Correction to: A PRISMA-compliant systematic review of the endpoints employed to evaluate symptomatic treatments for primary headaches.

Following publication of the original article [1], we have been notified that the name of author five was spelled incorrectly as M. Ferrili, when the correct spelling is MAN Ferilli.

Are paediatric headaches in the emergency department increasing? An Italian experience.

The aim of this study was to assess admissions, for headache, to the emergency department (ED) of the Di Cristina Children's Hospital in Palermo over a decade. The total number of ED admissions for headache was retrospectively analysed considering two 24- month periods: 2009-2010 and 2017-2018. Total admissions to the ED decreased from 55,613 to 50,096 (-10%) between the two periods considered, while the number of admissions for headache increased by 63.56% (p < 0.0001). There was also a significant increase in the number of multiple ED admissions by single children (9.5% versus 17.98% of the patients accessing the ED for headache). This significant increase in admissions for paediatric headache is probably due to limited efficacy of the Italian and international guidelines and of the educational strategies implemented in this setting, and also to communication difficulties, both with patients and between primary care networks and hospitals.

A PRISMA-compliant systematic review of the endpoints employed to evaluate symptomatic treatments for primary headaches.

BACKGROUND: Primary headache are prevalent and debilitating disorders. Acute pain cessation is one of the key points in their treatment. Many drugs have been studied but the design of the trials is not usually homogeneous. Efficacy of the trial is determined depending on the selected primary endpoint and usually other different outcomes are measured. We aim to critically appraise which were the employed outcomes through a systematic review. METHODS: We conducted a systematic review of literature focusing on studies on primary headache evaluating acute relief of pain, following the PRISMA guideline. The study population included patients participating in a controlled study about symptomatic treatment. The comparator could be placebo or the standard of care. The collected information was the primary outcome of the study and all secondary outcomes. We evaluated the studied drug, the year of publication and the type of journal. We performed a search and we screened all the potential papers and reviewed them considering inclusion/exclusion criteria. RESULTS: The search showed 4288 clinical trials that were screened and 794 full articles were assessed for eligibility for a final inclusion of 495 papers. The studies were published in headache specific journals (58%), general journals (21.6%) and neuroscience journals (20.4%). Migraine was the most studied headache, in 87.8% studies, followed by tension type headache in 4.7%. Regarding the most evaluated drug, triptans represented 68.6% of all studies, followed by non-steroidal anti-inflammatories (25.1%). Only 4.6% of the papers evaluated ergots and 1.6% analyzed opioids. The most frequent primary endpoint was the relief of the headache at a determinate moment, in 54.1%. Primary endpoint was evaluated at 2-h in 69.9% of the studies. Concerning other endpoints, tolerance was the most frequently addressed (83%), followed by headache relief (71.1%), improvement of other symptoms (62.5%) and presence of relapse (54%). The number of secondary endpoints increased from 4.2 (SD = 2.0) before 1991 to 6.39 after 2013 (p = 0.001). CONCLUSION: Headache relief has been the most employed primary endpoint but headache disappearance starts to be firmly considered. The number of secondary endpoints increases over time and other outcomes such as disability, quality of life and patients' preference are receiving attention.

Local arterial nanoparticle delivery of siRNA for NOX2 knockdown to prevent restenosis in an atherosclerotic rat model.

Both atherosclerosis and arterial interventions induce oxidative stress mediated in part by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases that have a pivotal role in the development of neointimal hyperplasia and restenosis. For small interfering RNA (siRNA) targeting of the NOX2 (Cybb) component of the NADPH oxidase to prevent restenosis, gene transfer with viral vectors is effective, but raises safety issues in humans. We developed a new approach using the amino-acid-based nanoparticle HB-OLD7 for local delivery of siRNA targeting NOX2 to the arterial wall. siRNA-nanoparticle complexes were transferred into the regional carotid artery walls after angioplasty in an atherosclerotic rat model. Compared with angioplasty controls, Cybb gene expression (measured by quantitative reverse transcriptase-PCR) in the experimental arterial wall 2 weeks after siRNA was reduced by >87%. The neointima-to-media-area ratio was decreased by >83%, and the lumen-to-whole-artery area ratio was increased by >89%. Vital organs showed no abnormalities and splenic Cybb gene expression showed no detectable change. Thus, local arterial wall gene transfer with HB-OLD7 nanoparticles provides an effective, nonviral system for efficient and safe local gene transfer in a clinically applicable approach to knock down an NADPH oxidase gene. Local arterial knockdown of the Cybb gene significantly inhibited neointimal hyperplasia and preserved the vessel lumen without systemic toxicity.

Optimization of adenovirus-mediated endothelial nitric oxide synthase delivery in rat hindlimb ischemia.

Adenovirus-mediated overexpression of endothelial nitric oxide synthase (eNOS) induces collateral artery development and substantially increases blood flow after induction of experimental acute hindlimb ischemia. However, the optimal technique of gene delivery for this or any other form of gene therapy in limb ischemia is still unknown. The purpose of this study was to determine the effect of the two most commonly used techniques, intra-arterial and intramuscular injection, on blood flow recovery, collateral artery development, and preservation of muscle mass. We compared intra-arterial injection under vascular isolation, intra-arterial injection under transient vascular occlusion, and intramuscular injection of phosphate buffered saline (PBS) or adenovirus encoding either the eNOS (AdeNOS) or LacZ (AdlacZ) gene after induction of acute hindlimb ischemia. Delivery of AdeNOS by both intra-arterial injection techniques increased eNOS activity (22.30 versus 10.56, P<0.01), blood flow (0.90+/-0.02 versus 0.69+/-0.07, P<0.001) and collateral artery development (17.56484 versus 13.74259, P<0.05) more than by intramuscular delivery. Intra-arterial injection under transient vascular occlusion led to better preservation of muscle mass, muscle architecture, and clinical ischemic index, but led to greater transgene expression in distant organs and contralateral limb muscles. Intra-arterial injection of AdeNOS under transient vascular occlusion is the optimal technique to reverse severe hindlimb ischemia in the rat. This is the first systematic comparison of different delivery techniques used in gene therapy of experimental hindlimb ischemia.

The incidence of iliac aneurysms in patients with abdominal aortic aneurysms: comparison of four centers in Europe and the USA.

BACKGROUND: The purpose of this study was to compare the anatomy of the aortoiliac vessels in patients scheduled for infrarenal abdominal aortic aneurysm (AAA) repair in four different countries. MATERIAL AND METHODS: Consecutives series of 100 preoperative CT-scans were evaluated at each center. Diameters of the suprarenal aorta, maximal diameter of the aneurysm, right and left common and external iliac artery as well as the hypogastric arteries were recorded and compared between each center. RESULTS: Configuration of the AAA above bifurcation was similar at each center. The dimensions of the aortic bifurcation and the common iliac arteries were different among the centers. Common iliac arteries with diameters over 25 mm were significantly more common at center 1 (p < 0.001, p = 0.002 and p < 0.001). Among centers 2, 3 and 4 there was no significant difference in common iliac diameters. CONCLUSIONS: Configuration of the iliac arteries in AAA was significantly different for Swiss patients compared to American, Austrian and German patients. Reasons for these differences are unclear, epidemiological or genetic factors may be responsible.

C-reactive protein levels and viable Chlamydia pneumoniae in carotid artery atherosclerosis.

BACKGROUND AND PURPOSE: An elevated serum level of C-reactive protein, an inflammatory marker, is an independent predictor of stroke and coronary artery disease. To determine whether chronic infection with Chlamydia pneumoniae, which has been identified in atherosclerotic plaques, is responsible for systemic inflammation, we studied the association between serum C-reactive protein levels and infection of carotid artery atherosclerotic plaque with viable C pneumoniae. METHODS: Serum C-reactive protein levels were obtained before endarterectomy for carotid artery stenosis. Plaques were tested for C pneumoniae mRNA, an indicator of viability, and DNA by polymerase chain reaction of DNA and cDNA, respectively. RESULTS: Forty-eight samples were studied, of which 18 (38%; 95% CI, 23 to 50) were infected with viable C pneumoniae as evidenced by isolated chlamydial mRNA. All 18 of these samples, plus 1 additional sample, were positive for chlamydial DNA. Serum C-reactive protein levels were higher in those with viable C pneumoniae compared with those without infection (median, 8 mg/L versus undetectable; P=0.045 by Wilcoxon rank-sum test). In multivariable models, the only independent predictor of the presence of viable C pneumoniae was a detectable C-reactive protein level (odds ratio, 4.2; 95% CI, 1.1 to 17; P=0.04). CONCLUSIONS: Viable C pneumoniae are present in a substantial portion of carotid artery atherosclerotic plaques and are associated with increased serum C-reactive protein levels. These findings may explain the link between elevated C-reactive protein levels and the risk of cardiovascular disease and stroke but should be reproduced in a larger cohort.

Extended iliac exposure from the groin.

Knowledge of iliac artery and inguinal anatomy enables extraperitoneal exposure of the iliac arteries for surgical treatment of unilateral inflow disease. A method is presented for exposing the distal common iliac artery, the iliac bifurcation, and the full length of the external iliac artery by detachment and retraction of the inguinal ligament though a single extended groin incision. The indications for unilateral iliac artery exposure, revascularization, surgical anatomy, and technique of iliofemoral exposure through a single, extended groin incision are presented. Extended iliac exposure through a single, extraperitoneal exposure facilitates all methods of unilateral iliac revascularization and provides access for delivery of endovascular devices.

Administration of adenoviral vectors induces gangrene in acutely ischemic rat hindlimbs: role of capsid protein-induced inflammation.

PURPOSE: The initial purpose of this study was to determine the effects of intravascular adenoviral vector-mediated gene transfer of endothelial nitric oxide synthase (AdeNOS) on experimental hindlimb ischemia in the rat. Unexpectedly, administration of AdeNOS immediately after induction of acute limb ischemia led to limb gangrene. We subsequently sought to define the molecular mechanisms responsible for this unusual effect and to devise adenoviral gene transfer strategies to prevent the development of gangrene in acutely ischemic limbs. METHODS: Phosphate-buffered saline or adenoviral vectors containing the bovine endothelial nitric oxide synthase gene (AdeNOS) or no transgene (Ad-E1) were injected intra-arterially into the hindlimb of a rat under vascular isolation immediately after surgical induction of severe ischemia. Hematoxylin and eosin staining was performed on muscle sections to evaluate inflammation. A separate group of animals was injected with an adenovirus containing a nontranscribable genome, treated with cyclosporine, or received delayed administration of the adenoviral vector. Gene expression after delayed adenoviral gene transfer was assessed with immunohistochemistry, Western blotting, and nitric oxide synthase (NOS) activity assay. RESULTS: Both AdeNOS and Ad-E1 caused gangrene of the entire hindlimb within 12 days in a dose-dependent manner, at a threshold concentration of 1 x 10(9) plaque-forming unit/mL. Adenoviral delivery was associated with more inflammation and edema compared with phosphate-buffered saline histologically. Inactivation of adenoviral DNA transcription did not affect induction of gangrene. However, gangrene was prevented by concurrent immunosuppression with cyclosporine or delayed administration of the vector. Delayed administration allowed adenoviral gene expression as determined by immunohistochemistry, NOS protein levels, and an assay of NOS enzyme activity. CONCLUSION: Intra-arterial administration of adenoviral vectors, under vascular isolation, immediately after induction of acute ischemia causes inflammation and subsequent limb gangrene. The inflammatory response is unrelated to the expression of the recombinant transgene or the adenoviral genome and is likely due to the adenoviral capsid proteins. However, administration of cyclosporine or delayed injection of the adenoviral vector is a method that can be used for adenoviral mediated gene transfer in limb ischemia.

Endoleak after endovascular repair of abdominal aortic aneurysm.

PURPOSE: We sought to assess the role of endovascular techniques in the management of perigraft flow (endoleak) after endovascular repair of an abdominal aortic aneurysm. METHOD: We performed endovascular repair of abdominal aortic aneurysm in 114 patients, using a variety of Gianturco Z-stent-based prostheses. Results were evaluated with contrast-enhanced computed tomography (CT) at 3 days, 3 months, 6 months, 12 months, and every year after the operation. An endoleak that occurred 3 days after operation led to repeat CT scanning at 2 weeks, followed by angiography and attempted endovascular treatment. RESULTS: Endoleak was seen on the first postoperative CT scan in 21 (18%) patients and was still present at 2 weeks in 14 (12%). On the basis of angiographic localization of the inflow, the endoleak was pure type I in 3 cases, pure type II in 9, and mixed-pattern in 2. Of the 5 type I endoleaks, 3 were proximal and 2 were distal. All five resolved after endovascular implantation of additional stent-grafts, stents, and embolization coils. Although inferior mesenteric artery embolization was successful in 6 of 7 cases and lumbar embolization was successful in 4 of 7, only 1 of 11 primary type II endoleaks was shown to be resolved on CT scanning. There were no type III or type IV endoleaks (through the stent-graft). Endoleak was associated with aneurysm dilation two cases. In both cases, the aneurysm diameter stabilized after coil embolization of the inferior mesenteric artery. There were two secondary (delayed) endoleaks; one type I and one type II. The secondary type I endoleak and the associated aneurysm rupture were treated by use of an additional stent-graft. The secondary type II endoleak was not treated. CONCLUSIONS: Type I endoleaks represent a persistent risk of aneurysm rupture and should be treated promptly by endovascular means. Type II leaks are less dangerous and more difficult to treat, but coil embolization of feeding arteries may be warranted when leakage is associated with aneurysm enlargement.

Exercise-induced hyperemia unmasks regional blood flow deficit in experimental hindlimb ischemia.

UNLABELLED: Many experimental models of hindlimb ischemia are characterized by spontaneous and rapid normalization of resting muscle blood flow (BF) rates which complicates the long-term evaluation of angiogenic therapies to reverse limb ischemia. We tested the hypothesis that peroneal nerve stimulation in an ischemic hindlimb would increase the oxygen (O(2)) demand and BF rate, thereby unmasking a severe blood flow deficit that is not apparent at rest. METHODS: Ischemia was induced in adult rats by ligation of the left common iliac, femoral arteries, and their branches. Peroneal nerves were stimulated to allow measurement of exercise-induced regional BF rates with fluorescent microspheres. Hemodynamics were monitored. Fluorescent microspheres were injected before and after 5 min of nerve stimulation 3, 10, and 24 days postischemia. The tibialis anterior (TA) and gastrocnemius (GC) muscles and skin were harvested and weighed, and fluorescence was measured. BF rate was calculated as milliters per minute per gram of tissue and compared to normal muscle and skin of unoperated control rats. In order to determine the accuracy of BF rate measurements in ischemic muscle when <400 microspheres was delivered per specimen, 3 rats were studied by simultaneous injection of 4 x 10(5) blue and 1 x 10(5) yellow-green fluorescent microspheres. The correlation coefficient between the number of different colored microspheres delivered was measured. RESULTS: The ischemia caused atrophy of the TA and GC muscles. The mean muscle mass of the ischemic TA and GC as a percentage of total body weight decreased over time vs control [TA 0.13 +/- 0.05% vs 0.25 +/- 0.03%, P < 0.05; GC 0.51 +/- 0.27% vs 0.70 +/- 0.07%, P = 0.07 at 24 days (24D)]. Despite clinical evidence of severe hindlimb ischemia in experimental groups, i.e., pressure sores, muscle atrophy, and weakness, resting BF rates were not significantly different from those of control. The BF rate of the TA was of 0.11 ml/min/g after 3D of ischemia, 0.14 ml/min/g after 10D, and 0.13 ml/min/g after 24D. The mean BF rate in normal muscle of unoperated controls was 0.16 ml/min/g (P > 0.05). However, the exercise-induced hyperemia in the skeletal muscle was significantly blunted in all of the ischemic groups. The unoperated control TA had a greater than 10-fold increase in BF to 1.95 ml/min/g in response to exercise while the ischemic TA had no increase in BF at 3D, 2-fold increase at 10D, and a 5-fold increase at 24D. Parallel findings were noted in the GC muscles. There was no significant difference in the BF rate in the skin. The accuracy of this microsphere technique in measuring very low BF rates found in ischemic muscle was supported by the significant correlation coefficient (r = 0.99) comparing two quantities of microspheres injected simultaneously. CONCLUSION: Despite clinical signs of severe hindlimb ischemia, resting BF rates in the ischemic groups were not significantly decreased. Peroneal nerve stimulation resulted in up to 10-fold increase in BF rate and unmasked a severe deficit in vascular reserve in the ischemic groups. Resting BF rate is not always an accurate reflection of the flow deficit in models of critical limb ischemia, and this model of exercise-induced hindlimb hyperemia may allow better long-term evaluation of angiogenic therapies designed to reverse critical limb ischemia.

An endovascular system for thoracoabdominal aortic aneurysm repair.

PURPOSE: To describe a stent-graft system for endovascular repair of thoracoabdominal aortic aneurysm (TAAA) that preserves side branch perfusion. TECHNIQUE: The modular endograft system includes 3 components. The primary stent-graft is custom-made from conventional graft fabric and Gianturco Z-stents. Covered nitinol Smart Stents are used for the visceral and renal extensions, and the distal extension is made from a modified Zenith system. With the supine patient under general anesthesia, the components are delivered sequentially through surgically exposed femoral and right brachial arteries in an operation that requires prolonged periods of magnified high-resolution imaging. This system was first used in a 76-year-old man with a contained rupture of a supraceliac ulcer and a large abdominal aortic aneurysm ending proximally at the celiac artery. The endograft was implanted successfully, but the patient developed paraplegia on day 2; imaging documented an excluded aneurysm and excellent flow through the endograft and all prosthetic branches. DISCUSSION: Endovascular repair of TAAA appears to be feasible. If there are no serious, specific, unavoidable complications, the potential advantages are enormous.

Endovascular repair of a presumed aortoenteric fistula: late failure due to recurrent infection.

PURPOSE: To describe a case of presumed aortoduodenal fistula that was treated by endovascular implantation of a stent-graft. METHODS AND RESULTS: A 76-year-old man was transferred from another hospital where he had been treated for upper gastrointestinal hemorrhage over a 2-month period. Ten years previously, he had undergone aortobifemoral bypass, the right limb of which recently thrombosed. At the time of transfer, computed tomographic scanning showed a large false aneurysm between the aorta and the duodenum. Endoscopy disclosed mucosal erosions in the fourth portion of the duodenum. Following implantation of 2 overlapping stent-grafts, the bleeding ceased and the false aneurysm disappeared. At no time did the patient have a fever. The patient initially did well, but 8 months after treatment, he presented with fever and chills. Recurrent infection had caused erosion of the aorta so that a large portion of the stent-graft was visible from the duodenum. The infected graft and stent-grafts were removed in a two-part operation, from which the patient recovered satisfactorily. CONCLUSIONS: Endovascular stent-grafts may have a role to play in the management of aortoduodenal fistula, if only as a temporary measure to control bleeding.

Adenoviral-mediated gene transfer of ICP47 inhibits major histocompatibility complex class I expression on vascular cells in vitro.

PURPOSE: Many viruses have evolved mechanisms to evade detection by the host immune system. The herpes simplex gene ICP47 encodes a protein that binds to the host antigen-processing transporter, inhibiting the formation of major histocompatibility complex class I (MHC-I) antigens in infected cells. MHC-I antigen expression is also important in acute allograft rejection. This study was designed to quantitate the effect of adenoviral-mediated gene transfer of ICP47 on MHC-I cell surface expression of human vascular cells. We hypothesized that the transduction of vascular cells with a replication-incompetent adenoviral vector that was expressing ICP47 (AdICP47) would inhibit constitutive and inducible MHC-I expression and thereby reduce the rate of cytolysis of ICP47-transduced vascular cells by sensitized cytotoxic T lymphocytes (CTL). METHODS: A replication-incompetent adenoviral vector, AdICP47, was created to express ICP47 driven by the cytomegalovirus immediate early promoter. Cultured human vascular endothelial and smooth muscle cells and human dermal fibroblasts were transduced with either AdICP47 or the control empty vector AddlE1. Cell surface constitutive and gamma-interferon-induced MHC-I expression were quantitated by flow cytometry. A standard 4-hour chromium release cytotoxicity assay was used to determine the percent cytolysis of transduced and nontransduced endothelial cells by sensitized CTL. Finally, to quantitate the specificity of the effect of ICP47 on MHC-I expression, adhesion molecule expression was quantitated in both transduced and nontransduced cells. RESULTS: Constitutive MHC-I expression in AdICP47-transduced endothelial cells was inhibited by a mean of 84% +/- 5% (SEM) in five experiments. After 48 hours of exposure to gamma-interferon, AdICP47-transduced cells exhibited a mean of 66% +/- 8% lower MHC-I expression than nontransduced cells. Similar inhibition in MHC-I expression was achieved in AdICP47-transduced vascular smooth muscle cells and dermal fibroblasts. Percent cytolysis of AdICP47-transduced endothelial cells by CTL was reduced by 72%. Finally, the specificity of the effect of transduction of ICP47 on vascular cell MHC-I expression was confirmed by a lack of significant change in either constitutive or tumor necrosis factor-induced vascular cell adhesion molecule/intercellular adhesion molecule expression. CONCLUSION: Transduction of vascular cells with AdICP47 strongly inhibits both constitutive and inducible MHC-I expression in human vascular cells. AdICP47-transduced cells exhibited a substantial reduction in cytolysis by CTL. Thus AdICP47 transduction holds promise as a technique to characterize the role of MHC-I expression in acute vascular allograft rejection in vivo and as a potential therapeutic intervention.

Endovascular aneurysm repair in high-risk patients.

PURPOSE: The purpose of this study was to evaluate the role of endovascular aneurysm repair in high-risk patients. METHODS: The elective endovascular repair of infrarenal aortic aneurysm was performed in 116 high-risk patients with either custom-made or commercial stent grafts. The routine follow-up examination included contrast-enhanced computed tomography (CT) before discharge, at 3, 6, and 12 months, and annually thereafter. Patients with endoleak on the initial CT underwent re-evaluation at 2 weeks. Those patients with positive CT results at 2 weeks underwent endovascular treatment. RESULTS: Endovascular repair was considered feasible in 67% of the patients. The mean age was 75 years, and the mean aneurysm diameter was 6.3 cm. The American Society of Anesthesiologists grade was II in 3.4%, III in 65.5%, IV in 30.1%, and V in 0.9%. There were no conversions to open repair. Custom-made aortomonoiliac stent grafts were implanted in 77.6% of the cases, custom-made aortoaotic stent grafts in 11.2%, and commercial bifurcated stent grafts in 11.2%. The 30-day rates of mortality, major morbidity, and minor morbidity were 3.4%, 20.7%, and 12%, respectively, in the first 58 patients and 0%, 3.4%, and 3.4%, respectively, in the last 58. The late complications included five cases of stent graft kinking, two cases of femorofemoral graft occlusion, and three cases of proximal stent migration, one of which led to aneurysm rupture. At 2 weeks after repair, endoleak was present in 10.3% of the cases. All the type I (direct perigraft) endoleaks underwent successful endovascular treatment, whereas only one type II (collateral) endoleak responded to treatment. The technical success rate at 2 weeks was 86.2%, and the clinical success rate was 96.6%. The continuing success rate was 87.9%. Seventeen patients died late, unrelated deaths. CONCLUSION: Endovascular aneurysm repair is safe and effective in patients at high risk, for whom it may be the preferred method of treatment.