Growth velocity of fetal sacrococcygeal teratoma as predictor of perinatal morbidity and mortality: multicenter study.

OBJECTIVE: To identify prenatal predictors of poor perinatal outcome in fetuses with isolated sacrococcygeal teratoma (SCT). METHODS: This was a retrospective study of fetuses with isolated (non-syndromic) SCT managed at one of five pediatric surgery and/or fetal medicine centers between January 2007 and December 2017. The primary outcome was the occurrence of poor perinatal outcome, defined as prenatal death (including termination), or neonatal death or severe compromise (hemorrhagic shock). Data regarding prenatal diagnosis (sonographic features both at referral and at the last ultrasound examination before pregnancy outcome, assessment of SCT growth velocity), perinatal complications and outcome, and neonatal course were analyzed to determine prenatal SCT characteristics associated with adverse perinatal outcome. RESULTS: Fifty-five fetuses were included, diagnosed with isolated SCT at a median gestational age of 22 (interquartile range, 18-23) weeks. There was a poor perinatal outcome in 31% (n = 17) of these cases, including intrauterine fetal demise (4%, n = 2), pregnancy termination (13%, n = 7) and neonatal severe compromise (15%, n = 8), leading to neonatal death in five cases. The overall survival rate after prenatal diagnosis of isolated SCT was 75% (n = 41 of 55). Earlier gestational age at diagnosis (P = 0.02), large tumor volume at referral (P < 0.001), presence of one or more hemodynamic complications (P = 0.02), fast tumor growth velocity (P < 0.001) and high tumor grade (highest tumor grade ≥ 3) (P = 0.049) were associated with poor perinatal outcome on univariate analysis. On stepwise logistic regression analysis, tumor growth velocity was the only remaining independent factor associated with poor perinatal outcome (odds ratio (OR) (per 1-mm/week increase), 1.48 (95% CI, 1.22-1.97), P = 0.001). The best predictive cut-off of tumor growth velocity for poor perinatal outcome was 7 mm/week (OR, 25.7 (95% CI, 5.6-191.3), P < 0.001), yielding a sensitivity of 88% and a specificity of 77%. CONCLUSIONS: Approximately 30% of fetuses with a diagnosis of isolated SCT have poor perinatal outcome. Tumor growth velocity ≥ 7 mm/week appears to be an appropriate discriminative cut-off for poor perinatal outcome. These results could help to inform prenatal management and counseling of parents with an affected pregnancy. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Genetic polymorphisms of CYP1A, CYP1B, CYP2C and risk of cervical cancer among rural population of Maharashtra: Findings from a hospital-based case-control study.

BACKGROUND: Last few decades, multiple studies all over the world revealed the association of genetic polymorphism in cytochrome P450 (CYP) genes with risk of developing different type of cancers, but contradictory outcomes were evidenced in case of cervical cancer (CC) risk. Therefore, the discrepancies in earlier reports influenced us to evaluate the association of CYP1A1*2A rs4646903, CYP1B1*3 rs1056836, CYP2C8*2 rs11572103, CYP2C9*2 rs1799853, CYP2C9*3 rs1057910, and CYP2C19*2 rs4244285 polymorphisms and CC susceptibility in the women of rural population of Maharashtra. MATERIALS AND METHODS: In this case-control study, genetic association of the polymorphisms in CYP genes was studied by using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. The study was conducted among 350 clinically confirmed CC patients and 350 healthy volunteers in a population of south-western Maharashtra. The odds ratio (OR) with 95% confidence interval (CI) and P value were evaluated to get the level of association where P ≤ 0.005 was considered as statistically significant. RESULTS: After the analysis of single-nucleotide polymorphism (SNPs) of CYP1A1, CYP1B1, CYP2C8, CYP2C9, and CYP2C19, we noticed that CYP1B1*3 rs1056836 (Leu4326Val) polymorphism possessed a significantly elevated risk (OR = 3.28; 95% CI: 2.18-4.94; P < 0.0001), whereas CYP2C19*2 rs4244285 showed significantly lower risk (OR: 0.53, 95% CI: 0.33-0.85 P < 0.009) of CC in the studied rural population. CONCLUSION: The findings from this study supported that rs1056836 SNP of CYP1B1*3 increase CC development, whereas rs4244285 of CYP2C19*2 lowers the CC risk in the studied population.

Pathological and sonographic review of early isolated severe lower urinary tract obstruction and implications for prenatal treatment.

OBJECTIVE: To identify favorable renal histology in fetuses with early severe lower urinary tract obstruction (LUTO) and determine the best timing and selection criteria for prenatal surgery. METHODS: This multicenter, retrospective study included male fetuses with severe LUTO which died before 24 weeks of gestation during the period January 2000 to December 2018. Age-matched controls were used as reference standard for renal histology. Prenatal ultrasound features and fetal serum and/or urine ß2microglobulin level were retrieved and kidney histology slides (hematein-eosin-safran and α-smooth-muscle-actin (αSMA) immunostaining) were prepared and reviewed. αSMA-positive staining of the blastema is due to its aberrant differentiation into myofibroblastic cells. Cases were sorted into histopathologic groups (favorable or unfavorable) according to the blastema's morphology and αSMA labeling and the data of these groups were compared. RESULTS: Included in the study were 74 fetuses with a median gestational age at outcome of 17 + 6 (range, 13 + 0 to 23 + 5) weeks. Parenchymal organization was preserved in 48% of the kidneys. A blastema was present in 90% of the kidneys, but it was morphologically normal in only 9% and αSMA-negative in only 1% of them. Most (82%) fetuses had an unfavorable prognosis, and 36% of fetuses died ≤ 18 weeks and had severe renal lesions detected on histology (early unfavorable prognosis). A favorable renal prognosis was associated with an earlier gestational age (P = 0.001). Fetuses with LUTO had a significantly lower number of mature glomeruli (P < 0.001) compared with controls. However, there was no significant difference in the number of glomeruli generations between the early-unfavorable-prognosis group (≤ 18 weeks) and the group with a favorable prognosis (P = 0.19). A comparison of prenatal ultrasound features and biochemical markers between groups could not identify any prenatal selection criteria. CONCLUSIONS: Before 18 weeks, around 30% of fetuses with severe LUTO still have potential for kidney development. Identification of these cases would enable them to be targeted for prenatal therapy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

How can we improve perinatal care in isolated multiple intestinal atresia? A retrospective study with a 30-year literature review.

INTRODUCTION: Multiple intestinal atresia (MIA) is a rare cause of neonatal intestinal obstruction. To provide an overview of the current prenatal, surgical, and nutritional management of MIA, we report our experience and a literature review of papers published after 1990. METHODS: All cases of isolated MIA (non-hereditary, not associated with apple-peel syndrome or gastroschisis) treated at our institution between 2005 and 2016 were reviewed and compared with cases found in the literature. RESULTS: Seven patients were prenatally suspected of having intestinal obstruction and were postnatally diagnosed with MIA, with a mean 1.7 (1-2) resections-anastomoses (RA) and 6 (1-10) strictureplasties performed, resulting in a mean resected bowel length of 15.1cm (15-25 cm). Median time to full oral feed was 46 days (14-626 days). All patients were alive and none had orality disorder after a mean follow-up of 3.1 years (0.2-8.1 years). Three surgical strategies were found in the literature review: multiple RA (68%, 34/50) including Santulli's technique in four of 34 (12%) and anastomoses over a transanastomotic tube (32%, 16/50), with a 98% survival rate, and short-bowel syndrome for only two patients. CONCLUSION: Bowel-sparing surgery and appropriate medical management are key to ensuring a favorable nutritional and gastrointestinal outcome and a good prognosis. Prenatal assessment and standardization of the surgical course of treatment remain challenging.

Biogenic synthesis of gold nanoparticles using Argemone mexicana L. and their cytotoxic and genotoxic effects on human colon cancer cell line (HCT-15).

BACKGROUND: Nanomedicine has evolved as precision medicine in novel therapeutic approach of cancer management. The present study investigated the efficacy of biogenic gold nanoparticles synthesized using Argemone mexicana L. aqueous extract (AM-AuNPs) against the human colon cancer cell line, HCT-15. RESULTS: Biosynthesis of AM-AuNPs was determined by ultraviolet-visible spectroscopy and further characterized by transmission electron microscopy, X-ray diffraction, and Fourier transition infrared spectroscopy analysis. The cytotoxic activity of AM-AuNPs was assessed by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, whereas genotoxicity was evaluated by the DNA fragmentation assay. The expression of apoptosis regulatory genes such as p53 and caspase-3 was explored through semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting to evidence apoptotic cell death in HCT-15 cells. Biogenic AM-AuNPs inhibited cell proliferation in HCT-15 cell line with a half maximal inhibitory concentration (IC50) of 20.53 µg/mL at 24 h and 12.03 µg/mL at 48 h of exposure. The altered cell morphology and increased apoptosis due to AM-AuNPs were also evidenced through nuclear DNA fragmentation and upregulated expression of p53 and caspase-3 in HCT-15 cells. CONCLUSION: The AM-AuNPs may exert antiproliferative and genotoxic effects on HCT-15 cells by cell growth suppression and induction of apoptosis mediated by activation of p53 and caspase-3 genes.

[Prenatal path of care following the diagnosis of a malformation for which a novel prenatal therapy is available]. / Parcours prénatal devant une malformation pour laquelle un traitement in utero émergent est disponible.

OBJECTIVES: Fetal therapy is part of the available care offer for several severe malformations. The place of these emergent prenatal interventions in the prenatal path of care is poorly known. The objective of this study is to describe the decision-making process of patients facing the option of an emergent in utero intervention. METHODS: We have conducted a retrospective monocentric descriptive study in the department of maternal-fetal medicine of Necker Hospital. We collected data regarding eligibility or not for fetal surgery and the pregnancy outcomes of patients referred for myelomeningocele, diaphragmatic hernia, aortic stenosis and low obstructive uropathies. RESULTS: All indications combined, 70% of patients opted for fetal surgery. This rate was lower in the case of myelomeningocele with 21% consent, than in the other pathologies: 69% for diaphragmatic hernias, 90% for aortic stenoses and 76% for uropathy. When fetal intervention was declined, the vast majority of patients opted for termination of pregnancy: 86%. In 14% of the considering fetal surgery, the patient was referred too far. CONCLUSION: The acceptance rate for fetal surgeries depends on condition. It offers an additional option and is an alternative for couples for which termination of pregnancy (TOP) is not an option. Timely referral to an expert center allows to discuss the place of a fetal intervention and not to deprive couples of this possibility.

Biometric and morphological features on magnetic resonance imaging of fetal bladder in lower urinary tract obstruction: new perspectives for fetal cystoscopy.

OBJECTIVES: Incompatibility between currently available fetoscopes and the anatomical constraints of the distended fetal bladder, with the resulting curvature around the bladder neck, account for most technical difficulties during fetal cystoscopy in lower urinary tract obstruction (LUTO). The aim of this anatomical study was to assess by magnetic resonance imaging (MRI) the variation in three bladder angles (bladder-neck angle (BNA), vesicourethral angle (VUA) and angle between bladder dome and posterior urethra (DUA)), according to gestational age (GA), bladder volume and the presence of LUTO. METHODS: From our fetal medicine database, we retrieved for review 46 MRI examinations of male fetuses between 2015 and 2019, including 17 with LUTO, examined at a mean GA of 28.1 (range, 17.3-35.0) weeks and 29 age-matched controls, examined at 29.9 (range, 21.9-35.0) weeks. We measured bladder volume, bladder-wall thickness and the three bladder angles, and used the Mann-Whitney U-test to compare values between groups. Variations according to GA and bladder volume were determined using analysis of variance (ANOVA). A reliability study was performed using the Bland-Altman method and Lin's correlation coefficient was calculated. RESULTS: Both bladder volume and bladder-wall thickness were significantly greater in the LUTO group (P < 0.01). BNA was significantly larger in LUTO compared with control fetuses: the mean (range) was 127.1° (101.6-161.6°) vs 111.2° (88.5-157.3°) (P < 0.01). DUA averaged 117° and showed no difference between the groups (P = 0.92). No statistical comparison was performed on VUA since this was not measurable in most control fetuses. ANOVA showed no variation of any angle with bladder volume in both LUTO fetuses and control fetuses. BNA in LUTO fetuses was the only angle to vary with GA, being larger after, compared with at or before, 25 weeks (P = 0.04). The reliability study showed an acceptable bias for both intra- and interobserver reproducibility for all three angles. CONCLUSION: The findings that BNA is increased by approximately 15° in fetuses with LUTO and DUA averages 117° could aid in development of a customized fetal cystoscope and help to overcome the current technical challenges of fetal cystoscopy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Endoluminal Atherosclerotic Plaque Debulking Using Enzymatic and Ultrasonic Energy.

BACKGROUND: Current procedures to treat severe atherosclerosis are traumatic to the arterial wall and often result in restenosis due to neointimal hyperplasia. We developed a novel therapy using a specially designed double occlusion balloon catheter, ultrasonic wire, and enzymatic digestion solution to atraumatically debulk atherosclerotic plaques. MATERIALS AND METHODS: A combination of different enzymes, chemicals, and treatment conditions were evaluated for its effect at reducing atherosclerotic plaque harvested from human carotid artery endarterectomies ex vivo. The optimized digestion solution was examined in harvested intact human superficial femoral arteries in situ. A conventional Yorkshire/Landrace and a genetically modified Yucatan minipig homozygous for a nonfunctional LDLR mutation were used to evaluate the endovascular therapy in nonatherosclerotic and atherosclerotic environments in vivo. RESULTS: Ex vivo, the technology successfully digested human carotid artery plaques by 75%. In situ, the therapy successfully reduced plaque area in harvested superficial femoral arteries by 46%. In vivo, the endovascular therapy was technically feasible and demonstrated initial safety with no thrombosis, dissection, or aneurysmal dilatation in a nonatherosclerotic porcine model. In an atherosclerotic porcine model, the therapy demonstrated initial efficacy by successfully reducing atherosclerotic plaque while preserving the arterial wall with an intact internal elastic lamina. CONCLUSIONS: Using human plaque, human artery, and a normal and atherosclerotic pig model, we demonstrated that delivery of our therapy to the vasculature is technically feasible, appears safe, and shows initial efficacy. Our percutaneous plaque debulking method is a unique and promising therapy for the treatment of atherosclerosis and warrants further study.

Nitric oxide affects UbcH10 levels differently in type 1 and type 2 diabetic rats.

BACKGROUND: Nitric oxide (NO) more effectively inhibits neointimal hyperplasia in type 2 diabetic versus nondiabetic and type 1 diabetic rodents. NO also decreases the ubiquitin-conjugating enzyme UbcH10, which is critical to cell-cycle regulation. This study seeks to determine whether UbcH10 levels in the vasculature of diabetic animal models account for the differential efficacy of NO at inhibiting neointimal hyperplasia. MATERIALS AND METHODS: Vascular smooth muscle cells (VSMCs) harvested from nondiabetic lean Zucker (LZ) and type 2 diabetic Zucker diabetic fatty (ZDF) rats were exposed to high glucose (25 mM) and high insulin (24 nM) conditions to mimic the diabetic environment in vitro. LZ, streptozotocin-injected LZ (STZ, type 1 diabetic), and ZDF rats underwent carotid artery balloon injury (±10 mg PROLI/NO), and vessels were harvested at 3 and 14 d. UbcH10 was assessed by Western blotting and immunofluorescent staining. RESULTS: NO more effectively reduced UbcH10 levels in LZ versus ZDF VSMCs; however, addition of insulin and glucose dramatically potentiated the inhibitory effect of NO on UbcH10 in ZDF VSMCs. Three days after balloon injury, Western blotting showed NO decreased free UbcH10 and increased polyubiquitinated UbcH10 levels by 35% in both STZ and ZDF animals. Fourteen days after injury, immunofluorescent staining showed increased UbcH10 levels throughout the arterial wall in all animal models. NO decreased UbcH10 levels in LZ and STZ rats but not in ZDF. CONCLUSIONS: These data suggest a disconnect between UbcH10 levels and neointimal hyperplasia formation in type 2 diabetic models and contribute valuable insight regarding differential efficacy of NO in these models.

Anatomic suitability of aortoiliac aneurysms for next generation branched systems.

BACKGROUND: Preservation of internal iliac flow is an important consideration to prevent ischemic complications during endovascular aneurysm repair. We sought to determine the suitability of aortoiliac aneurysms for off-the-shelf iliac branched systems currently in clinical trial. METHODS: Patients undergoing abdominal aortic aneurysm repair from 2004 to 2013 at 2 institutions were reviewed. Centerline diameters and lengths of aortoiliac morphology were measured using three-dimensional workstations and compared with inclusion/exclusion criteria for both Cook and Gore iliac branch devices. RESULTS: Of the nearly 2,400 aneurysm repairs performed during the study period, 99 patients had common iliac aneurysms suitable for imaging review. Eighteen of the 99 (18.2%) patients and 25/99 (25.3%) patients fit the inclusion criteria and would have been able to be treated using the Cook and Gore iliac branch devices, respectively. The most common reason for exclusion from Cook was internal iliac diameter of <6 or >9 mm (68/99, 68.7%). The most common reason for exclusion from Gore was proximal common iliac diameter of <17 mm (39/99, 39.4%) and inadequate internal iliac artery diameter of <6.5 or >13.5 mm (37/99, 37.3%). Comparing the included patients across both devices, a total of 35/99 (35.4%) of patients would be eligible for the treatment of aortoiliac aneurysms based on anatomic criteria. CONCLUSIONS: Only 35% of the aneurysm repairs involving common iliac arteries would have been candidates for the 2 iliac branch devices currently in trial based on anatomic criteria. The major common reason for exclusion is the internal iliac landing zone for both devices. Design modifications for future generation iliac branch technology should focus on diameter accommodations for the hypogastric branch stent and proximal and distal sizes of the iliac branch components. Familiarity with alternate branch preserving techniques is still needed in the majority of cases.

Reentry device aided endovascular aneurysm repair in patients with abdominal aortic aneurysm and unilateral iliac artery occlusion.

BACKGROUND: We report 2 cases of patients undergoing endovascular aneurysm repair (EVAR) using reentry devices to recanalize unilateral iliac artery occlusions and complete a bifurcated endovascular repair. METHODS: Patient 1 is a 70-year-old male with an enlarging 6.5-cm abdominal aortic aneurysm (AAA) and disabling left leg claudication with L external iliac occlusion with patent common and internal iliac arteries. Patient 2 is a 67-year-old male with an asymptomatic 4.0-cm AAA and L iliac chronic total occlusion (CTO) and disabling claudication. Both patients were poor operative candidates for open repair. RESULTS: Both patients underwent elective percutaneous EVAR along with left iliac artery revascularization. Initial angiography in both cases showed a blind ending of the left common iliac artery. Retrograde subintimal dissection through the occluded iliac segment was attempted but in both cases the wire was unable to traverse back into the true aortic lumen. Using either the Outback LTD or Pioneer reentry catheter, direct visualization of the true aortic lumen was obtained to re-enter the true lumen. The subintimal iliac tract was then predilated to facilitate routine EVAR in both cases. Both patients were discharged the following day and 1-year and 6-month follow-up imaging revealed aneurysm exclusion, no endoleak, and patent bilateral common iliac arteries with resolution of claudication symptoms and normal ankle-brachial indexes. The previously patent internal iliac artery was preserved. CONCLUSIONS: While not always technically possible, reentry device aided EVAR is safe, feasible, and durable in the mid-term and avoids the morbidity and mortality related to aortouniiliac/femoral-femoral bypass and open repair. This technique should be considered in patients with iliac artery CTO and concurrent AAA to allow total endovascular repair.

Renal function changes after snorkel/chimney repair of juxtarenal aneurysms.

OBJECTIVE: The snorkel approach for endovascular aneurysm repair (EVAR) has been found to be a safe and viable alternative to open repair for juxtarenal abdominal aortic aneurysms with good short-term outcomes. Concerns about long-term durability and renal branch patency with this technique have been raised with the increasing availability of fenestrated devices. We sought to evaluate renal function changes in patients undergoing "snorkel" EVAR (sn-EVAR). METHODS: Patients who underwent sn-EVAR from 2009 to 2012 were included in this analysis. Creatinine values were obtained throughout the patient's preoperative, perioperative, and postoperative course. Glomerular filtration rate (GFR) was estimated by the simplified Modification of Diet in Renal Disease formula. Acute renal dysfunction was analyzed according to the RIFLE (Risk, Injury, Failure, Loss, End stage) criteria, whereas chronic renal dysfunction was stratified by the chronic kidney disease staging system. RESULTS: Forty-three consecutive patients underwent sn-EVAR (31 double renal, 12 single renal) for juxtarenal aortic aneurysms. Mean follow-up time was 21 months. Mean aneurysm size was 6.6 cm (range, 5.1-10.5 cm) with anatomy not suitable for treatment with standard EVAR (mean neck length, 1.6 mm); 74 renal snorkel stents were placed in these patients with a 2-year primary patency of 95%. On average, the cohort at baseline was stratified as having moderate renal dysfunction. Mean baseline, maximum postoperative, and latest follow-up creatinine concentrations were 1.20, 1.49, and 1.43, respectively (P = .004). Mean baseline, maximum postoperative, and latest follow-up GFRs were 57.4, 47.8, and 49.2, respectively (P = .014). With use of RIFLE criteria, 14 patients (32.6%) experienced some form of acute kidney injury, although 10 of these patients (23.3%) were classified as mild (25%-50% decline in GFR). On analysis without the RIFLE criteria, 21.4% of patients had postoperative creatinine concentration >1.5 mg/dL, 28.6% had postoperative creatinine concentration increase >30%, and 28.6% had postoperative GFR decline >30%. For the entire study cohort at latest follow-up, 51% experienced no decline of chronic renal dysfunction and 8.1% had improvement in renal function. Renal function declined by one stage in 35.2% of the cohort and by two stages in 5.4%. On analysis without chronic kidney disease staging, 24.3% of patients had latest follow-up creatinine concentration >1.5 mg/dL, 29.7% had latest follow-up creatinine concentration increase >30%, and 24.3% had latest follow-up GFR decline >30%. Mean survival time from significant renal decline was 23.4 months. CONCLUSIONS: sn-EVAR continues to demonstrate a high rate of technical success and results in only mild rates of acute and midterm renal function decline according to a number of established definitions for renal dysfunction. Continued monitoring of renal function, renal stent behavior, and abdominal aortic aneurysm sac changes remains critically important in the long-term management of patients undergoing sn-EVAR, particularly given the high comorbidities associated with juxtarenal aortic aneurysms.

Nitric oxide differentially affects ERK and Akt in type 1 and type 2 diabetic rats.

BACKGROUND: We have shown that nitric oxide (NO) is more effective at inhibiting neointimal hyperplasia in type 2 diabetic rats than in nondiabetic rats, but is not effective in type 1 diabetic rats. Insulin signaling is mediated by the ERK and Akt pathways, and thus we hypothesized that NO differentially affects ERK and Akt activity in type 1 versus type 2 diabetic rats. MATERIALS AND METHODS: To investigate this hypothesis, we induced type 2 diabetes in Zucker diabetic fatty (ZDF) rats by feeding them Purina 5008 chow. To induce type 1 diabetes, lean Zucker (LZ) rats were injected with streptozotocin (STZ; 60 mg/kg). The carotid artery injury model was performed. Groups included injury and injury + PROLI/NO (20 mg/kg) (n = 6/group). RESULTS: Three days following injury, all animal models exhibited an increase in pERK levels. Whereas NO reduced pERK levels in LZ and STZ rats, NO had no effect on pERK levels in ZDF rats. Following a similar pattern, NO reduced pAkt levels in LZ and STZ rats but increased pAkt levels in ZDF rats. Fourteen days following injury, NO increased total pERK levels throughout the arterial wall in both the STZ and ZDF rats. These changes were greatest in the adventitia. Interestingly, whereas NO decreased total pAkt levels in LZ and STZ rats, NO increased pAkt levels in ZDF rats. Evaluation of the pERK:pAkt ratio revealed that NO increased this ratio in LZ and STZ rats but decreased the ratio in ZDF rats. CONCLUSIONS: We report that NO differentially affects the expression of pERK and pAkt in type 1 versus type 2 diabetic rats. Given that NO is more effective at inhibiting neointimal hyperplasia in type 2 diabetic animals, the pERK:pAkt ratio may be the best surrogate to predict efficacy.

Effect of nitric oxide on neointimal hyperplasia based on sex and hormone status.

Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have been performed only in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in vivo based on sex and hormone status. In hormone-replete medium, male VSMC proliferated at greater rates than female VSMC. In hormone-depleted medium, female VSMC proliferated at greater rates than male VSMC. However, in both hormone environments, NO inhibited proliferation and migration to a greater extent in male compared to female VSMC. These findings correlated with greater G0/G1 cell cycle arrest and changes in cell cycle protein expression in male compared to female VSMC after exposure to NO. Next, the rat carotid artery injury model was used to assess the effect of NO on neointimal hyperplasia in vivo. Consistent with the in vitro data, NO was significantly more effective at inhibiting neointimal hyperplasia in hormonally intact males compared to females using weight-based dosing. An increased weight-based dose of NO in females was able to achieve efficacy equal to that in males. Surprisingly, NO was less effective at inhibiting neointimal hyperplasia in castrated animals of both sexes. In conclusion, these data suggest that NO inhibits neointimal hyperplasia more effectively in males compared to females and in hormonally intact compared to castrated rats, indicating that the effects of NO in the vasculature may be sex- and hormone-dependent.

Insulin enhances the effect of nitric oxide at inhibiting neointimal hyperplasia in a rat model of type 1 diabetes.

Diabetes confers greater restenosis from neointimal hyperplasia following vascular interventions. While localized administration of nitric oxide (NO) is known to inhibit neointimal hyperplasia, the effect of NO in type 1 diabetes is unknown. Thus the aim of this study was to determine the efficacy of NO following arterial injury, with and without exogenous insulin administration. Vascular smooth muscle cells (VSMC) from lean Zucker (LZ) rats were exposed to the NO donor, DETA/NO, following treatment with different glucose and/or insulin concentrations. DETA/NO inhibited VSMC proliferation in a concentration-dependent manner to a greater extent in VSMC exposed to normal-glucose vs. high-glucose environments, and even more effectively in normal-glucose/high-insulin and high-glucose/high-insulin environments. G(0)/G(1) cell cycle arrest and cell death were not responsible for the enhanced efficacy of NO in these environments. Next, type 1 diabetes was induced in LZ rats with streptozotocin. The rat carotid artery injury model was performed. Type 1 diabetic rats experienced no significant reduction in neointimal hyperplasia following arterial injury and treatment with the NO donor PROLI/NO. However, daily administration of insulin to type 1 diabetic rats restored the efficacy of NO at inhibiting neointimal hyperplasia (60% reduction, P < 0.05). In conclusion, these data demonstrate that NO is ineffective at inhibiting neointimal hyperplasia in an uncontrolled rat model of type 1 diabetes; however, insulin administration restores the efficacy of NO at inhibiting neointimal hyperplasia. Thus insulin may play a role in regulating the downstream beneficial effects of NO in the vasculature.

Critical limb ischemia.

Critical limb ischemia (CLI) continues to be a significantly morbid disease process for the aging population. Rigid guidelines for the management of patients with CLI are inappropriate due to the complexities that are involved in optimally treating these patients. A thin line exists in the decision process between medical management vs surgical management by revascularization or amputation, and the perception of "success" in this patient population is evolving. This review explores these issues and examines the challenges the treating physician will face when managing the care of patients with CLI. The epidemiology and natural history of CLI is discussed, along with the pathophysiology of the disease process. A review of the literature in regards to the different treatment modalities is presented to help the physician optimize therapy for patients with CLI. New scoring systems to help predict outcomes in patients with CLI undergoing revascularization or amputation are discussed, and an overview of the current status of patient-oriented outcomes is provided. Finally, we briefly examine emerging therapies for the treatment of CLI and provide an algorithm to help guide the practicing physician on how to approach the critically ischemic limb with regard to the complicated issues surrounding these patients.

Basic science review: nitric oxide--releasing prosthetic materials.

Prosthetic devices that come into contact with blood ultimately fail secondary to thrombus formation. This limits the utility of a variety of materials used to surgically treat cardiovascular disease, including vascular grafts and stents, as well as sensors and catheters placed within the circulatory system. Moreover, systemic anticoagulation that is used to prevent malfunction of these devices has potential for serious complications. It is known that nitric oxide (NO) produced via the endothelium imparts thromboresistant properties to native blood vessels. Thus, if NO were delivered locally to the site of the prosthetic material, it has the potential to halt thrombus formation while limiting life-threatening side effects. This review serves to examine the variety of NO-releasing materials that have been created with the two different classes of NO donors, the diazeniumdiolates and S-nitrosothiols, and the clinical applications of these prosthetics for potential future use.

Heightened efficacy of nitric oxide-based therapies in type II diabetes mellitus and metabolic syndrome.

Type II diabetes mellitus (DM) and metabolic syndrome are associated with accelerated restenosis following vascular interventions due to neointimal hyperplasia. The efficacy of nitric oxide (NO)-based therapies is unknown in these environments. Therefore, the aim of this study is to examine the efficacy of NO in preventing neointimal hyperplasia in animal models of type II DM and metabolic syndrome and examine possible mechanisms for differences in outcomes. Aortic vascular smooth muscle cells (VSMC) were harvested from rodent models of type II DM (Zucker diabetic fatty), metabolic syndrome (obese Zucker), and their genetic control (lean Zucker). Interestingly, NO inhibited proliferation and induced G0/G1 cell cycle arrest to the greatest extent in VSMC from rodent models of metabolic syndrome and type II DM compared with controls. This heightened efficacy was associated with increased expression of cyclin-dependent kinase inhibitor p21, but not p27. Using the rat carotid artery injury model to assess the efficacy of NO in vivo, we found that the NO donor PROLI/NO inhibited neointimal hyperplasia to the greatest extent in type II DM rodents, followed by metabolic syndrome, then controls. Increased neointimal hyperplasia correlated with increased reactive oxygen species (ROS) production, as demonstrated by dihydroethidium staining, and NO inhibited this increase most in metabolic syndrome and DM. In conclusion, NO was surprisingly a more effective inhibitor of neointimal hyperplasia following arterial injury in type II DM and metabolic syndrome vs. control. This heightened efficacy may be secondary to greater inhibition of VSMC proliferation through cell cycle arrest and regulation of ROS expression, in addition to other possible unidentified mechanisms that deserve further exploration.