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.

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.

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.

Systemic delivery of the interleukin-1 receptor antagonist protein using a new strategy of direct adenoviral-mediated gene transfer to skeletal muscle capillary endothelium in the isolated rat hindlimb.

Current gene therapy strategies using adenoviral vectors to target the lung or liver have been complicated by an acute inflammatory response that can result in loss of transgene expression as well as tissue injury and necrosis. Skeletal muscle comprises 40% of total body weight; it possesses a high density, accessible capillary network that is resistant to injury and thus may be a logical target for adenoviral vectors. We hypothesized that adenoviral transduction of the rat skeletal muscle capillary bed during vascular isolation would achieve efficient gene transfer sufficient to achieve systemic serum levels of a recombinant protein without significant tissue injury. During vascular isolation of the hindleg, a replication-incompetent adenovirus (Ad) encoding for either the marker gene, human placental alkaline phosphatase (hpAP), or interleukin-1 receptor antagonist (IL-1ra) was infused and subsequently flushed from the circulation after a 30-min dwell period. Gene transfer over a 10(9)-10(12) particle/ml range to the gastrocnemius capillary endothelium and muscle fibers was highly efficient and titer-dependent, reaching maximum transduction rates of 71 +/- 7% and 25 +/- 5%, respectively, 5 days after gene transfer (n = 3-8 rats/group, p < 0.05). hpAP transgene expression was barely detectable at 14 days. No significant tissue injury or necrosis of the skeletal muscle was observed at 5 and 14 days, and distant organ gene transfer was minimal or absent. Gastrocnemius muscle from rats (n = 4) given Ad-IL-1ra had 241 +/- 66 pg IL-1ra/mg protein at 5 days, while those given Ad-hpAP, negative control (n = 3) had 35 +/- 14 pg IL-1ra/mg protein (p < 0.05). Ad-IL-1ra rats (n = 4) had serum levels of 185 +/- 20 pg/ml IL-1ra at 5 days whereas Ad-hpAP control rats (n = 5) had no IL-1ra detectable (p < 0.0001). Athymic rats given Ad-IL-1ra (n = 6) had serum levels of 493 +/- 62 pg/ml IL-1ra 14 days after transduction, and IL-1ra was detected for up to 98 days. Sera from Ad-IL-1ra athymic rats significantly inhibited IL-1 beta-induced (1 ng/ml) prostaglandin E2 (PGE2) production from cultured endothelial cells by 82 +/- 2% (p < 0.001). Thus, this gene transfer strategy is the first to result in substantial transduction of both skeletal muscle capillary endothelium and fibers, sufficient to achieve pharmacologic levels of IL-1ra. Although no acute tissue injury or necrosis was observed, persistence of transgene expression in athymic rats suggests that loss of expression in normal rats was by an immune-mediated mechanism.

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.

Successful aortic valvotomy for severe congenital valvular aortic stenosis in the newborn infant.

The preoperative evaluation, surgical course, and early follow-up results of 11 newborn infants less than 30 days of age who underwent aortic valvotomy for severe valvular aortic stenosis between 1976 and 1983 were reviewed to determine our current surgical mortality and the early prognosis of these neonates. Ten of the 11 patients had severe congestive heart failure and dyspnea. Preoperative cardiac catheterization and angiography detected features characteristic of congenital aortic valvular stenosis in newborn infants. Emergency aortic valvotomy was performed in all during cardiopulmonary bypass, for which a cold (4 degrees C) blood prime and moderate systemic hypothermia were used. An effort was made to achieve maximal relief of the stenosis without causing aortic insufficiency. Mean cardiopulmonary bypass time was 21 minutes and mean cross-clamp time was 6.4 minutes. There was a single operative death, and there have been no late deaths during a mean follow-up period of 2.2 years. All patients are currently free of heart failure. Four patients underwent postoperative cardiac catheterization for clinical suspicion of severe residual stenosis. However, three had only mild or moderate residual stenosis. The fourth had a large gradient, 70 mm Hg, and has since undergone successful repeat valvotomy. These results indicate that neonates with severe valvular aortic stenosis can undergo valvotomy safely and have a favorable early prognosis. The factors responsible for the low mortality appear to include prompt recognition and diagnosis followed by emergency operation, use of a 4 degree C cold pump prime, brief cross-clamp times, and conservative valvotomy to avoid the development of significant aortic insufficiency.

The effects of cardiopulmonary bypass on coronary blood flow in the dog.

The effects of cardiopulmonary bypass on autoregulation, maximum coronary flow, and regional blood flow in the heart were investigated in 25 dogs. A Gregg cannula was inserted into the left main coronary artery, and pressure-flow relations were then measured in the autoregulating state or with vasodilation produced by intracoronary adenosine infusion before, during, and after cardiopulmonary bypass. Seventeen of the dogs had radioactive microspheres injected to investigate regional blood flow changes at the same times. (1) Autoregulation was not present after bypass for at least 3 hours. (2) Blood flow was shifted toward the subendocardium on bypass (increased subendocardial/subepicardial ratio) and tended to return to prebypass distribution following bypass. (3) Blood flow after bypass was not significantly different to the subendocardium and subepicardium. (4) Response to a coronary vasodilator (maximum coronary flow) was significantly affected by cardiopulmonary bypass: blood flow to all layers of the heart could be increased with adenosine after bypass. (5) Global lactate and oxygen metabolism were not adversely affected by bypass. We conclude that cardiopulmonary bypass abolished the normal autoregulation of coronary flow; this may predispose the incompletely revascularized patient to a "coronary steal" syndrome. However, the heart with normal coronary arteries is not underperfused in any layer after bypass. Thus, the bypass technique is not the cause of the subendocardial ischemia that sometimes complicates cardiac operations.

Clinical significance of routine imaging of iliac and calf veins by color flow duplex scanning in patients suspected of having acute lower extremity deep venous thrombosis.

BACKGROUND: Because duplex ultrasonography is used increasingly to evaluate patients suspected of having acute deep venous thrombosis of the lower extremity, the clinical significance of limiting venous duplex scanning to the common femoral, superficial femoral, and popliteal veins becomes an important question. METHODS: We prospectively studied by venous color flow duplex ultrasonography 181 patients referred for evaluation to rule out acute deep venous thrombosis to determine (1) the frequency with which the iliac and calf veins could be imaged adequately to determine the presence or absence of acute deep venous thrombosis, (2) the frequency of acute venous thrombosis in these venous segments, and (3) the time required to scan these additional segments. RESULTS: In 79% of the patients studied, one segment of the iliac venous system was imaged adequately to determine the presence or absence of venous thrombosis. In the lower extremity, the common femoral vein, the superficial femoral vein, and the popliteal vein were imaged adequately in 94% of the patients. In 76% of the patients all three calf veins were imaged adequately to determine whether acute deep venous thrombosis was present or absent. The anterior tibial vein was the most difficult vein to image consistently and was imaged adequately in 76% of the patients referred. The mean time to scan the affected limb was 8 minutes 37 seconds. Forty-seven patients (26%) of the 180 patients studied had positive venous scans. Twenty-three percent of the patients who had positive scans were found to have iliac vein involvement. Thirty-two percent who had positive venous scans were found to have thrombosis of the calf veins. Fifteen percent of the 47 patients who had positive scans had either an isolated iliac or calf vein thrombosis. CONCLUSIONS: We believe this frequency of isolated iliac or calf vein thrombosis coupled with the frequency of successful imaging of these venous segments and the short additional time required to image these segments justifies the inclusion of routine imaging of the iliac and calf veins in patients undergoing venous duplex scanning to rule out acute deep venous thrombosis.

A prospective study of clinically and endoscopically documented colonic ischemia in 100 patients undergoing aortic reconstructive surgery with aggressive colonic and direct pelvic revascularization, compared with historic controls.

Clinically and endoscopically proved ischemia of the colon complicates elective aortic reconstruction in 1% to 2% and 6% to 7% of cases, respectively. Operative mortality exceeds 60% when transmural infarction occurs. A prospective study of colonic ischemia was undertaken in 100 male patients (mean age, 62.4 +/- 7.9 years) undergoing operation for aortic aneurysms (58) or aortoiliac occlusive disease (42). Conventional aortic surgery was undertaken in 88 patients, and in 12 patients adjunctive procedures to enhance colonic perfusion were performed 14 times, including IMA reimplantation (8), direct bypass to the internal iliac artery (4), and anastomosis of an aortofemoral bypass limb to adjacent common iliac artery (2). Colonoscopy was performed within 24 to 48 hours of aortic reconstruction. Three patients had endoscopic evidence of colonic ischemia. Transmural infarction did not develop in any patient, and bowel resections or diverting colostomies were not necessary. Three patients died, none manifesting colonic ischemia. The 12% utilization of adjunctive procedures to enhance blood flow in the colon was substantially greater than the 4% frequency of an earlier experience from our institution in which nearly half of the 5.7% operative mortality was attributed to colonic infarction. Attention to factors contributing to ischemia of the colon, and more frequent adjunctive revascularization of the colon, may lessen this complication of aortic reconstructive surgery.

Common brachiocephalic trunk: strategies for revascularization.

BACKGROUND: A common brachiocephalic trunk, in which both common carotid arteries and the right subclavian artery arise from a single trunk off the arch, is a normal variant of aortic arch branching that occurs in approximately 10% of the population. Because three of the four primary sources of cerebral blood flow arise from a single aortic branch, stenosis or occlusion of a common trunk can cause severe ischemic consequences. Common trunk revascularization has been described, but there have been no reports focusing on the management options for occlusive disease of this vascular anatomy. METHODS: A retrospective review of our experience with innominate artery revascularization identified 6 patients who underwent revascularization of a common brachiocephalic trunk between 1977 and 1997. All patients were symptomatic, with either total occlusion (n = 3) or critical stenosis (n = 3) caused by atherosclerosis (n = 5) or Takayasu's arteritis (n = 1). Revascularization was achieved by a prosthetic bypass graft from the ascending aorta to the innominate or left common carotid arteries or both (n = 5); or transarterial endarterectomy (n = 1). Concomitant endarterectomy of branch vessels was performed in 3 patients. RESULTS: There was one perioperative death from myocardial infarction, and one perioperative stroke, with death occurring 1 month after hospital discharge. One patient developed cerebral hyperperfusion syndrome 1 week after endarterectomy that resolved without sequelae with antihypertensive medications. During a follow-up period ranging from 1 to 20 years, there was one late death from congestive heart failure 5 years after operation. All surviving patients are alive and free from symptomatic recurrence. CONCLUSIONS: Revascularization for occlusive disease of a common brachiocephalic trunk can be achieved with effective and durable relief of symptoms using either a prosthetic bypass graft or endarterectomy. However, neurologic complications in 2 patients, which were fatal in 1, attest to the potential cerebral ischemic threat posed by occlusive disease of a common brachiocephalic trunk.

Pseudoaneurysm of the inferior gluteal artery presenting as sciatic nerve compression.

A pseudoaneurysm of the inferior gluteal artery presenting as sciatic nerve compression is reported in a 40-year-old woman. Following a transvaginal needle biopsy for endometriosis, the patient developed left sciatic pain and a nonpulsatile mass palpable in the left buttock thought to represent a pyriformis hematoma. Sequential computed tomographic scans were consistent with this diagnosis. Persistent pain and progression of neurological deficits led to surgical exploration. Posterior exposure of the pyriformis muscle and proximal sciatic nerve revealed a large pseudoaneurysm of the inferior gluteal artery compressing the nerve. A laparotomy was performed and the internal iliac artery was ligated, followed by evacuation of the aneurysm contents and repair of the aneurysm neck via a posterior approach. The patient has remained pain-free with progressive improvement in neurological function after 1 year follow-up. Aneurysms of the gluteal artery are unusual, predominantly occur after significant pelvic trauma, and rarely present as sciatica. Pertinent aspects of the patient history and clinical findings are atypical for discogenic sciatica. Because of the rarity of this entity, preoperative diagnosis is usually not achieved. Angiography or magnetic resonance imaging should be performed in patients with atypical sciatica and a mass in the region of the proximal sciatic nerve, particularly after trauma.

Visceral artery aneurysms.

Visceral artery aneurysms are an uncommon form of vascular disease that have a significant potential for rupture or erosion into an adjacent viscera, resulting in life-threatening hemorrhage. During the last decade, hepatic artery aneurysms have become the most commonly reported visceral artery aneurysm. This change likely reflects the increased use of percutaneous diagnostic and therapeutic biliary procedures, as well as increased use of diagnostic computed tomography after blunt abdominal trauma. A second significant development is the increased use of percutaneous catheter-based therapy in the management of visceral artery aneurysms. Nonetheless, a continued aggressive approach to the diagnosis and management of these unusual aneurysms remains warranted.

Aortomonoiliac endovascular grafting combined with femorofemoral bypass: an acceptable compromise or a preferred solution?

The relative merits of aortomonoiliac and bifurcated stent-graft configurations depend on the patient's arterial anatomy and clinical status. Aortomonoiliac stent-grafts are simple to make, simple to insert, and versatile. They are most useful when the iliac artery anatomy is severely distorted and the patient is old, sick, and inactive. The main problems with this approach are all consequences of femorofemoral bypass. The bifurcated stent-graft is the preferred alternative in healthy patients, because it ensures flow to both common iliac arteries, thereby eliminating the need for femorofemoral bypass. However, bifurcated stent-grafts and their delivery systems are difficult to make and difficult to deploy, especially when the iliac anatomy is distorted or emergency circumstances preclude preoperative sizing. This article addresses the advantages and disadvantages of the aortomonoiliac graft.

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.

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.