Eur Heart J. 2012 Jan; 33(2): 151-2
Taylor J

J Infect Dis. 2012 Feb 20;
Gershon AA

J Infect Dis. 2012 Feb 20;
Delaby A, Gorvel L, Espinosa L, Lépolard C, Raoult D, Ghigo E, Capo C, Mege JL

Background. The outcome of Q fever, an infectious disease caused by Coxiella burnetii, is associated with granuloma formation. Granulomas are present in patients with resolutive Q fever but are lacking in patients with chronic Q fever.Methods. Study of granuloma formation requires invasive approaches. Here, we took advantage of a recently described method that enables in vitro generation of human granulomas specific for C. burnetii.Results. Circulating mononuclear cells progressively accumulated around beads coated with C. burnetii extracts, and complete granulomas were generated in 8 days. Granuloma cells consisted of macrophages, lymphocytes, and, to a lesser extent, epithelioid cells and multinucleated giant cells. Early events that govern granuloma formation were studied using live-imaging microscopy. Monocytes migrated toward C. burnetii-coated beads independently of the presence of T lymphocytes and then recruited T lymphocytes. About 90% of patients with chronic Q fever failed to form granulomas. This deficiency was associated with defective migration of monocytes toward coated beads.Conclusions. Monocytes were involved in the early stages of granuloma formation and recruited T lymphocytes to complete granuloma formation. This article describes a direct relationship between defective granuloma formation and defective migration of monocytes.

J Exp Med. 2012 Feb 20;
Cook N, Frese KK, Bapiro TE, Jacobetz MA, Gopinathan A, Miller JL, Rao SS, Demuth T, Howat WJ, Jodrell DI, Tuveson DA

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease that is refractory to medical intervention. Notch pathway antagonism has been shown to prevent pancreatic preneoplasia progression in mouse models, but potential benefits in the setting of an established PDA tumor have not been established. We demonstrate that the gamma secretase inhibitor MRK003 effectively inhibits intratumoral Notch signaling in the KPC mouse model of advanced PDA. Although MRK003 monotherapy fails to extend the lifespan of KPC mice, the combination of MRK003 with the chemotherapeutic gemcitabine prolongs survival. Combination treatment kills tumor endothelial cells and synergistically promotes widespread hypoxic necrosis. These results indicate that the paucivascular nature of PDA can be exploited as a therapeutic vulnerability, and the dual targeting of the tumor endothelium and neoplastic cells by gamma secretase inhibition constitutes a rationale for clinical translation.

J Exp Med. 2012 Feb 20;
Scarlett UK, Rutkowski MR, Rauwerdink AM, Fields J, Escovar-Fadul X, Baird J, Cubillos-Ruiz JR, Jacobs AC, Gonzalez JL, Weaver J, Fiering S, Conejo-Garcia JR

We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable anti-tumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but anti-tumor T cells become less responsive, whereas their enduring activity is abrogated by different microenvironmental immunosuppressive DCs. Correspondingly, depleting DCs early in the disease course accelerates tumor expansion, but DC depletion at advanced stages significantly delays aggressive malignant progression. Our results indicate that phenotypically divergent DCs drive both immunosurveillance and accelerated malignant growth. We provide experimental support for the cancer immunoediting hypothesis, but we also show that aggressive cancer progression after a comparatively long latency period is primarily driven by the mobilization of immunosuppressive microenvironmental leukocytes, rather than loss of tumor immunogenicity.

Arch Surg. 2012 Feb; 147(2): 124
White LE, Hassoun HT

Rheumatology (Oxford). 2012 Feb 20;
Barnes TC, Anderson ME, Edwards SW, Moots RJ

Objective. Reactive oxygen species (ROS) are implicated in the pathogenesis of SSc. Neutrophils constitute a major source of ROS during inflammation. Here, we examined endogenous and stimulated ex vivo ROS production of SSc neutrophils compared with control neutrophils with and without prior priming with TNF-α.Methods. ROS generation was measured using luminol-enhanced chemiluminescence. Neutrophils isolated from SSc patients and healthy controls were unprimed or were primed with TNF-α. ROS production was stimulated in vitro with phorbol 12-myristate 13-acetate (PMA) and formyl-met-leu-phe (fMLP). To examine the effects of serum mediators on ROS generation, control neutrophils were also stimulated with SSc or control serum.Results. Neutrophil stimulation with PMA and fMLP resulted in a greater increase in ROS generation in SSc neutrophils compared with controls. However, unstimulated SSc neutrophils generated lower levels of ROS than controls. SSc neutrophils demonstrated an increased response to fMLP in the absence of in vitro TNF-α priming indicating priming of SSc neutrophils in vivo. SSc serum did not stimulate neutrophil ROS generation in vitro.Conclusion. SSc neutrophils are primed for ROS generation. Neutrophils binding to activated endothelium in SSc, may induce local production of ROS, perpetuating endothelial dysfunction and mediating fibrosis.

Reproduction. 2012 Feb 20;
Guazzone VA, Jacobo P, Denduchis B, Lustig L

The testis is considered an immunologically privileged site where germ cell antigens are protected from autoimmune attack. Yet in response to infections, inflammatory diseases or trauma, there is an influx of leukocytes to testicular interstitium. Interactions between endothelial cells (EC) and circulating leukocytes are implicated in the initiation and evolution of inflammatory processes. Chemokines are a family of chemoattractant cytokines characterized by their ability to both recruit and activate cells. Thus, we investigated the expression of CCL3, its receptors and adhesion molecules CD31 and CD106 in an in vivo model of experimental autoimmune orchitis (EAO). In EAO, the highest content of CCL3 in testicular fluid coincides with onset of the disease. However, CCL3 released in vitro by testicular macrophages is higher during the immunization period. The specific chemokine receptors, CCR1 and CCR5, were expressed by testicular monocytes/macrophages and the increased number of CCR5+ cells was associated with the degree of testicular lesion. EC also play an essential role by facilitating leukocyte recruitment via their ability to express cell surface adhesion molecules that mediate interactions with leukocytes in the bloodstream. Rats with EAO showed a significant increase in the percentage of CD31+ EC that up-regulates the expression of CD106. The percentage of leukocytes isolated from peripheral blood and lymph nodes expressing CD49d (CD106 ligand) also increases during orchitis. These data suggest that cell adhesion molecules, in conjunction with chemokines, contribute to the formation of a chemotactic gradient within the testis, causing the leukocyte infiltration characteristic of EAO histopathology.

Pediatrics. 2012 Feb 20;
Bremer AA, Mietus-Snyder M, Lustig RH

Despite a lack of consistent diagnostic criteria, the metabolic syndrome (MetS) is increasingly evident in children and adolescents, portending a tsunami of chronic disease and mortality as this generation ages. The diagnostic criteria for MetS apply absolute cutoffs to continuous variables and fail to take into account aging, pubertal changes, and race/ethnicity. We attempt to define MetS mechanistically to determine its specific etiologies and to identify targets for therapy. Whereas the majority of studies document a relationship of visceral fat to insulin resistance, ectopic liver fat correlates better with dysfunctional insulin dynamics from which the rest of MetS derives. In contrast to the systemic metabolism of glucose, the liver is the primary metabolic clearinghouse for 4 specific foodstuffs that have been associated with the development of MetS: trans-fats, branched-chain amino acids, ethanol, and fructose. These 4 substrates (1) are not insulin regulated and (2) deliver metabolic intermediates to hepatic mitochondria without an appropriate "pop-off" mechanism for excess substrate, enhancing lipogenesis and ectopic adipose storage. Excessive fatty acid derivatives interfere with hepatic insulin signal transduction. Reactive oxygen species accumulate, which cannot be quenched by adjacent peroxisomes; these reactive oxygen species reach the endoplasmic reticulum, leading to a compensatory process termed the "unfolded protein response," driving further insulin resistance and eventually insulin deficiency. No obvious drug target exists in this pathway; thus, the only rational therapeutic approaches remain (1) altering hepatic substrate availability (dietary modification), (2) reducing hepatic substrate flux (high fiber), or (3) increasing mitochondrial efficiency (exercise).

Arch Surg. 2012 Feb 20;
Moriya T, Traverso LW

OBJECTIVE: To determine the occurrence of new disease in the pancreatic remnant after resection for intraductal papillary mucinous neoplasms. DESIGN: A longitudinal level II cohort study. SETTING: Virginia Mason Medical Center, Seattle, Washington. PATIENTS: The primary cohort was a "resection cohort" of 203 patients who underwent partial pancreatic resection for an intraductal papillary mucinous neoplasm. MAIN OUTCOME MEASURES: The occurrence rate of lesions in the pancreatic remnant after resection for an intraductal papillary mucinous neoplasm, determined by use of an annual computed tomographic scan of the pancreas. RESULTS: New lesions were observed in the remnant of 17 of the 203 patients (8%) after a median follow-up of 40 months and a median interval of 38 months from the initial resection. Only 1 of these 17 patients with new lesions had a surgical margin that was positive for an adenoma at the time of resection. Comparing the 17 patients with new lesions with the 186 patients without new lesions, we found no difference in age, sex, procedure type, location in ductal system, original histology, or original margin status. In the new lesion group, no treatment was used for 12 patients who had side-branch disease detected by imaging (6% of all patients). Surgical treatment was used for 5 patients (2% of all patients): 2 with adenomas, 1 with a carcinoma in situ, and 2 with an invasive ductal carcinoma (1 with liver metastases). CONCLUSIONS: We found that, following a partial pancreatic resection for an intraductal papillary mucinous neoplasm and a 40-month follow-up with an annual computed tomographic scan of the pancreas, 17 of 203 patients (8%) developed a new intraductal papillary mucinous neoplastic lesion in the pancreatic remnant. As follow-up time increases, we suspect that new lesions will constantly appear regardless of whether the surgical margin was negative at initial resection.

Arch Surg. 2012 Feb 20;
Schold JD, Buccini LD, Kattan MW, Goldfarb DA, Flechner SM, Srinivas TR, Poggio ED, Fatica R, Kayler LK, Sehgal AR

OBJECTIVE: To evaluate the association of community health indicators with outcomes for kidney transplant recipients. DESIGN: Retrospective observational cohort study using multivariable Cox proportional hazards models. SETTING: Transplant recipients in the United States from the Scientific Registry of Transplant Recipients merged with health indicators compiled from several national databases and the Centers for Disease Control and Prevention, including the National Center for Health Statistics, the Behavioral Risk Factor Surveillance System, and the National Center for Chronic Disease Prevention and Health Promotion. PATIENTS: A total of 100 164 living and deceased donor adult (aged ≥18 years) kidney transplant recipients who underwent a transplant between January 1, 2004, and December 31, 2010. MAIN OUTCOME MEASURES: Risk-adjusted time to posttransplant mortality and graft loss. RESULTS: Multiple health indicators from recipients' residence were independently associated with outcomes, including low birth weight, preventable hospitalizations, inactivity rate, and smoking and obesity prevalence. Recipients in the highest-risk counties were more likely to be African American (adjusted odds ratio, 1.59, 95% CI, 1.51-1.68), to be younger (aged 18-39 years; 1.46; 1.32-1.60), to have lower educational attainment (

Arch Surg. 2012 Feb 20;
Katz MH, Hu CY, Fleming JB, Pisters PW, Lee JE, Chang GJ

OBJECTIVE: To calculate conditional survival estimates for patients with pancreatic adenocarcinoma. DESIGN: We constructed separate multivariate survival models adjusted for 7 clinicopathologic factors for patients who did and did not undergo radical surgical resection. PARTICIPANTS: Patients with pancreatic adenocarcinoma diagnosed between 1988 and 2005 included in the Surveillance Epidemiology End Results cancer registry. Main Outcome Measure  Internet browser-based calculator to compute personalized survival estimates. RESULTS: Conditional survival probabilities increased over time for all patients with pancreatic cancer regardless of patient characteristics, disease stage, or treatment. For patients with resected stage I, II, or III disease, 3-year conditional cancer-specific survival increased from 38% to 70%, 19% to 54%, and 8% to 39%, respectively, over the 3 years following diagnosis. The relative improvement in survival over time was larger for patients with advanced disease. A customizable, Internet browser-based clinical calculator was implemented that may be used to compute in real time personalized conditional survival estimates based on an individual's unique clinicopathologic profile. CONCLUSIONS: Conditional survival estimates provide a more accurate-and typically more optimistic-assessment of prognosis for patients with pancreatic cancer than traditional survival estimates that apply only at the initial diagnosis.