The role of carotid surgery in prevention of stroke in frail elderly patients.
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Aged↗
Biomedical subjects
Glenn C Hunter
Publications and source records attributed to Glenn C Hunter.
Current advances in the pathogenesis of varicose veins.
Varicose veins have a wide prevalence and are characterized by their tortuous, dilated, and serpentine appearance. This pattern is the result of disruption of the normal arrangement of the extracellular matrix (ECM) and smooth muscle cells (SMC) in veins. Valvular incompetence and the effect of increased hydrostatic pressure have been implicated in the pathogenesis of varicose veins. Alterations in the ECM and varied expression of metalloproteinases and their inhibitors can effect changes in venous wall remodeling. Gene expression and specific candidate markers have been identified in varicose veins. Differential gene transcription may influence the adaptive response of the venous wall to stimuli and the remodeling of the ECM that leads to the development of varicose veins.
Extracellular Matrix Proteins↗
Delayed presentation of traumatic aortocaval fistula: a report of two cases and a review of the associated compensatory hemodynamic and structural changes.
Chronic aortocaval fistula (ACF) is a rare complication of gunshot wounds to the abdomen. Herein we report two cases of traumatic ACF: one asymptomatic and the other presenting with congestive heart failure (CHF) 20 and 30 years, respectively, after their initial injury. The recent onset of CHF, the presence of a continuous abdominal bruit, and, in the second patient, a history of penetrating trauma suggested the diagnosis of ACF. The diagnosis was confirmed by computed tomography scanning in both patients. Surgical repair of the ACF in the symptomatic patient resulted in resolution of the CHF and reversed the dilatation of the aorta and inferior vena cava. The asymptomatic patient was lost to follow-up. CHF in a young male patient with a history of penetrating abdominal trauma should alert the surgeon to this rare complication.
Abdominal Injuries↗
Disseminated intravascular coagulation scoring systems in the critically ill.
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Algorithms↗
Gene therapy and vein graft patency in coronary artery bypass graft surgery.
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Coronary Artery Bypass↗
Apoptosis of allospecifically activated human helper T cells is blocked by calcineurin inhibition.
BACKGROUND: Classical transplantation immunosuppression relies heavily upon the interruption of interleukin-2 (IL-2) signaling by calcineurin inhibition. However, recent evidence in murine models suggests that IL-2 is necessary for activation-induced cell death (AICD) of allograft-specific lymphocytes. METHODS: We examined the apoptotic effects of the calcineurin inhibitor cyclosporine A and mTOR inhibitor rapamycin on the apoptotic alterations that occur in allospecifically activated human lymphocytes in a one-way mixed lymphocyte culture (MLC). RESULTS: Cyclosporine increased caspase-3 activation in MLC, which corresponded with a decrease in lymphocyte apoptosis in MLC. Cyclosporine also reduced apoptosis in the CD4+ helper T cell subset, while CD8+ cells had similar or increased apoptosis when compared to controls. In contrast, rapamycin-treated cultures had normal levels of CD4+ T cell apoptosis when compared to control MLC, with decreases seen in CD8+ T lymphocytes. CONCLUSIONS: In humans, blockade of IL-2 receptor signal with rapamycin allows apoptosis of allospecifically activated CD4+ lymphocytes to occur, while blockade of IL-2 production with cyclosporine results in decreased apoptosis in this T cell subset. As helper T cells are integral to the immune response, these results may explain the tolerogenic effects of rapamycin.
Apoptosis↗
Arterialization of deep dorsal vein of penis for penile ischemia.
Penile ischemia, a rare complication of diabetic end-stage renal disease, is usually treated by penectomy once conservative measures fail. We present a patient with diabetes mellitus and end-stage renal disease with penile ischemia that was successfully treated with an arteriovenous interposition bypass graft between the common femoral artery and the deep dorsal vein of the penis. Retrograde flow into the corpus spongiosum resulted in immediate pain relief and healing of the ischemic lesions.
Aged↗
Methemoglobinemia: an unusual cause of postoperative cyanosis.
Methemoglobinemia, although rare, must be considered in surgical patients presenting with acute respiratory distress and cyanosis. We report two cases of methemoglobinemia in patients undergoing aortic reconstruction. The first patient developed methemoglobinemia while on a nitroglycerin infusion, and the second after receiving benzocaine spray before intubation. Both patients were treated with methylene blue and ascorbic acid, with resolution of their hypoxia and cyanosis. The pathophysiology, etiology, diagnosis, and treatment of methemoglobinemia are reviewed.
Aged↗
Aortic eNOS expression and phosphorylation in Apo-E knockout mice: differing effects of rapamycin and simvastatin.
BACKGROUND: The inhibition of nitric oxide (NO) by hypercholesterolemia may be mediated, in part, by interactions with caveolin-1 (Cav-1). Because of the facilitatory effects of statins on endothelial function and the adverse effects of rapamycin (RAPA) on plasma lipids, we compared the effects of simvastatin (SMV) and RAPA on endothelial NO synthase (eNOS) and Cav-1 protein expression and phosphorylation in the aortas of apolipoprotein E (Apo-E) knockout (-/-) mice. METHODS: Apo-E -/- mice (n = 38) fed a high-cholesterol diet were given SMV (100 mg/kg/day po), RAPA (3 mg/kg/day ip), or no treatment for 10 weeks. Blood was drawn for serum lipid analysis, and protein was extracted for Western immunoblotting. Selected aortic specimens from 2 animals in each group were examined by histology and immunohistochemistry. The data are expressed as the mean +/- SEM and compared by the Student t test and ANOVA. Significance was established as P < .05. RESULTS: Lipid levels at 10 weeks were similar in the 3 groups except for higher triglyceride levels in RAPA-treated animals. eNOS expression was highest in RAPA-treated mice, but the p-eNOS to eNOS protein expression ratio was significantly greater in the SMV treatment group compared to both RAPA and controls (P < .05). Both Cav-1 and p-Cav-1 expression was significantly lower in the SMV-treated animals (P < .05) compared to mice treated with RAPA. CONCLUSIONS: Although eNOS expression was greatest in the RAPA-treated mice, the expression of p-eNOS was similar in the RAPA- and SMV-treated animals. The increase in eNOS induced by RAPA and the inverse relationship between p-eNOS and Cav-1 protein expression observed with SMV treatment suggest different mechanisms for the regulation of aortic eNOS expression in Apo-E mice by these 2 agents.
Animals↗
Immunomodulation of hepatic ischemic injury via increased Bcl-X(L) and decreased Bcl-X(S).
BACKGROUND: Although classic ischemia-reperfusion injury is mediated by reactive oxygen intermediaries, increasing evidence implicates a role for immune-mediated apoptosis during ischemic injury in transplantation. Herein, we report the effects of polyclonal rabbit anti-thymocyte globulin (rATG) on mediators of hepatic apoptosis during cold storage. METHODS: Three-month-old male Lewis rats were placed under halothane anesthesia and the portal vein cannulated. University of Wisconsin (UW) solution (35 ml) with (n = 5) and without (n = 5) 20 mg/kg anti-rat rATG was infused before hepatectomy. The liver was stored in UW solution +/- rATG (143 ng/ml) at 4 degrees C for various times up to 24 h. Specimens were terminal deoxyuridine nick end labeling-stained for apoptosis. Tissue lysates were analyzed by Western blotting and densitometry. RESULTS: Compared to UW alone, significantly fewer apoptotic cells were present in UW + rATG perfused and stored livers. There were early and sustained significant increases in Bcl-X(L) and decreases in Bcl-X(S) with rATG. There was an initial, but not sustained, significant decrease in Bax with rATG. Moreover, there was a significant one-third decrease in caspase-9 production with rATG at 0, 6, 12, and 18 h. CONCLUSION: Decreased proapoptotic Bcl-X(S) and increased antiapoptotic Bcl-X(L), as well as decreased downstream proapoptotic caspase-9 expression, during liver ischemia after treatment with rATG, all favor cell survival. Because apoptotic ischemic injury results in allograft dysfunction, preservation strategies that ameliorate such immunological effects may improve organ function.
Adenosine↗
Differential effects of interleukin-2 blockade on apoptosis in naïve and activated human lymphocytes.
BACKGROUND: Certain transplantation immunosuppressive strategies are primarily based on the interruption of interleukin (IL)-2 signaling by calcineurin inhibition or anti-IL-2 receptor-antibody blockade. However, recent evidence suggests that IL-2 is necessary for peripheral deletion of allograft-specific lymphocytes. STUDY DESIGN: In this study, we examined the apoptotic effects of the calcineurin inhibitor, cyclosporine A, the chimeric anti-interleukin-2 receptor monoclonal antibody, basiliximab, and the rabbit antihuman thymocyte preparation Thymoglobulin (rATG) on phytohemagglutinin-activated human lymphocyte models designed to simulate initial exposure to the graft or ongoing rejection of the graft. RESULTS: We found that rATG increases Fas expression, decreases Bcl-2 expression, and induces early apoptosis in naïve lymphocytes. However, rATG has more of a necrotic effect on activated lymphocytes. Basiliximab and cyclosporine had little effect on apoptosis, but did alter Bcl-2 and Fas expression. CONCLUSIONS: Compared with IL-2 pathway inhibitors, rATG increases lymphocyte apoptosis, probably via Bcl-2 pathway inhibition. Because apoptosis is required for the development of graft tolerance, induction strategies that use IL-2-independent pathways may be advantageous.
Animals↗
Differential gene expression in primary and recurrent carotid stenosis.
Apoptosis of the cellular components of complex atherosclerotic plaque may lead to plaque instability and rupture. In this study, five primary plaques and one recurrent fibrointimal lesion obtained from patients undergoing carotid endarterectomy for symptomatic carotid stenosis > or = 70% were analyzed by immunohistochemistry and cDNA microarray to identify gene expression patterns that may determine plaque susceptibility or resistance to apoptosis. Immunohistochemistry showed expression of active caspase 3, an effector of apoptosis, in macrophages and lymphocytes surrounding the lipid core, in smooth muscle cells in the fibrous cap, and media of primary plaques as well as in occasional smooth muscle cells in the recurrent lesion. Among the genes demonstrating increased expression in primary plaques were IGFR2, DR4, DAPK1, Bak, and ERK 1 and 2 and those showing decreased expression included the TNF receptors 1 and 2, akt1, and IGFBP3. When comparing the recurrent lesion to the normal tissue, the expression of 13 genes was decreased by 3-fold, including IGFBP2 and IGFBP3, and none were increased by more than 1.5-fold. The analysis of gene expression patterns in primary and recurrent stenotic lesions provides a powerful approach to identify the signaling pathways that alter cellular apoptotic patterns in such lesions.
Apoptosis↗
Altered expression of vascular endothelial growth factor and its receptors in normal saphenous vein and in arterialized and stenotic vein grafts.
BACKGROUND: Myointimal thickening is a major cause saphenous vein graft failure. The prominence of medial and adventitial microvessels in stenotic vein grafts and the known angiogenic effects of vascular endothelial growth factor (VEGF) lead us to investigate the expression of VEGF and its receptors in vein graft arterialization and stenosis. METHODS: Normal and arterialized vein graft segments were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) for expression of VEGF-R1 (flt), VEGF-R2 (KDR), and neuropilin-1. The cells expressing VEGF, VEGF-R1, VEGF-R2, and neuropilin-1 were identified in normal, stenotic, and arterialized vein graft segments by immunohistochemistry. RESULTS: Vascular endothelial growth factor, detected in the wall in endothelial cells and adventitial microvessels in normal vein, localized to smooth muscle cells, endothelial cells and adventitial microvessels in arterialized and stenotic vein. VEGF-R1 and VEGF-R2 were expressed infrequently on endothelial cells, macrophages, and smooth muscle cells in arterialized and stenotic vein. Neuropilin-1 was detected in all specimens. RT-PCR demonstrated significantly greater expression of neuropilin-1 in normal vein compared with arterialized vein (P <0.05). CONCLUSIONS: The differential expression of VEGF and its receptors in normal, arterialized, and stenotic vein grafts suggests that alterations in VEGF/VEGF-R2/neuropilin-1 interactions may be important determinants of the adaptive response of vein grafts to arterialization.
Graft Occlusion, Vascular↗
Morphologic characteristics of varicose veins: possible role of metalloproteinases.
BACKGROUND: Although varicose veins are a common cause of morbidity, etiologic factors predisposing to dilatation, elongation, and tortuosity of the saphenous vein and its tributaries are poorly understood. We compared histologic features of normal and varicose saphenous veins and investigated the role of enzyme or inhibitor imbalance in development of varicosities. METHODS: Eight normal and 10 varicose (C(2,3)E(P,S)A(S)P(R,O)) vein segments were used for this analysis. Matrix metalloproteinase (MMP) expression and activity were analyzed with Western blotting and zymography. Venous architecture and protein localization were determined with histology and immunohistochemistry. RESULTS: Western blot analysis demonstrated the presence of MMP- 1, MMP-2, MMP-9, and MMP-12, as well as small quantities of tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 in protein isolates from normal and varicose veins. Both vein types demonstrated MMP-2, MMP-9, and MMP-12 activity by gelatin zymography, although varicose vein expressed less MMP-9 activity than normal vein did. Compared with normal veins, changes in varicose veins were not uniformly distributed along the circumference; areas of intimal thickening were often interspersed with focal areas of dilatation. Fragmentation of elastic lamellae and loss of circular and longitudinal muscle fibers were evident in the varicosities. Focal aggregates of macrophages were detected within the media and adventitia of both normal and varicose veins. MMP-1 and MMP-9 were expressed in both types of vein segments; however, their immunohistochemical localization was distinctly different. In normal vein, endothelial cells, occasional smooth muscle cells (SMC), and adventitial microvessels expressed MMP-1, whereas its expression was localized to fibroblasts, SMC, and endothelial cells throughout involved portions of varicose veins. MMP-9 was localized to endothelial cells, medial SMC, and adventitial microvessels in both normal and varicose veins, although varicose veins demonstrated increased medial smooth muscle cell staining. MMP-12 was found in SMC and fibroblasts in both normal and varicose veins. Neither TIMP-1 nor TIMP-2 were detected with immunohistochemistry in any specimens examined. CONCLUSIONS: There are distinct differences in the structural architecture and localization of MMP expression in normal and varicose veins. Although the changes observed are not sufficiently definitive to enable a causal relationship, they do suggest a possible mechanism for the alterations in matrix composition observed between normal and varicose veins.
Aged↗
Deep venous thrombosis prophylaxis in trauma: improved compliance with a novel miniaturized pneumatic compression device.
OBJECTIVE: Intermittent pneumatic compression (IPC) devices prevent lower-extremity deep venous thrombosis (LEDVT) when used properly, but compliance remains an issue. Devices are frequently discontinued when patients are out of bed, and they are rarely used in emergency departments. Trauma patients are at high risk for LEDVT; however, IPCs are underused in this population because of compliance limitations. The hypothesis of this study was that a new miniaturized, portable, battery-powered pneumatic compression device improves compliance in trauma patients over that provided by a standard device. METHODS: This was a prospective trial in which trauma patients (mean age, 46 years; revised trauma score, 11.7) were randomized to DVT prophylaxis with a standard calf-length sequential IPC device (SCD group) or a miniaturized sequential device (continuous enhanced-circulation therapy [CECT] group). The CECT device can be battery-operated for up to 6 hours and worn during ambulation. Timers attached to the devices, which recorded the time each device was applied to the legs and functioning, were used to quantify compliance. For each subject in each location during hospitalization, compliance rates were determined by dividing the number of minutes the device was functioning by the total minutes in that location. Compliance rates for all subjects were averaged in each location: emergency department, operating room, intensive care unit, and nursing ward. RESULTS: Total compliance rate in the CECT group was significantly higher than in the SCD group (77.7% vs. 58.9%, P =.004). Compliance in the emergency department and nursing ward were also significantly greater with the CECT device (P =.002 and P =.008 respectively). CONCLUSIONS: Previous studies have demonstrated that reduced compliance with IPC devices results in a higher incidence of LEDVT. Given its ability to improve compliance, the CECT may provide superior DVT prevention compared with that provided by standard devices.
Aged↗
Use of kidneys from hepatitis C seropositive donors shortens waitlist time but does not alter one-yr outcome.
Utilization of hepatitis C seropositive kidney donors remains controversial. We examined the use of hepatitis C seropositive donors for renal transplantation. Data for creatinine, liver function tests, cold ischemia time, and graft and patient survival were analyzed from 20 hepatitis C seropositive recipients receiving cadaveric renal allografts from seropositive donors and were compared with 20 hepatitis C seropositive recipients receiving allografts from seronegative donors. Recipients receiving a kidney from a hepatitis C seropositive donor were on the waitlist for 9.9 +/- 1.8 months, compared with 17.8 +/- 3.3 months for those receiving a kidney from a seronegative donor (p < 0.05). There were no significant differences in graft or patient survival. Incidences of acute cellular rejection and acute tubular necrosis were similar. There were no significant differences in creatinine, alanine aminotransferase, alkaline phosphatase, or bilirubin values. While there was a significant difference in aspartate aminotransferase at 2 wk and 6 months, these differences were of questionable clinical importance. In conclusion, donor seropositivity for hepatitis C should not preclude renal transplantation into a hepatitis C seropositive recipient and utilization of these organs decreases waitlist time for hepatitis C seropositive recipients.
Adult↗
Mitochondrial integrity and function in atherogenesis.
BACKGROUND: Coronary atherosclerotic disease remains the leading cause of death in the Western world. Although the exact sequence of events in this process is controversial, reactive oxygen and nitrogen species (RS) likely play an important role in vascular cell dysfunction and atherogenesis. Oxidative damage to the mitochondrial genome with resultant mitochondrial dysfunction is an important consequence of increased intracellular RS. METHODS AND RESULTS: We examined the contribution of mitochondrial oxidant generation and DNA damage to the progression of atherosclerotic lesions in human arterial specimens and atherosclerosis-prone mice. Mitochondrial DNA damage not only correlated with the extent of atherosclerosis in human specimens and aortas from apolipoprotein E(-/-) mice but also preceded atherogenesis in young apolipoprotein E(-/-) mice. Apolipoprotein E(-/-) mice deficient in manganese superoxide dismutase, a mitochondrial antioxidant enzyme, exhibited early increases in mitochondrial DNA damage and a phenotype of accelerated atherogenesis at arterial branch points. CONCLUSIONS: Mitochondrial DNA damage may result from RS production in vascular tissues and may in turn be an early event in the initiation of atherosclerotic lesions.
Animals↗
Polymorphic metabolizing genes and susceptibility to atherosclerosis among cigarette smokers.
Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smoking is a major contributing factor to the disease. Like cigarette smoking in lung cancer, genetic susceptibility may be an important factor in determining who is more likely to develop AR. However, the current emphasis has been on susceptibility based on altered cardiovascular homeostasis. In this investigation, we studied 120 AR patients and 90 matched controls to elucidate the association between polymorphisms in some metabolizing genes (GSTM1, GSTT1, CYP2E1, mEH, PON1, and MPO) and susceptibility to AR. We found that the GSTT1 null allele and the fast allele of mEH(*) (exon 4) are associated with risk for AR. Furthermore, the combined genotypes GSTM1 null/ CYP2E1(*)5B, GSTM1 null/mEH YY, and GSTT1 null/mEH YY are significantly associated with susceptibility to AR (OR = 15.42, 95% CI = 1.33-77.93, P = 0.021; OR = 3.48, 95% CI = 1.63-8.04, P = 0.0008; OR = 3.4; 95% CI = 0.99-17.38, P = 0.05; respectively). We have also conducted cytogenetic analysis to elucidate if induction of chromosome aberrations (CAs) is a biomarker of AR susceptibility. We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05). This association was not found among nonsmokers. In addition, individuals who had inherited the CYP2E1(*)5B allele exhibited a significantly higher CA frequency (8.0 +/- 0.82) compared to those with the CYP2E1 wild-type genotype (4.31 +/- 0.35). Since the analysis of genetic susceptibility factors is still in its infancy, our study may stimulate additional investigations to understand the roles of genetic susceptibility and cigarette smoking in AR.
Adult↗