Long-term Outcome of Endovascular Treatment for Mycotic Aortic Aneurysm.

OBJECTIVE/BACKGROUND: Endovascular repair (EVAR) of mycotic aortic aneurysm (MAA) has become an alternative treatment for high risk patients. The aim of this study was to evaluate long-term survival and outcomes. METHODS: Retrospective analysis of 40 consecutive patients with MAAs undergoing EVAR and subsequent intravenous antibiotic treatment between September 2009 and April 2015. Follow-up was truncated on 30 April 2015. Uni- and multivariate logistic regression were used to assess risk factors of adverse outcomes. Cumulative survival was calculated using the Kaplan-Meier method. RESULTS: Median age at repair was 73 years (range 48-88 years) and 31 (77%) were men. Eleven (27%) patients were infected with Salmonella, 12 (30%) with non-Salmonella species, and 17 (42%) had negative cultures. Anatomical locations included the aortic arch/thoracic area in 10 (25%), the paravisceral area in seven (17%), and the infrarenal area in 23 (57%). Ten (25%) patients presented with aneurysm rupture and underwent emergency repair. Median follow-up was 25 months (range 1-69 months). Cumulative 1 and 5 year survival rates were 71% and 53%, respectively. Persistent or recurrent infection occurred in 20% (n = 8). Patients with persistent infection were treated with long-term medical therapy, but all died (75%; n = 6) within 6 months of repair. No survival difference was found between patients with or without Salmonella infections. However, there was a trend toward better survival in culture negative patients. CONCLUSION: EVAR of MAA is an acceptable alternative treatment of MAA. However, persistent infection after endovascular treatment does occur and is often fatal without surgical treatment.

Case Series: Heart Transplantation After Fontan Operation-Single-Center Experience.

BACKGROUND: Fontan failure (FF) occurs rarely. In patients with Fontan failure, heart transplantation is believed to be the most effective therapy. We review our experience in heart transplantations after the Fontan operation. METHODS: From July 1987 to December 2014, 4 of 513 patients underwent orthotopic heart transplantation (OHT). Among them, 4 were due to FF. We reviewed these 4 cases via retrospective chart review. Clinical history, laboratory data, surgical technique, perioperative variables, and outcomes of long-term follow-up are presented herein. The primary outcomes were hospital mortality, 1-year-survival rate, and 4-year-survival rate. The secondary outcome is the improvement in patients with protein-losing enteropathy. RESULTS: The hospital mortality rate was 0% in the 4 FF patients receiving OHT. No surgically related hemorrhage or infection was observed. The 1-year-survival rate was 100% (n = 4) and the 4-year-survival rate 50% (n = 2). One patient died of posttransplantation lymphoproliferative disorder. Hypoalbuminemia improved in 1 of 3 patients 4 months after OHT. CONCLUSIONS: Despite technical challenges, heart transplantation can be performed successfully in patients with Fontan operation. However, protein-losing enteropathy might not be resolved quickly after heart transplantation.

Malignancy After Heart Transplantation Under Everolimus Versus Mycophenolate Mofetil Immunosuppression.

BACKGROUND: With advances in immunosuppressive therapy, heart transplantation is currently recommended as the only established surgical treatment for refractory heart failure. However, chronic immunosuppression increases the risk for malignancy. Everolimus (EVR) is a potent mammalian target of rapamycin inhibitor that is used after transplantation and to treat advanced malignancies, as we have done in Taiwan after heart transplantation since 2004. Mycophenolate mofetil (MMF) and EVR are frequently used as cell-cycle inhibitors to optimize post-transplantation outcomes. METHODS: We retrospectively analyzed the characteristics and outcomes of 454 patients who received either MMF (n = 232) or EVR (n = 222) after heart transplantation at the National Taiwan University Hospital from March 1, 1990, to March 1, 2015. Patient characteristics and Kaplan-Meier survival curves were compared between groups. RESULTS: During a median follow-up of 69.2 months, malignancy was diagnosed in 27 patients receiving MMF (n = 23) or EVR (n = 4). There was a significant difference in malignancy risk between groups (9.91% vs 1.80%, P = .001). The most common malignancies were non-Hodgkin lymphoma, skin cancers, and lung squamous cell carcinoma. The 2-year overall survival after malignancy was 50% in the EVR group and 47% in the MMF group (P = .745). CONCLUSIONS: EVR treatment after heart transplant is associated with a lower risk of malignancy than is MMF treatment. The 2-year survival rate after malignancy was similar between EVR and MMF groups.

Low Incidence of Malignancy After Heart Transplantation in Taiwan.

BACKGROUND: Malignancy is the leading cause of death in Taiwan. The risk of malignancy is higher in heart transplant recipients than in the general population. We reviewed the malignancy incidence among the patients who underwent heart transplantation (HT) at the National Taiwan University Hospital (NTUH) during the past 28 years. We found that the incidence of malignancy is low in Taiwan and that the pattern of malignancy is different from that in the Western population. METHODS: From July 1987 to March 2015, 518 patients underwent HT at NTUH. Forty-four patients who died within 1 month after transplantation were excluded from this study. Thus, a total of 476 patients were enrolled in this study. There were 393 male and 83 female patients, with a mean age of 45 years at transplantation. The major indications for HT were dilated cardiomyopathy (52%) and ischemic cardiomyopathy (33%). After HT, all patients received triple immunosuppressive therapy, including a calcineurin inhibitor (cyclosporine or tacrolimus), cell-cycle inhibitor (azathioprine, mycophenolate mofetil, or everolimus), and steroid. After 1995, induction with rabbit anti-human thymocyte globulin was routinely performed. Survival was estimated by means of the Kaplan-Meier method. RESULTS: Twenty-seven patients without pre-transplantation malignancy developed malignancies after HT. The median survival time (MST) of these 27 HT patients was 76.8 months. After malignancy was diagnosed, the overall MST was 20.7 months. The 3- and 5-year overall survival rates were 44% and 27%, respectively. Twenty-one patients (77.8%) died, 10 of them because of cancer. The most common malignancy was non-Hodgkin lymphoma (n = 6), followed by skin cancer (including 2 keratoacanthomas, 2 squamous cell carcinomas, and 1 basal cell carcinoma; n = 5) and lung squamous cell carcinoma (n = 3). The univariate analysis identified cancer stage (P = .044) and comorbidity (P = .002) as factors associated with poor malignancy survival. In the multivariate analysis, comorbidity was an independent prognostic factor for greater risk of death because of post-transplantation malignancy (P = .002). CONCLUSIONS: In Taiwan, the risk of malignancy after HT is low (5.7%), as is the incidence of skin cancer. The most common malignancy was non-Hodgkin lymphoma, followed by skin cancer and lung cancer. Comorbidity was an independent factor for overall survival in cancer patients who previously underwent HT.

Higher serum uric acid level increases risk of prehypertension in subjects with normal glucose tolerance, but not pre-diabetes and diabetes.

Although the association between serum uric acid (SUA) levels and prehypertension has been reported in previous studies, it is unknown whether their relationship is similar in subjects with diabetes, pre-diabetes and normal glucose tolerance (NGT). This study thus aimed to investigate the relationship between SUA and prehypertension in subjects with different glycemic status, including NGT, pre-diabetes and diabetes. A total of 12 010 participants were included after excluding subjects with blood pressure ⩾140/90 mm Hg, history of hypertension, leukaemia, lymphoma, hypothyroidism, medication for hypertension and hyperuricemia and missing data. Subjects were divided into four groups based on SUA quartiles (male Q1: ⩽345.0, Q2: 345.0-392.6, Q3: 392.6-440.2, Q4: ⩾440.2 µmol l(-1) and female Q1: ⩽249.8, Q2: 249.8-285.5, Q3: 285.5-333.1, Q4: ⩾333.1 µmol l(-1)). Diabetes, pre-diabetes and NGT were assessed according to the 2010 American Diabetes Association diagnostic criteria. Normotension and prehypertension were defined according to the JNC-7 (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) criteria. The SUA was significantly higher in prehypertensive subjects as compared with normotensive subjects. SUA, as a continuous variable, was positively associated with prehypertension in subjects with NGT but not pre-diabetes and diabetes. Besides, NGT subjects with the highest quartile of SUA exhibited a higher risk of prehypertension after adjustment for other confounding factors. In pre-diabetes and diabetes groups, none of SUA quartiles was significantly related to prehypertension. SUA was significantly associated with an increased risk of prehypertension in subjects with NGT but insignificantly in subjects with pre-diabetes and diabetes.

Current status of heart transplantation in Taiwan.

PURPOSE: We reviewed the national results of heart transplantation in Taiwan. METHODS: From July 1987 to December 2012, 1354 patients underwent heart transplantation in 18 qualified heart centers in Taiwan. The transplantation volume and survival rate were reviewed. RESULTS: The median age of recipients was 49 years at surgery, with 37% in the International Society for Heart and Lung Transplantation (ISHLT)-1A, 30% in ISHLT-1B, and 32% in ISHLT-2. The allograft 1-, 3-, 5-, and 10-year survival rates were 78%, 68%, 61%, and 47%, respectively. Mostly difficult recipients were bridged by extracorporeal membrane oxygenation (ECMO) instead of ventricular assist device (VAD). CONCLUSION: The results of heart transplantation in Taiwan are comparable with ISHLT world results. In Taiwan, we use more ECMO than VAD for mechanical circulatory support to bridge critical recipients to heart transplantation.

Ethnicity and waterpipe smoking among US students.

OBJECTIVES: To examine the effect of ethnicity on waterpipe smoking among college students. DESIGN: A cross-sectional study utilized data from University of Houston students through an online survey (n = 2334) from March to April 2011. The survey included questions on demographic characteristics (sex, age, race/ethnicity), tobacco use experience, risk perception, social acceptability and popularity. Multivariate logistic regression was used to determine predictors of waterpipe use with three outcomes: ever-use vs. no use, past-year use vs. no use and past-month use vs. no use. RESULTS: Half of the sample had previously smoked tobacco using a waterpipe, approximately a third in the past year and 12.5% in the past month. Significant predictors included Middle Eastern ethnicity, Middle Eastern friend, past cigarette or cigar use. Perception of harm was associated with less use in the ever-use model, while perceived addictiveness, social acceptability and popularity of waterpipes were predictors in all models. CONCLUSION: Our findings underscore the importance of developing culturally appropriate interventions to control waterpipe smoking among Middle Eastern Americans and those of Indian/Pakistani descent to curb further spread in US society, and highlight the importance of developing interventions that target the perceived addictiveness, social acceptability and popularity of waterpipe smoking.

Endomyocardial biopsy in heart transplantation: schedule or event?

BACKGROUND: Endomyocardial biopsy is the gold standard to identify rejection after heart transplantation. Due to its invasiveness, discomfort, and difficult vascular access, some patients are not willing to accept routine scheduled biopsies years after heart transplantation. The purpose of this study was to identify whether there was a difference in outcomes among the scheduled versus event biopsy groups. METHODS: We studied 411 patients who underwent heart transplantation from 1987 to 2011, reviewing biopsy results and pathology reports. There were 363 patients who followed the scheduled biopsy protocol, and 48 patients who were assigned to the event biopsy group. We extracted data on biopsy results, rejection episodes, rejection types, and survival time. RESULTS: The 2481 reviewed biopsies over 24 years, showed most rejection episodes (86.4%) to occur within 2 years after heart transplantation. The rejection incidence was low (2.1%) at 3 years after transplantation. The major reason for an event biopsy was poor vascular access, such as tiny central vein or congenital disease without a suitable central vein. Event biopsy group patients were younger than schedule biopsy patients (19.7 years old vs 47.6 years old; P < .05). The 10-year survival rates were 64% among the event versus 53% among the scheduled biopsy group (P = .029). The 10-year rates of freedom from rejection were similar. CONCLUSIONS: The rejection rate was low after 3 years; episodes occurred within 2 years. Although the long-term survival in the event group was better, they had a younger man age. The rejection and freedom from rejection rates were similar. As the rejection rate was low at 3 years after transplantation, we suggest that the event principle could be applied for biopsy at 3 years after heart transplantation.

Clinical experience of tacrolimus with everolimus in heart transplantation.

BACKGROUND: Tacrolimus (Tac) in combination with mycophenolate mofetil is widely used after heart transplantation (HT). Everolimus (EVR), a new potent proliferation signal inhibitor can be used with a carcineurin inhibitor to reduce the occurrence of rejection. The purpose of this study was to evaluate the efficacy and safety of Tac combined with EVR in de novo HT. MATERIALS AND METHODS: From January 2009 to April 2011, 33/62 patients who underwent HT were prescribed Tac and EVR as de novo immunosuppression. The main exclusion criteria were poor kidney function (serum creatinine > 2.8 mg/dL), panel-reactive antibodies > 25%, donors > 60 years old, or cold ischemia time > 6 hours. All patients received Tac (C0 blood level 5-10 ng/mL during the first 6 months, then 3-5 ng/mL), EVR (C0 target 3-8 ng/mL), and corticosteroids. After transplantation, routine examinations included echocardiogram and protocol endomyocardial biopsy. RESULTS: There was no operative mortality. The 1- and 3-year actuarial survivals were 95.74% ± 3.49%. One patient who had undergone coronary artery bypass grafting previously and received intra-aortic balloon pumping and extracorporeal membrane oxygenator-assisted cardiopulmonary resuscitation before HT died of Aspergillus septicemia 58 days after HT. No biopsy-proven acute rejection > grade 2R or acute rejection associated with hemodynamic compromise was observed. Hyperlipemia was noted in 16 cases (48.5%), hypertension in 11 (33.3% 5%), and diabetes mellitus in 12 (36.4%). No other severe adverse events were noted. CONCLUSIONS: Concentration-controlled EVR (C0 target 3-8 ng/mL) in combination with Tac achieved good efficacy and safety. The 1- and 3-year actuarial survivals were 95.74% ± 3.49%.

High-glucose environment reduces human ß-defensin-2 expression in human keratinocytes: implications for poor diabetic wound healing.

BACKGROUND: Wound healing is a dynamic and complicated process in which inflammation, re-epithelialization and angiogenesis play important roles. Intriguingly, all three processes have been found to be defective during diabetic wound healing conditions. One common denominator associated with regulation of these events is human ß-defensin-2 (hBD2). It has been shown that skin wounding induces cutaneous hBD2 expression, and diabetic wounds have been associated with inadequate hBD expression. OBJECTIVES: The current study was launched to explore the effects of a high-glucose environment on cultured human keratinocytes. METHODS: Human keratinocytes were exposed to indicated culture conditions. The mRNA and protein levels of hBD2 were determined, and activation of relevant pathways was evaluated. The small interference RNA approach was used to validate the functional role of the proposed pathway on hBD2 expression. RESULTS: We showed that high-glucose cultivated keratinocytes expressed reduced levels of hBD2 and phosphorylated signal transducer and activator of transcription (pSTAT)-1 constitutively. In addition, pSTAT-1 signalling is critically involved in hBD2 expression. Formation of advanced glycation endproducts, a direct consequence of a high-glucose environment, involves constitutive downregulation of pSTAT-1 and hBD2. The addition of interleukin-1ß, an important cytokine during the cutaneous wound healing process, enabled the upregulation of hBD2 expression of both normal- and high-glucose cultivated keratinocytes, but the absolute levels of hBD2 were still significantly lower in the high-glucose-treated group. CONCLUSIONS: As hBD2 plays multifaceted roles during the wound healing process, the inadequate expression of hBD2 during diabetic conditions contributes to impaired wound healing.

Can cyclosporine blood level be reduced to half after heart transplantation?

BACKGROUND: Cyclosporine (CsA) is widely used after heart transplantation. The purpose of this prospective randomized study was to evaluate the safety and efficacy of reduction of CsA blood level to one-half of the traditional blood concentration under a regimen of everolimus (EVL), CsA, and steroid. MATERIALS AND METHODS: This prospective, 6 month, randomized, open-label study included adult (aged 18 to 65 years) recipients of a primary heart transplant with serum creatinine60 years old, had cold ischemia time>6 hours, or had plasma renin activity>or=25%. All patients received CsA (C2 blood level 1000-1400 ng/mL), EVL (C0 target 3-8 ng/mL), and corticosteroids to day 60, before random entry into one of 2 groups: SE (C2 blood level from days 60-149=800-1200 ng/mL, and days 150-180 C2=600-1000 ng/mL), or RE group with CsA reduced by one-half after 3 months (days 90-149 C2=400-600 ng/mL, and from days 150-180 C2=300-500 ng/mL). RESULTS: The 25 recipients eligible for this study included 13 patients in the SE and 12 in the RE group. There was no operative mortality in either group. No death or graft loss was noted within 6-months in either group. Mean serum creatinine at month 6 tended to be lower in the RE cohort (1.23+/-0.44 mg/dL versus 1.55+/-0.85 mg/dL; P=.093). Biopsy-proven acute rejection>or=grade 3A was observed in only 1 patient (7.7%), who was in the SE group. There were no acute rejection episodes associated with hemodynamic compromise. The incidences of adverse events in each group were similar. CONCLUSIONS: Concentration-controlled EVL (C0 target 3-8 ng/mL) in combination with reduced CsA exposure of one-half the usual concentration achieved good efficacy and safety over 6 months. The renal function at 6 months among the RE group showed a trend toward improvement, suggesting a benefit of halving the target CsA blood level after heart transplantation.

The significance of endograft geometry on the incidence of intraprosthetic thrombus deposits after abdominal endovascular grafting.

OBJECTIVES: To examine the incidence and risk factors of intraprosthetic thrombotic deposits in abdominal aortic endografts. METHODS: The clinical records of 51 patients (44 males; mean age 76.3 years, range: 63-90 years) with abdominal aortic aneurysm treated with transfemoral implantation of bifurcated stent graft between the years 2002 and 2008 were retrospectively reviewed. Patients underwent three-phase helical computed tomographic (CT) examinations at 1-, 3-, 6- and 12-month intervals and then annually. The formation of intraprosthetic thrombus associated with use of anti-platelet, preoperative mural thrombus in the aneurysm, ratio of cross-sectional area between the mainbody and bilateral limb grafts and length of mainbody were evaluated. RESULTS: Over a 10-month mean follow-up, intraluminal deposits of thrombotic material were observed in eight of 51 patients (15.6%, 95% confidence interval: 8.2-28). The first signs of thrombus formation occurred on average 9.8 months after endografting (range: 1-24 months). Intraprosthetic thrombotic deposits was not related to preoperative mural thrombus formation (p=0.38) or postoperative anti-platelet or anticoagulation medication (p=0.40). However, it was significantly related to the ratio of the cross-sectional area between the mainbody and the bilateral limb grafts and the length of mainbody (p=0.04 and p=0.01). There were three graft limbs occlusion owing to kinking with no intraprosthetic thrombus detected on CT scans taken prior to occlusion. One patient developed distal left proximal superior femoral artery embolisation 4 months after detectable intraprosthetic mainbody thrombus in a CT scan follow-up. In no case did the thrombotic deposits clear completely from the prosthesis lumen during follow-up. CONCLUSIONS: This short experience demonstrates that incidentally found thrombotic deposits in abdominal aortic endografts are common. The deposition of thrombus is mostly influenced by the geometry of the aortic stent graft with wider mainbody diameter coupled with smaller limb grafts and longer mainbody graft. Most of these thrombi are clinically silent and require no additional treatment.

Cardiac arrest after methylprednisolone pulse therapy rescued using extracorporeal membrane oxygenation in patients with acute cardiac rejection: two case reports.

Patients receive methylprednisolone pulse therapy (MPT) when acute cardiac rejection occurs. Although the regimen is generally safe and effective, severe complications occasionally develop. From 1997 to 2007, there were 210 cardiac transplantation procedures performed at our hospital. Among these patients, there were 23 episodes of acute rejection treated with MPT, 10 mg/kg/d. Two patients in our series had cardiac arrest within 36 hours after initiating the therapy. Endomyocardial biopsy specimens showed International Society for Heart Transplantation grade 1B allograft rejection in both cases. Emergent intubation and cardiopulmonary resuscitation were performed. Venoarterial extracorporeal membrane oxygenation (ECMO) was used to rescue the patients. The cardiac function in both patients recovered gradually. Left ventricular ejection fraction increased from 16.2% to 47% in one patient and from 27% to 30% in the other patient. One patient was successfully weaned from ECMO after 2 days of support. The other patient was discharged against medical advice because of hypoxia-related brain death after 3 days. Both patients had a history of tachyarrhythmias before initiation of MPT. Although the relationship between mechanisms of cardiac arrest and MPT is uncertain, the risk of cardiac arrest cannot be overlooked when initiating MPT, especially in patients with a history of tachyarrhythmia. Meanwhile, ECMO can serve as a rescue method if cardiac arrest occurs.

Tuberculous empyema.

The clinical courses of 35 tuberculous empyema patients were investigated retrospectively from November 1990 through November 1995. Most patients had nonspecific symptoms and signs but with far-advanced pulmonary parenchymal lesions in their chest roentgenographs. The effusions showed neutrophilic leukocytosis with a 60% positive culture rate for Mycobacterium tuberculosis. Multidrug resistant strains were found in 7 out of 18 cultures. All patients received chemotherapy and eight of them underwent additional surgical management. Twenty-two (62.9%) patients had been treated successfully and one patient is still under treatment. The remaining 12 patients either died during treatment or defaulted; and four (11.4%) of them had died of tuberculosis. We conclude that the treatment outcome of tuberculous empyema is less satisfactory than that of pulmonary tuberculosis, however, modern multidrug chemotherapy with repeated drainage and opportune surgical interventions could be in prospect of successful treatment of tuberculous empyema.

Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb.

Alterations in expression of or responsiveness to transforming growth factor beta (TGF-beta) are frequently found in human and animal epithelial cancers and are though to be important for loss of growth control in the neoplastic cell. We show here that keratinocyte cell lines from mice with a targeted deletion of the TGF-beta 1 gene have significantly increased frequencies of gene amplification in response to the drug N-phosphonoacetyl-L-aspartate (PALA) compared to TGF-beta 1-expressing control keratinocyte cell lines. In contrast to the control lines, the PALA-mediated G1 arrest did not occur in the TGF-beta 1 null keratinocytes despite the presence of wild-type p53 in both genotypes. Exogenous TGF-beta 1 suppresses gene amplification in the null keratinocytes at concentrations that do not cause a G1 growth arrest and in human tumor cell lines that are insensitive to TGF-beta 1-mediated growth inhibition. The pathway of TGF-beta 1 suppression is independent of the p53 and Rb genes, but requires an intact TGF-beta type II receptor. These studies reveal a novel TGF-beta-mediated pathway regulating genomic stability and suggest that defects in TGF-beta signaling may have profound effects on tumor progression independent of cell proliferation.

Binding of zinc finger protein ZPR1 to the epidermal growth factor receptor.

ZPR1 is a zinc finger protein that binds to the cytoplasmic tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Deletion analysis demonstrated that this binding interaction is mediated by the zinc fingers of ZPR1 and subdomains X and XI of the EGFR tyrosine kinase. Treatment of mammalian cells with EGF caused decreased binding of ZPR1 to the EGFR and the accumulation of ZPR1 in the nucleus. The effect of EGF to regulate ZPR1 binding is dependent on tyrosine phosphorylation of the EGFR. ZPR1 therefore represents a prototype for a class of molecule that binds to the EGFR and is released from the receptor after activation.

JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain.

The ultraviolet (UV) response of mammalian cells is characterized by a rapid and selective increase in gene expression mediated by AP-1 and NF-kappa B. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. Here, we describe the molecular cloning and characterization of JNK1, a distant relative of the MAP kinase group that is activated by dual phosphorylation at Thr and Tyr during the UV response. Significantly, Ha-Ras partially activates JNK1 and potentiates the activation caused by UV. JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. Thus, JNK1 is a component of a novel signal transduction pathway that is activated by oncoproteins and UV irradiation. These properties indicate that JNK1 activation may play an important role in tumor promotion.