oncogene 1 and 2, bind to the PLK2 promotor. Moreover, inhibition of PLK2 by the PLK inhibitor, BI 6727 (volasertib), or PLK2 knockdown was proapoptotic in CCA cells. BI 6727 administration or PLK2 knockdown decreased cellular protein levels of antiapoptotic myeloid cell leukemia 1 (Mcl-1), an effect reversed by the proteasome inhibitor, MG-132. Finally, BI 6727 administration reduced Mcl-1 protein expression in CCA cells, resulting in CCA cell apoptosis and tumor suppression in vivo. CONCLUSION: PLK2 appears to be an important mediator of Hh survival signaling. These results suggest PLK inhibitors to be of therapeutic value for treatment of human CCA.

Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma.

Cancer-associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAFs are "activated" and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma as a desmoplastic tumor model, we investigated the sensitivity of liver CAFs to the cytotoxic drug navitoclax, a BH3 mimetic. Navitoclax induced apoptosis in CAF and in myofibroblastic human hepatic stellate cells but lacked similar effects in quiescent fibroblasts or cholangiocarcinoma cells. Unlike cholangiocarcinoma cells, neither CAF nor quiescent fibroblasts expressed Mcl-1, a known resistance factor for navitoclax cytotoxicity. Explaining this paradox, we found that mitochondria isolated from CAFs or cells treated with navitoclax both released the apoptogenic factors Smac and cytochrome c, suggesting that they are primed for cell death. Such death priming in CAFs appeared to be due, in part, to upregulation of the proapoptotic protein Bax. Short hairpin RNA-mediated attenuation of Bax repressed navitoclax-mediated mitochondrial dysfunction, release of apoptogenic factors, and apoptotic cell death. In a syngeneic rat model of cholangiocarcinoma, navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth, and improving host survival. Together, our findings argue that navitoclax may be useful for destroying CAFs in the tumor microenvironment as a general strategy to attack solid tumors.

Characterization of organic chemical contaminants in sediments from Jobos Bay, Puerto Rico.

Jobos Bay, located on the southeastern coast of Puerto Rico, contains a variety of habitats including mangroves, seagrass meadows, and coral reefs. The watershed surrounding the bay includes a number of towns, agricultural areas, and the Jobos Bay National Estuarine Research Reserve (NERR). Jobos Bay and the surrounding watershed are part of a Conservation Effects Assessment Project (CEAP), involving the Jobos Bay NERR, the US Department of Agriculture, and the National Oceanic and Atmospheric Administration (NOAA) to assess the benefits of agricultural best management practices (BMPs) on the terrestrial and marine environments. As part of the Jobos Bay CEAP, NOAA collected sediment samples in May 2008 to characterize over 130 organic chemical contaminants. This paper presents the results of the organic contaminant analysis. The organic contaminants detected in the sediments included polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls, and the pesticide DDT. PAHs at one site in the inner bay near a boat yard were significantly elevated; however, all organic contaminant classes measured were below NOAA sediment quality guidelines that would have indicated that impacts were likely. The results of this work provide an important baseline assessment of the marine environment that will assist in understanding the benefits of implementing BMPs on water quality in Jobos Bay.

Estimating cyanobacterial bloom transport by coupling remotely sensed imagery and a hydrodynamic model.

The ability to forecast the transport of harmful cyanobacterial blooms in the Laurentian Great Lakes is beneficial to natural resource managers concerned with public health. This manuscript describes a method that improves the prediction of cyanobacterial bloom transport with the use of a preoperational hydrodynamic model and high temporal resolution satellite imagery. Two scenarios were examined from separate cyanobacterial blooms in western Lake Erie, USA. The first scenario modeled bloom position and extent over the span of 13 days. A geographic center, or centroid, was calculated and assigned to the bloom from observed satellite imagery. The bloom centroid was projected forward in time, and the projected position was compared to the final observed bloom centroid. Image pixels flagged as cyanobacterial bloom were compared between the initial image and the final image, and this was assumed as persistence. The second bloom scenario was modeled for a period of 12 days, and the results were framed in an ecological context in an effort to gain further understanding of cyanobacterial bloom dynamics. These modeling techniques can be incorporated into an operational forecasting system.

Assessment of coastal storm impacts on contaminant body burdens of oysters collected from the Gulf of Mexico.

This study evaluated changes in oyster tissue contaminant levels following North Atlantic tropical cyclones to determine if changes in contaminant concentrations were predictable. The basis for this study was analysis of coastal chemical contaminant data from the National Oceanic and Atmospheric Administration's (NOAA) National Status and Trends Mussel Watch Program and NOAA's National Weather Service storm track data. The tendency for contaminant (metals and organic compounds) body burdens to increase or decrease in oyster tissue after a storm was assessed using contingency and correspondence analyses. Post-storm contaminant levels in oysters revealed a consistent pattern of distribution, which could be described as follows: (1) most of the organic contaminants stay within their long-term concentration ranges, (2) very few organic contaminants decreased, and (3) metals overwhelmingly tend to increase.