It is encouraging that we are improving the technical aspects of treatment modalities for biliary atresia. However, it is clear that more needs to be done to best develop new treatment plans while applying the modalities we have (porto-enterostomy or liver transplantation or both) in a way that will afford the best survival and quality-of-life. This review article will discuss a number of points that are vital to improving care and illustrates the need to further scrutinize treatment decisions.
View details for DOI 10.1111/petr.12040
View details for Web of Science ID 000315467000009
View details for PubMedID 23347466
NK cells are important in the immune response against tumors and virally infected cells. A balance between inhibitory and activating receptors controls the effector functions of NK cells. We examined the fate of circulating NK cells and the expression of the NK cell-activating receptors in pediatric liver transplant recipients. Blood specimens were collected from 38 pediatric liver transplant recipients before transplant, and at one wk, one, three, six, and nine months, and one yr post-transplant. PBMCs were isolated and analyzed for the levels of NK cell activation receptors NKp30, NKp46, and NKG2D in the CD56(dim) CD16(+) and CD56(bright) CD16(+/-) subsets of NK cells. We demonstrated that there is a significant decrease in the percentage of circulating NK cells post-transplant (pretransplant 7.69 ± 1.54 vs. one wk post-transplant 1.73 ± 0.44) in pediatric liver transplant recipients. Interestingly, NKp30 expression is significantly increased, while NKp46 and NKG2D levels remain stable on the NK cells that persist at one wk post-transplant. These data indicate that the numbers and subsets of circulating NK cells are altered in children after liver transplantation.
View details for DOI 10.1111/j.1399-3046.2012.01653.x
View details for Web of Science ID 000300709600017
View details for PubMedID 22360401
Inflammation is associated with the formation of aortic aneurysm. This study investigates the role of inducible Cys-X-Cys chemokine receptor 3 and its ligands in the pathogenesis of arterial aneurysms.Plasma samples from patients with or without a diagnosis of thoracic aortic aneurysms were analyzed by enzyme-linked immunosorbent assay for the T-helper 1 cytokine interferon-? and the interferon-?-inducible chemokine receptor 3 ligands: interferon-inducible protein-10, interferon-inducible T-cell alpha chemoattractant, and monokine induced by interferon gamma. Patient charts were reviewed for demographics, initial aortic diameter, and growth rates. Aneurysm diameter and growth rates were correlated with plasma cytokine and chemokine levels using linear regression analysis. We used an animal model of aneurysm formation, where calcium chloride is applied topically to the carotid arteries of wild-type and Cys-X-Cys chemokine receptor 3(-/-) mice. After 10 weeks, the arteries were harvested and analyzed by histology and immunohistochemistry.Patients with thoracic aortic aneurysms had significant elevations in circulating interferon-?, interferon-inducible protein-10, interferon-inducible T-cell alpha chemoattractant, and monokine induced by interferon gamma compared with referent patients (P < .001). Cytokine and chemokine plasma levels did not correlate with aneurysm size or growth rates. Cys-X-Cys chemokine receptor 3(-/-) mice were protected from aneurysm formation and showed decreased vascular infiltration by CD45(+) leukocytes.Elevated plasma levels of interferon-? and Cys-X-Cys chemokine receptor 3-binding chemokines are present in patients with thoracic aortic aneurysms. The Cys-X-Cys chemokine receptor 3 receptor is necessary for vascular inflammation and the formation of arterial aneurysms in mice.
View details for DOI 10.1016/j.jtcvs.2011.08.036
View details for Web of Science ID 000300617300030
View details for PubMedID 21962843
View details for DOI 10.1007/s10620-011-1776-x
View details for Web of Science ID 000295164600020
View details for PubMedID 21695402
View details for DOI 10.1007/s10620-010-1471-3
View details for Web of Science ID 000286664900007
View details for PubMedID 21063775
Atherosclerosis is an inflammatory disease in which interferon (IFN)-gamma, the signature cytokine of Th1 cells, plays a central role. We investigated whether interleukin (IL)-17, the signature cytokine of Th17 cells, is also associated with human coronary atherosclerosis.Circulating IL-17 and IFN-gamma were detected in a subset of patients with coronary atherosclerosis and in referent outpatients of similar age without cardiac disease but not in young healthy individuals. IL-17 plasma levels correlated closely with those of the IL-12/IFN-gamma/CXCL10 cytokine axis but not with known Th17 inducers such as IL-1beta, IL-6, and IL-23. Both IL-17 and IFN-gamma were produced at higher levels by T cells within cultured atherosclerotic coronary arteries after polyclonal activation than within nondiseased vessels. Combinations of proinflammatory cytokines induced IFN-gamma but not IL-17 secretion. Blockade of IFN-gamma signaling increased IL-17 synthesis, whereas neutralization of IL-17 responses decreased IFN-gamma synthesis; production of both cytokines was inhibited by transforming growth factor-beta1. Approximately 10-fold fewer coronary artery-infiltrating T helper cells were IL-17 producers than IFN-gamma producers, and unexpectedly, IL-17/IFN-gamma double producers were readily detectable within the artery wall. Although IL-17 did not modulate the growth or survival of cultured vascular smooth muscle cells, IL-17 interacted cooperatively with IFN-gamma to enhance IL-6, CXCL8, and CXCL10 secretion.Our findings demonstrate that IL-17 is produced concomitantly with IFN-gamma by coronary artery-infiltrating T cells and that these cytokines act synergistically to induce proinflammatory responses in vascular smooth muscle cells.
View details for DOI 10.1161/CIRCULATIONAHA.108.827618
View details for Web of Science ID 000264243700011
View details for PubMedID 19255340
Stage III, locally advanced non-small-cell lung cancer represents an incredibly heterogeneous group of patients. The majority of patients are treated with curative intent, but optimal therapy is controversial and the role of surgery is not well defined. Consensus has shown that the majority of patients with IIIB disease are not amenable to resection. The exceptions are selected patients with tumor stage 4 (T4) by virtue of a satellite nodule or those with isolated invasion of the spine, superior sulcus, carina, or vena cava. Surgery is more widely used for stage IIIA disease. Patients with nodal stage 2 (N2) disease represent the largest population of patients in stage III. Increasing evidence supports the use of surgery as part of a multimodality approach for N2 disease. The impact of surgery is partially determined by the bulk of the mediastinal node involvement. Patients with micrometastatic disease and single-station nodal involvement have the greatest chance for cure, and surgery appears to play a significant role in their treatment. Patients with bulky multistation disease are frequently not amenable to complete resection and may be best approached with definitive chemotherapy and radiation. In addition, the ability to sterilize mediastinal lymph nodes with induction therapy correlates strongly with survival following resection, but the ideal induction regime that balances the safety and efficacy has yet to be determined.
View details for PubMedID 17588348
View details for DOI 10.1016/j.athoracsur.2006.12.018
View details for Web of Science ID 000245975700002
Although type A aortic dissections represent a surgical emergency, some patients present late after the onset of symptoms. Optimal management of this cohort has not been defined.Data on 195 patients with type A dissections followed up at a single institution between 1985 and 2005 were collected prospectively. Of these, 93 patients (47.2%) presented 48 hours or later after the initial onset of pain (group A), and the remaining 102 patients underwent immediate operative repair (group B). Median follow-up was 41.8 months (range, 0 to 386 months).Patients in group A were older (68.8 versus 59.3 years, p = 0.0005) and had a higher incidence of coronary artery disease (42.5% versus 14.6%, p < 0.0001), pulmonary disease (26.6% versus 8.4%, p = 0.0023), and congestive heart failure (14.1% versus 1.0%, p = 0.0004). Long-term survival was similar, although group B showed a trend toward improved 30-day mortality (16.5% versus 8.7%, p = 0.1035). Of the 92 patients in group A, 53 (57.6%) eventually underwent operative repair a median of 8.2 days after symptom onset. There was a trend toward improved long-term survival among patients undergoing repair (p = 0.1031).Initial medical management with interval operative repair of selected patients referred greater than 2 days following an acute type A dissection is a viable option. Delayed repair after optimization of the clinical condition and detailed evaluation of concomitant diseases results in excellent long-term results.
View details for PubMedID 17462364
Patients with bicuspid aortic valve (BAV) are at risk for valvular disease and ascending aortic aneurysms and dissections. Although others have investigated the need for concomitant repair, the natural history of aortic disease has not been addressed.A review of our institutional clinical database identified 514 patients (326 male, 188 female) with unrepaired ascending aortic aneurysms followed from 1985 to 2005. Seventy patients (13.4%) diagnosed with BAV form group A; the remaining 445 patients form group B. Growth rates and risk factors for complications were assessed.Patients in group A had a lower incidence of hypertension (p = 0.0185), carotid artery disease, and stroke (p = 0.0184), and presented at an earlier age (49.0 versus 64.2 years, p < 0.0001). Group A also had a higher rate of aortic growth (0.19 versus 0.13 cm/year, p = 0.0102). The incidence of rupture and dissection were similar. Overall survival was better among patients with BAV (p < 0.0001). Among patients with BAV, those with aortic stenosis had a higher risk of rupture, dissection, or death before operative repair than did those with normally functioning valves (odds ratio 10.475, 95% confidence interval: 1.153 to 95.155).Aortic stenosis presents a significant added risk for patients with aneurysmal disease in the face of BAV. Despite faster rates of growth, however, patients with BAV have similar rates of aortic rupture, dissection, and death and improved long-term survival. Contributing to this finding may be the lower incidence of comorbidities, the younger age at presentation, and the more attentive follow-up with earlier operative repair.
View details for DOI 10.1016/j.athoracsur.2006.10.074
View details for Web of Science ID 000245178900017
View details for PubMedID 17383337
Inflammation is associated with the pathogenesis of coronary atherosclerosis, although the mechanisms remain unclear. We investigated whether cytokine secretion by innate immune responses could contribute to the production of proarteriosclerotic Th1-type cytokines in human coronary atherosclerosis. Cytokines were measured by ELISA in the plasma of patients with coronary atherosclerosis undergoing cardiac catheterization. IL-18 was detected in all subjects, whereas a subset of patients demonstrated a coordinated induction of other IFN-gamma-related cytokines. Specifically, elevated plasma levels of IL-12 correlated with that of IFN-gamma and IFN-gamma-inducible chemokines, defining an IFN-gamma axis that was activated independently of IL-6 or C-reactive protein. Systemic inflammation triggered by cardiopulmonary bypass increased plasma levels of the IFN-gamma axis, but not that of IL-18. Activation of the IFN-gamma axis was not associated with acute coronary syndromes, but portended increased morbidity and mortality after 1-year follow-up. IL-12 and IL-18, but not other monokines, elicited secretion of IFN-gamma and IFN-gamma-inducible chemokines in human atherosclerotic coronary arteries maintained in organ culture. T cells were the principal source of IFN-gamma in response to IL-12/IL-18 within the arterial wall. This inflammatory response did not require, but was synergistic with and primed for TCR signals. IL-12/IL-18-stimulated T cells displayed a cytokine-producing, nonproliferating, and noncytolytic phenotype, consistent with previous descriptions of lymphocytes in stable plaques. In contrast to cognate stimuli, IL-12/IL-18-dependent IFN-gamma secretion was prevented by a p38 MAPK inhibitor and not by cyclosporine. In conclusion, circulating IL-12 may provide a mechanistic link between inflammation and Th1-type cytokine production in coronary atherosclerosis.
View details for Web of Science ID 000243120900067
View details for PubMedID 17182600
Since the first description of aortic dissection in the 1700s, the understanding and treatment of this catastrophic disease has evolved. Aortic dissections are identified as a tear in the aortic intima and inner layer of the media that allows for blood flow within the aortic wall. The area of the vessel involved determines its classification. The classification, in turn, helps to predict outcomes, which allows for appropriate treatment planning. The goal of this article is to outline the operative indications and timing for Stanford type A and type B dissections, based on prior reported data and our own clinical experience with 176 patients treated surgically at the Yale Center for Thoracic Aortic Disease. With this data we will revisit the importance of looking at each patient individually to devise an appropriate operative plan, with the knowledge that treatment for type A dissections is operative and treatment for type B dissections is medical unless patients present with actual or impending rupture, malperfusion, or failure of medical management.
View details for PubMedID 16253827
To elucidate molecular mechanism(s) of cellular response to mercaptopurine, a widely used antileukemic agent, we assessed mercaptopurine (MP) sensitivity in mismatch repair (MMR) proficient and MMR deficient human acute lymphoblastic leukemia (ALL) cells. Sensitivity to thiopurine cytotoxicity was not dependent on MMR (i.e., MutSalpha) competence among six cell lines tested. Using electrophoretic mobility shift assay analysis, we found that the incubation of nuclear extracts from ALL cells with synthetic 34-mer DNA duplexes containing deoxythioguanosine (G(S)) within either G(S).T or G(S).C pairs, resulted in formation of a DNA-protein complex distinct from the DNA-MutSalpha complex and unaffected by ATP. Isolation and sequence analysis of proteins involved in this DNA-protein complex identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a component. Western blot analysis of nuclear extracts from a panel of human lymphoblastic leukemia cell lines revealed markedly different basal levels of GAPDH in nuclei, which was significantly related to thiopurine sensitivity (p = 0.001). Confocal analysis revealed markedly different intracellular distribution of GAPDH between nucleus and cytosol in six human ALL cell lines. Redistribution of GAPDH from cytosol to nucleus was evident after MP treatment. These findings indicate that a new DNA-protein complex containing GAPDH and distinct from known MMR protein-DNA complexes binds directly to thioguanylated DNA, suggesting that this may act as a sensor of structural alterations in DNA and serve as an interface between these DNA modifications and apoptosis.
View details for Web of Science ID 000166549200026
View details for PubMedID 11160874