Jeffrey S. Carson

Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

Abdominal aortic aneurysm is a dynamic vascular disease characterized by inflammatory cell invasion and extracellular matrix degradation. Damage to elastin in the extracellular matrix results in release of elastin-derived peptides (EDPs), which are chemotactic for inflammatory cells such as monocytes. Their effect on macrophage polarization is less well known. Proinflammatory M1 macrophages initially are recruited to sites of injury, but, if their effects are prolonged, they can lead to chronic inflammation that prevents normal tissue repair. Conversely, anti-inflammatory M2 macrophages reduce inflammation and aid in wound healing. Thus, a proper M1/M2 ratio is vital for tissue homeostasis. Abdominal aortic aneurysm tissue reveals a high M1/M2 ratio in which proinflammatory cells and their associated markers dominate. In the current study, in vitro treatment of bone marrow–derived macrophages with EDPs induced M1 macrophage polarization. By using C57BL/6 mice, Ab-mediated neutralization of EDPs reduced aortic dilation, matrix metalloproteinase activity, and proinflammatory cytokine expression at early and late time points after aneurysm induction. Furthermore, direct manipulation of the M1/M2 balance altered aortic dilation. Injection of M2-polarized macrophages reduced aortic dilation after aneurysm induction. EDPs promoted a proinflammatory environment in aortic tissue by inducing M1 polarization, and neutralization of EDPs attenuated aortic dilation. The M1/M2 imbalance is vital to aneurysm formation.

National trends in minimally invasive and open operative experience of graduating general surgery residents: implications for surgical skills curricula development?

BACKGROUND The aim of this study was to analyze national trends in minimally invasive and open cases of all graduating residents in general surgery. METHODS A retrospective analysis was performed on data obtained from Accreditation Council for Graduate Medical Education logs (1999-2008) of graduating residents from all US general surgery residency programs. Data were analyzed using Mantel-Haenszel χ(2) tests and the Bonferroni adjustment to detect trends in the number of minimally invasive and open cases. RESULTS Minimally invasive procedures accounted for an increasing proportion of cases performed (3.7% to 11.1%, P < .0001), with a proportional decrease in open cases. An increase in minimally invasive procedures with a proportional decrease in open procedures was noted in subcategories such as alimentary tract, abdominal, vascular, thoracic, and pediatric surgery (P < .0001). CONCLUSIONS The results of this study demonstrate that general surgery residents in the United States are performing a greater number of minimally invasive and fewer open procedures for common surgical conditions.

Age and disease-related geometric and structural remodeling of the carotid artery

BACKGROUND Carotid artery geometry has been suggested as a risk factor for atherosclerotic carotid artery disease (ACD). Although normal aging and development of disease can both lead to geometric changes in the artery, whether geometric changes in a given artery actually predispose to disease or are just a consequence of remodeling during aging is unclear. We investigated carotid artery geometric changes with aging to identify geometric features associated with the presence of ACD. METHODS Carotid artery geometry was quantified by measuring carotid artery diameter, tortuosity, and bifurcation angle using three-dimensional reconstructions of thin-section computed tomography angiography scans in 15 healthy individuals (average age, 43 ± 18 years; range, 15-64 years). The same geometric features were measured in 17 patients (68 ± 10 years old) with unilateral ACD. Geometric features associated with presence of ACD were determined by using the nondiseased contralateral carotid artery as an intrinsic control. Elastin-stained carotid arteries were analyzed to assess age-related structural changes in 12 deceased individuals. RESULTS Increases were noted in bulb diameter (0.64 mm), bifurcation angle (10°), and tortuosity of the common carotid (CCA; 0.03) and internal carotid arteries (ICA; 0.04) for every decade of life. Density and continuity of circumferential and longitudinal elastin in the CCA and ICA decreased with age. Compared with normal carotid arteries, those with ACD demonstrated larger bulb diameters (P = .001) but smaller bifurcation angles (P = .001). CCA tortuosity (P = .038) increased in ACD arteries compared with normal carotid arteries, but ICA tortuosity was decreased (P = .026). CONCLUSIONS With increasing age, bulb diameter, tortuosity, and bifurcation angle increases in carotid arteries. These geometric changes may be related to degradation and fragmentation of intramural elastin. Arteries with atherosclerotic occlusive disease demonstrate decreased ICA tortuosity and smaller bifurcation angles compared with nondiseased carotid arteries.

Undescended testes: Does age at orchiopexy affect survival of the testis?

PURPOSE The optimal age at which to perform orchiopexy for cryptorchidism has long been debated. The aim of this study was to determine if age at orchiopexy affected testicular atrophy. METHODS A retrospective review of patients undergoing orchiopexy from 2000 to 2010 was conducted. An individual testis, rather than patient, was used as the dependent variable. A total of 349 testicles from 1126 charts (ICD-9=752.51) were identified. Primary study outcome was testicular survival without atrophy. RESULTS Mean follow up for the study was 25 months. There was postoperative atrophy in 27 testes (7.7%). Intraabdominal testicle was independently associated with increased postsurgical atrophy (p<0.0001). The odds of postsurgical atrophy were 15.66 times higher for an abdominal vs. inguinal location (95% CI: 5.5-44.6). Testicular atrophy was highest for orchiopexy at ages 13-24 months (n=16 of 133, 12%) vs. those less than 13 months (n=3 of 64, 5%), and those greater than 24 months (n=8 of 152, 5%) (p=0.0024). After adjusting for location, age was not statistically significant with postsurgical atrophy (p=0.055). CONCLUSIONS From this study we conclude that there is no increase in testicular atrophy in patients less than 13 months.

Antibodies against malondialdehyde-acetaldehyde adducts can help identify patients with abdominal aortic aneurysm

OBJECTIVE Abdominal aortic aneurysm (AAA) is a pathologic dilation of the aorta. Inflammation of the aortic wall has been shown to be involved in AAA formation. Malondialdehyde-acetaldehyde (MAA) adducts are MAA/protein hybrids with immunogenic, proinflammatory, and profibrotic properties. Levels of MAA adducts are elevated in patients with coronary artery disease; however, the role of MAA adducts in AAA is unclear. We hypothesize that levels of circulating antibodies against MAA adducts are increased in patients with AAA. METHODS Plasma samples were collected from mice and patients with AAA and control patients with atherosclerosis but not AAA. AAA was induced in mice by a standard CaCl2 protocol, with matching sham mice. Plasma levels of anti-MAA antibodies were quantified by enzyme-linked immunosorbent assay. RESULTS Patients with AAA exhibited higher levels of immunoglobulin G and immunoglobulin A anti-MAA antibody subtypes (P = .049 and .026, respectively) compared with control patients. Conversely, immunoglobulin M anti-MAA antibodies in AAA patients were lower compared with control patients (P = .018). In CaCl2-treated mice, immunoglobulin G anti-MAA antibodies were elevated after AAA formation (P = .006). CONCLUSIONS The pattern of anti-MAA antibodies is able to distinguish between patients with AAA and patients with atherosclerosis but no AAA. These results demonstrate that MAA adducts are associated with AAA and suggest that they may play a role in either initiating or propagating chronic inflammation in AAA.

Premature aortic smooth muscle cell differentiation contributes to matrix dysregulation in Marfan Syndrome

Thoracic aortic aneurysm and dissection are life-threatening complications of Marfan syndrome (MFS). Studies of human and mouse aortic samples from late stage MFS demonstrate increased TGF-β activation/signaling and diffuse matrix changes. However, the role of the aortic smooth muscle cell (SMC) phenotype in early aneurysm formation in MFS has yet to be fully elucidated. As our objective, we investigated whether an altered aortic SMC phenotype plays a role in aneurysm formation in MFS. We describe previously unrecognized concordant findings in the aortas of a murine model of MFS, mgR, during a critical and dynamic phase of early development. Using Western blot, gelatin zymography, and histological analysis, we demonstrated that at postnatal day (PD) 7, before aortic TGF-β levels are increased, there is elastic fiber fragmentation/disorganization and increased levels of MMP-2 and MMP-9. Compared to wild type (WT) littermates, aortic SMCs in mgR mice express higher levels of contractile proteins suggesting a switch to a more mature contractile phenotype. In addition, tropoelastin levels are decreased in mgR mice, a finding consistent with a premature switch to a contractile phenotype. Proliferation assays indicate a decrease in the proliferation rate of mgR cultured SMCs compared to WT SMCs. KLF4, a regulator of smooth muscle cell phenotype, was decreased in aortic tissue of mgR mice. Finally, overexpression of KLF4 partially reversed this phenotypic change in the Marfan SMCs. This study indicates that an early phenotypic switch appears to be associated with initiation of important metabolic changes in SMCs that contribute to subsequent pathology in MFS.

IL-1β (Interleukin-1β) and TNF-α (Tumor Necrosis Factor-α) Impact Abdominal Aortic Aneurysm Formation by Differential Effects on Macrophage Polarization

Objective— Abdominal aortic aneurysms are inflammatory in nature and are associated with some risk factors that also lead to atherosclerotic occlusive disease, most notably smoking. The purpose of our study was to identify differential cytokine expression in patients with abdominal aortic aneurysm and those with atherosclerotic occlusive disease. Based on this analysis, we further explored and compared the mechanism of action of IL (interleukin)-1&bgr; versus TNF-&agr; (tumor necrosis factor-&agr;) in abdominal aortic aneurysm formation. Approach and Results— IL-1&bgr; was differentially expressed in human plasma with lower levels detected in patients with abdominal aortic aneurysm compared with matched atherosclerotic controls. We further explored its mechanism of action using a murine model and cell culture. Genetic deletion of IL-1&bgr; and IL-1R did not inhibit aneurysm formation or decrease MMP (matrix metalloproteinase) expression. The effects of IL-1&bgr; deletion on M1 macrophage polarization were compared with another proinflammatory cytokine, TNF-&agr;. Bone marrow-derived macrophages from IL-1&bgr;−/− and TNF-&agr;−/− mice were polarized to an M1 phenotype. TNF-&agr; deletion, but not IL-1&bgr; deletion, inhibited M1 macrophage polarization. Infusion of M1 polarized TNF-&agr;−/− macrophages inhibited aortic diameter growth; no inhibitory effect was seen in mice infused with M1 polarized IL-1&bgr;−/− macrophages. Conclusions— Although IL-1&bgr; is a proinflammatory cytokine, its effects on aneurysm formation and macrophage polarization differ from TNF-&agr;. The differential effects of IL-1&bgr; and TNF-&agr; inhibition are related to M1/M2 macrophage polarization and this may account for the differences in clinical efficacy of IL-1&bgr; and TNF-&agr; antibody therapies in management of inflammatory diseases.

Massive adrenal vein aneurysm mimicking an adrenal tumor in a patient with hemophilia A: a case report and review of the literature

BackgroundVisceral venous aneurysms are exceedingly rare, and until now, there have been no reports of this phenomenon in the adrenal vasculature. This report details the first adrenal venous aneurysm reported in the literature. The aneurysm presented as an 18-cm mass that was initially suspected to be a hematoma or tumor on the basis of the complex medical history of the patient, which included hemophilia A and testicular cancer. After surgical excision, pathologic examination confirmed this mass to be a 15.9-cm adrenal vein aneurysm, the largest aneurysm of any type or location recorded in the medical literature.Case presentationA 58-year-old caucasian male with hemophilia A presented to the emergency room of another institution with abdominal pain, blood in the stool, and a history of diverticulosis and symptomatic hemorrhoids. A large, left-sided adrenal mass was detected by computed tomography, and because of the patient’s hemophilia A and imaging consistent with a hemorrhagic mass, a hematoma was initially suspected. The patient was transferred to our institution, monitored for further bleeding with a stable hospital course, and discharged from the hospital under close monitoring. After 7–8 weeks with no change in the size of the mass, concerns grew regarding increasing symptoms of both satiety and mass effects from the large anomaly, as well as about the patient’s complicated medical history, which also included cancer. Surgical excision was recommended because of the concerns about increasing symptoms and the possibility of a malignancy. Correction and maintenance of factor VIII levels were incorporated pre-, intra-, and postoperatively, and en bloc surgical resection was performed to minimize bleeding and provide oncologic extirpation of the mass. A bowling ball-sized mass was removed, and careful pathologic examination revealed the mass to be a venous adrenal aneurysm. After a brief hospital stay, the patient made a full recovery. Extensive review of the literature revealed 11 reports of adrenal artery aneurysms but no reported case of an adrenal aneurysm arising from the venous system.ConclusionsSeveral case reports suggest a correlation between hemophilia and aneurysms. In patients with inherited clotting disorders such as hemophilia A, aneurysms may present in atypical fashions and should be carefully ruled out.

Radiographically Negative, Asymptomatic, Sentinel Lymph Node Positive Cutaneous T-Cell Lymphoma in a 3-Year-Old Male: A Case Report

We present a case of a 3-year-old male originally diagnosed with a CD30+ anaplastic cutaneous T-cell lymphoma with no evidence of systemic disease after CT scan, PET scan, and bone marrow aspiration. Sentinel lymph node biopsy (SLNB) was performed as an additional step in the workup and showed microscopic disease. Current management/recommendations for cutaneous T-cell lymphoma do not include SLNB. Medical and surgical management of cutaneous malignancies is dramatically different for local versus advanced disease. Therefore adequate evaluation is necessary to properly stage patients for specific treatment. Such distinction in extent of disease suggests more extensive therapy including locoregional radiation and systemic chemotherapy versus local excision only. Two international case reports have described SLNB in cutaneous T-cell lymphoma with one demonstrating evidence of node positive microscopic disease despite a negative metastatic disease workup. This case is being presented as a novel case in a child with implications including lymphoscintigraphy and SLNB as a routine procedure for evaluation and staging of cutaneous T-cell lymphoma if the patient does not demonstrate evidence of metastatic disease on routine workup.

(Sar-1,D-Ala-12)Galanin-1-16-NH 2

(Sar-1,D-Ala-12)Galanin-1-16-NH2 is a peptide fragment of the endogenous neurotransmitter …