The role of carotid surgery in prevention of stroke in frail elderly patients.
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Aged↗
Biomedical subjects
Kenneth J Woodside
Publications and source records attributed to Kenneth J Woodside.
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↗
Postoperative acute respiratory distress syndrome development in the thoracic surgery patient.
Acute respiratory distress syndrome (ARDS) in the thoracic surgery patient is a dreaded complication that occurs in 4% to 5% of pneumonectomies. This peculiar syndrome is indistinct from other forms of ARDS yet is associated with an exceedingly higher mortality rate. Current management parallels ARDS treatment of other etiologies.
Humans↗
Disseminated intravascular coagulation scoring systems in the critically ill.
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Algorithms↗
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↗
Streptococcus viridans endocarditis from tongue piercing.
Body piercing and tattooing have undergone a revival in popularity. We present the case of a 27-year-old man with a recent tongue piercing and infective endocarditis of the aortic valve. He was treated with a 6-week course of intravenous antibiotics, but eventually required a Ross procedure for progressive aortic insufficiency.
Adult↗
Transgenic and gene knock-out techniques and burn research.
The development of transgenic technology has given researchers a powerful tool to examine biological effects, and the response to injury is no exception. Techniques such as pronuclear injection, targeted homologous recombination, and Cre/loxP gene excision are being used to construct animals with specific genetic designs; these are exploited to learn the role of genes in the response to severe burn. We review the construction of transgenic animals, pitfalls and benefits of this relatively new technique, and how this technique has been used in burn research.
Animals↗
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↗
Expression of Dlx and Lhx family homeobox genes in fetal thymus and thymocytes.
Homeobox genes comprise a nearly ubiquitous and highly conserved superfamily of developmental regulatory genes that encode transcription factors involved in the determination of axis and tissue identity. While homeobox gene expression has been well characterized in a variety of embryonic tissues, their expression has not been extensively studied in lymphoid progenitor cells or in sites of lymphogenesis. To examine homeobox gene expression in the developing thymus, we screened an embryonic day 13.5 thymus cDNA library by polymerase chain reaction (PCR) using degenerate oligonucleotides within the highly conserved homeodomain region of eight homeobox gene families. The resulting PCR products were then cloned and sequenced. Transcripts for multiple Dlx family members and Lhx2 were repeatedly detected in this screen. Screening of embryonic day 16.5 and adult murine thymus and Thy1+ thymocytes was performed for selected members of these homeobox gene families. Transcripts encoding Lhx2, Lhx3, and Lhx9, as well as Dlx1 and Dlx2 were detected in both thymus and purified thymocytes. Dlx1 is a member of the distal-less homeobox gene family that has been shown to regulate embryonic craniofacial development. Significantly, Dlx1 is expressed in the third branchial arch, which contributes to the thymus. Although Dlx1 knockout mice did not display any obvious developmental defects in thymus or thymocyte development, the expression of these homeobox genes in neural crest derivatives suggests a possible role in cell migration and development that may overlap with other homeobox genes.
Animals↗
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↗
T-modification of sternotomy to accommodate a low-lying tracheostomy.
A low-lying tracheostomy can complicate a sternotomy for coronary artery bypass grafting. A modified "T" exposure, transecting the manubrium at the first intercostal space, can be utilized to maintain sternoclavicular architecture and avoid injury to the tracheostomy at the sternal notch.
Humans↗
Insulin-like growth factor-I/insulin-like growth factor binding protein-3 alters lymphocyte responsiveness following severe burn.
PURPOSE: Following severe burn, patients are immunocompromised, making them at increased risk for infection. Exogenous growth hormone has been shown to partially restore immune function. Herein, we investigated Th1/Th2 cytokine profiles and cellular proliferation in isolated mononuclear cells after treatment with exogenous insulin-like growth factor-I (IGF-I), the indirect mediator of many growth hormone effects, in severely burned patients. METHODS: Eight children and 2 adults with >20% total body surface area burns were prospectively randomized to receive either placebo or 4 mg/kg rhIGF-I/IGFBP-3 for one-week intervals (2 groups), with another group receiving placebo for both cycles. Normal children were examined for comparison. Isolated whole blood lymphocyte production of Th1 (IL-2, IFN-gamma) and Th2 (IL-4, IL-10) cytokines, and proliferative responses to specific T-cell mitogens were measured. RESULTS: Depressed Th1 and exaggerated Th2 cytokine responses were seen in all burned subjects compared to non-burned controls (P < 0.05). IL-2 and IFN-gamma production increased in patients treated with IGF-I/IGFBP-3 (P < 0.05). IL-4 production significantly decreased, while IL-10 levels did not change. Cytokine production did not change in those receiving two courses of placebo. Proliferative responses of isolated mononuclear cells to IL-2 as a Th1 specific mitogen increased with IGF-I/IGFBP-3 treatment (P < 0.05). CONCLUSIONS: Following severe burn, a shift occurs toward a predominant Th2 phenotype. Exogenous IGF-I/IGFBP-3 treatment partially reverses this response.
Adolescent↗
Transthoracic image-guided biopsy of lung nodules: when is benign really benign?
PURPOSE: A pathologic diagnosis of malignancy by image-guided transthoracic fine needle aspiration (FNA) with or without (+/-) core biopsy is definitive. However, a benign diagnosis of a lung nodule by FNA +/- core biopsy presents a management dilemma of resection for confirmation versus follow-up imaging and/or medical treatment. We propose three separate pathologic categories of benign diagnosis after FNA +/- core biopsy: (i) benign specific (ie, aspergillosis); (ii) benign nonspecific (ie, fibrosis); and (iii) nondiagnostic. Our goal was to define when to resect "benign" nodules to avoid an unacceptably high false-negative rate. MATERIALS AND METHODS: All FNA +/- core biopsy diagnoses considered nonmalignant at a single institution from 1996 to 2001 were retrospectively reviewed for management and outcomes by radiologic or pathologic follow-up. RESULTS: Ninety-five of 836 total cases with FNA +/- core biopsies over the 5-year period were identified as nonmalignant and had complete pathologic or radiologic follow-up. Twenty-one of 95 had a benign specific diagnosis; all were true-negative for malignancy on radiologic (n = 17) or surgical (n = 4) follow-up. The remaining 74 had either benign nonspecific (n = 53) or nondiagnostic (n = 21) diagnoses. Seven of 53 benign nonspecific specimens (13%) and six of 21 nondiagnostic specimens (29%) were malignant at excisional biopsy or radiologic follow-up. Sixteen of 95 (17%) had a postprocedural pneumothorax requiring a chest tube. CONCLUSION: Transthoracic FNA +/- core biopsy may yield a nonmalignant diagnosis as (i) benign specific, (ii) benign nonspecific, or (iii) nondiagnostic. Diagnosis-directed medical management is recommended for a benign specific diagnosis. Additional diagnostic studies, repeat biopsy, or resection is necessary for benign nonspecific and nondiagnostic biopsy results as a result of an unacceptably high rate of malignancy.
Algorithms↗
Burn-induced gut mucosal homeostasis in TCR delta receptor-deficient mice.
Gammadelta T lymphocytes make up approximately 50% of lymphocytes in the intestine. These cells have been shown to prime macrophages for TNF-alpha production after burn. We previously showed that neutralizing anti-TNF-alpha antibodies reduce mucosal atrophy by decreasing gut epithelial apoptosis after severe burn. We hypothesized that burn-induced mucosal turnover is diminished in T cell receptor delta gene knockout (TCR delta-/-) mice through diminished TNF-alpha activity. Forty-two wild-type and 42 TCR delta-/- mice (C57-BL6) were randomly assigned to burn and sham burn groups. The burn group underwent a 25% total body surface area (TBSA) scald burn. The proximal small intestine was harvested at 2, 12, and 48 h. To assess mucosal atrophy, mucosal height and cell numbers in the villi and crypts were determined on hematoxylin and eosin-stained tissue sections. Apoptotic gut epithelium was identified by terminal deoxyuridine nick-end labeling (TUNEL) staining, and cell proliferation was detected by immunostaining for proliferative cell nuclear antigen (PCNA). TNF-alpha mRNA expression was measured by RT-PCR. Caspase-8 activity was measured by colorimetric assay. Statistical analysis was performed with two-way analysis of variance and t testing. Significance was accepted at P < 0.05. Data are expressed as means +/- SEM. TNF-alpha mRNA expression was significantly decreased in TCR delta-/- mice at 2 h after burn. Gut epithelial apoptosis and proliferation in both wild-type and TCR delta-/- mice were significantly increased after burn, but TCR delta-/- mice had a significantly lower levels of apoptosis (P < 0.01) and proliferation (P < 0.05) when compared with wild-type mice. Burn-induced mucosal atrophy was identified in groups by decreasing villus height, crypt depth, and villus and crypt cell number (P < 0.001) compared with sham, but no difference was found between wild-type and TCR delta-/- mice. Caspase-8 activity was significantly diminished in TCR delta-/- mice compared with wild-type mice. Gammadelta T cells are associated with increased TNF-alpha expression and gut epithelial turnover in the small bowel after severe burn. However, absence of delta T cell receptor did not inhibit mucosal atrophy after severe burn. This study suggests that gut mucosal atrophy after severe burn is a multifactorial process associated with increased TNF-alpha activity.
Animals↗
Late renal allograft rupture in a patient with small vessel vasculitis following discontinuation of immunosuppression.
We report the case of a 21-year-old man with antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis who experienced spontaneous renal allograft rupture 21 months after engraftment. Because of chronic allograft nephropathy, the patient's immunosuppressive regimen had been discontinued approximately 3 weeks prior to his presentation with abdominal pain and evidence of internal hemorrhage. He was emergently taken to the operating room, where a ruptured allograft was found and transplant nephrectomy was performed. Postoperatively, the cause of rupture was determined to have been acute cellular rejection. This case may be the longest interval reported between renal transplant and spontaneous allograft rupture.
Adult↗
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↗