Centripetal Propagation of Vasoconstriction at the Time of Headache Resolution in Patients with Reversible Cerebral Vasoconstriction Syndrome.

BACKGROUND AND PURPOSE: Reversible cerebral vasoconstriction syndrome is characterized by thunderclap headache and diffuse segmental vasoconstriction that resolves spontaneously within 3 months. Previous reports have proposed that vasoconstriction first involves small distal arteries and then progresses toward major vessels at the time of thunderclap headache remission. The purpose of this study was to confirm centripetal propagation of vasoconstriction on MRA at the time of thunderclap headache remission compared with MRA at the time of reversible cerebral vasoconstriction syndrome onset. MATERIALS AND METHODS: Of the 39 patients diagnosed with reversible cerebral vasoconstriction syndrome at our hospital during the study period, participants comprised the 16 patients who underwent MR imaging, including MRA, within 72 hours of reversible cerebral vasoconstriction syndrome onset (initial MRA) and within 48 hours of thunderclap headache remission. RESULTS: In 14 of the 16 patients (87.5%), centripetal propagation of vasoconstriction occurred from the initial MRA to remission of thunderclap headache, with typical segmental vasoconstriction of major vessels. These mainly involved the M1 portion of the MCA (10 cases), P1 portion of the posterior cerebral artery (10 cases), and A1 portion of the anterior cerebral artery (5 cases). CONCLUSIONS: This study found evidence of centripetal propagation of vasoconstriction on MRA obtained at the time of thunderclap headache remission, compared with MRA obtained at the time of reversible cerebral vasoconstriction syndrome onset. If clinicians remain unsure of the diagnosis during early-stage reversible cerebral vasoconstriction syndrome, this time point represents the best opportunity to diagnose reversible cerebral vasoconstriction syndrome with confidence.

Neuroradiologic Diagnosis of Minor Leak prior to Major SAH: Diagnosis by T1-FLAIR Mismatch.

BACKGROUND AND PURPOSE: In major SAH, the only method to diagnose a preceding minor leak is to ascertain the presence of a warning headache by interview; however, poor clinical condition and recall bias can cause inaccuracy. We devised a neuroradiologic method to diagnose previous minor leak in patients with SAH and attempted to determine whether warning (sentinel) headaches were associated with minor leaks before major SAH. MATERIALS AND METHODS: We retrospectively evaluated 127 patients who were admitted with SAH within 48 hours of ictus. Previous minor leak before major SAH was defined as T1WI-detected clearly bright hyperintense subarachnoid blood accompanied by SAH blood on FLAIR images that was distributed over a larger area than bright hyperintense subarachnoid blood on T1WI (T1-FLAIR mismatch). RESULTS: The incidence of warning headache before SAH was 11.0% (14 of 127 patients, determined by interview). The incidence of T1-FLAIR mismatch (neuroradiologic diagnosis of minor leak before major SAH) was 33.9% (43 of 127 patients). Of the 14 patients with warning headache, 13 had a minor leak diagnosed by T1-FLAIR mismatch at the time of admission. Variables identified by multivariate analysis as significantly associated with minor leak diagnosed by T1-FLAIR mismatch included 80 years of age or older, rebleeding after admission, intracerebral hemorrhage on CT, and mRS scores of 3-6. CONCLUSIONS: We conclude that warning headaches diagnosed by interview are not a product of recall bias but are the result of actual leaks from aneurysms.

Noise models and cryo-EM drift correction with a direct-electron camera.

Blurring due to specimen-holder drift is a common occurrence in cryo-EM images. Cameras employing active-pixel sensors are capable of high frame rates such that a single low-dose exposure can be acquired as a series of frames. In this paper we consider the possibility of tracking and compensating for overall drift in typical single-particle specimens through the analysis of frame sequences. A problem that arises in tracking through cross-correlation of frames obtained with the DE-12 camera from Direct Electron LLC is the presence of "hot-pixel noise". This random pattern of bright pixels is highly correlated among frames. We show how a model of this noise can be employed to greatly reduce its effects. A filter function is derived that optimizes the tracking of image shifts by cross-correlation, and we demonstrate the tracking of specimen drift in typical cryo-EM specimens.

Growth rates of abdominal aortic aneurysms in Japanese patients observed in one institute.

AIM: The aim of this paper was to investigate the growth rate of abdominal aortic aneurysms (AAA) in Japanese patients. METHODS: We retrospectively studied patients conservatively followed with infrarenal AAA in terms of AAA diameter measured using computed tomography (CT) in our hospital between 1999 and 2009. The AAA surgery criterion in our institute was a diameter ≥ 5.0 cm or a growth rate ≥5 mm/year. We estimated operation-free ratios by initial AAA diameter and changes in AAA growth rates. Patients with an initial AAA diameter < 5.0 cm were divided into 2 groups. Patients with AAA that met the criteria for surgery were classified into the expansion group, and those remaining into the non-expansion group. Their AAA growth rates were compared. RESULTS: The group consisted of 124 patients (average age, 73.7±8.6 years (range 54-92)) who had at least 2 recorded AAA measurements. The average follow-up period was 3.0±2.2 years (range 0.3-10.2). There were no cases of rupture during follow-up. Twenty-six patients (21.0%) underwent surgery (open replacement [N.=20]; endovascular abdominal aneurysm repair [N.=6]). The growth rate determined from the initially measured diameter was significantly faster in AAAs measuring 5.0-5.4 cm than in AAAs measuring 4.5-4.9 cm (P=0.01). More than 90% of patients with an initial AAA diameter <5.0 cm were observed conservatively for 2 years or more. However, more than half of the patients with an initial AAA diameter ≥4.0 cm needed surgery within 5 years. The growth rates of AAAs for each size during growth were significantly faster when the AAA diameter was 4.5-4.9 cm than when it was 4.0-4.4 cm (P=0.006), and when the AAA diameter was 5.0-5.4 cm than when it was 4.5-4.9 cm (P = 0.009). The expansion and non-expansion groups consisted of 38 (34.2%) and 73 (75.8%) patients, respectively. The AAA growth rate in the expansion group was significantly faster than that in the non-expansion group (3.4±2.2 mm/year vs. 1.4±1.3 mm/year, P=0.0001). CONCLUSION: It may be considered that the appropriate indication for AAA repair is defined by a diameter of 5.0 cm for Japanese patients. Patients with AAA that is growing continuously by ≥3 mm/year and who have low operative risk may undergo surgery even if their AAA is <5.0 cm.

Treatment with cyclosporine A improves SLE disease activity of Japanese patients with diffuse proliferative lupus nephritis.

AIMS: Cyclosporine A (CyA), a representative calcineurin inhibitor, may be useful for the treatment of lupus nephritis. In contrast to knowledge about its strong effects against proteinuria, however, there is little information about the beneficial effects of CyA against clinical disease activity of diffuse proliferative lupus nephritis. METHODS: To elucidate this issue, we investigated the effects of low-dose CyA treatment (< 2.5 mg/kg/d) in 11 Japanese adult patients (1 male, 10 female) with uncontrolled diffuse proliferative lupus nephritis with severe clinical SLE disease activity. RESULTS: In addition to amelioration of the proteinuric state, the clinical SLE disease activities, estimated by serological markers and the SLE disease activity index (SLEDAI), were significantly improved in all patients within 1 month. The required amounts of corticosteroid were decreased in these patients. These favorable effects continued for 2 y without serious adverse effects. Kidney function was not changed in the patients with satisfactory kidney function prior to CyA therapy (serum creatinine < 1.1 mg/dl, and eGFR > 45 ml/ min/1.73 m2). CONCLUSION: The current study results suggest that low-dose CyA treatment could ameliorate the severe clinical SLE disease activity as well as improve proteinuria in Japanese patients with diffuse proliferative lupus nephritis. This treatment would be safe and useful for SLE patients with satisfactory kidney function.

[Thoracoscopic surgery for intractable pneumothorax under epidural and local aesthesia].

Thoracoscopic surgery under epidural and local anesthesia for intractable pneumothorax were performed in 26 patients. A total of 29 thoracoscopic operation were performed in 26 patients. Twenty-three patients undervent only a single thoracoscopic operation, and 3 patients underwent twice thoracoscopic operations. We could control the air leak of intractable pneumothorax with the covering of polyglycolic acid sheets using aerosolized fibrin glue in 25 patients. In all patients postoperative course was uneventful and there was no operative death.

Transfection of human HGF plasmid DNA improves limb salvage in Buerger's disease patients with critical limb ischemia.

AIM: Hepatocyte growth factor is a potent angiogenic agent. This study investigated the efficacy and safety of intramuscular injection of naked plasmid DNA encoding the human hepatocyte growth factor gene in Japanese patients with Buerger's disease and critical limb ischemia. METHODS: An open-label clinical study was performed at eight hospitals in Japan from May 2004 to April 2008. Ten patients were enrolled. They had Buerger's disease with ischemic ulcers, were not candidates for revascularization, and were unresponsive to conventional drug therapy. Treatment consisted of 8 injections (total dose: 4 mg) of hepatocyte growth factor plasmid, which were administered into the calf muscles and/or distal thigh muscles of the ischemic limbs under ultrasound guidance. Administration was done twice at an interval of 4 weeks. If there was no improvement after 2 doses, a 3rd dose could be administered. The response to treatment was evaluated from the reduction of ischemic ulcer size. RESULTS: The size of ischemic ulcers showed a decrease in 6/9 (66.7%) patients and the ulcers healed completely in 5/9 (55.6%) patients after gene therapy. Major amputation was not required. There were no deaths and no major safety concerns. CONCLUSION: Hepatocyte growth factor gene therapy is safe and effective for critical limb ischemia in patients with Buerger's disease.

Expression and localization of vascular endothelial growth factor in normal abdominal aorta and abdominal aortic aneurysm.

AIM: The genesis of abdominal aortic aneurysms is associated with remodeling of the vascular wall by angiogenesis as well as proteolysis. Vascular endothelial growth factor (VEGF) is known to be a regulator of angiogenesis and to simultaneously stimulate elastolytic proteinases. We analyzed the expression and localization of VEGF in human abdominal aortic aneurysms compared to normal human aorta METHODS: Eighteen infrarenal aortic aneurysm samples were collected at the time of abdominal aortic aneurysm surgery, while nine normal aortic samples were obtained from autopsy specimens. Immunohistochemical staining was performed to detect VEGF. Immunoenzyme or immunofluorescent double staining was also used to identify those cells presenting VEGF. RESULTS: VEGF was expressed in 18 (100%) of the 18 abdominal aortic aneurysm samples, while 0 (0%) in the 9 normal abdominal aorta samples. Of the 18 samples of aneurysms, all 18 displayed positive VEGF immunostaining in macrophages, 12 in smooth muscle cells (SMCs), and 9 in endothelial cells (ECs). CONCLUSION: Our study clearly demonstrated the expression of VEGF in ECs, and SMCs, and macrophages of abdominal aortic aneurysms as well as its absence in those cells of normal abdominal aorta, suggesting that VEGF may play an important role in aneurysm formation via its direct and/or indirect actions.

Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia.

Hepatocyte growth factor (HGF) is a potent angiogenic factor. The efficacy and safety of intramuscular injection of a naked plasmid encoding human HGF gene (beperminogene perplasmid, Collategene) was investigated in patients with critical limb ischemia (CLI) in a multicenter, randomized, double-blind, placebo-controlled trial. The randomization ratio for plasmid to placebo was 2:1. Injection sites were selected in each patient limb based on angiographic findings. Placebo or plasmid was injected on days 0 and 28. Evaluation of efficacy was carried out after 12 weeks. The primary end point was the improvement of rest pain in patients without ulcers (Rutherford 4) or the reduction of ulcer size in patients with ulcer(s) (Rutherford 5). Secondary end points were ankle-brachial pressure index, amputation, and quality of life (QOL). Forty-four patients were treated, and we performed interim analysis of efficacy in 40 patients. The overall improvement rate of the primary end point was 70.4% (19/27) in HGF group and 30.8% (4/13) in placebo group, showing a significant difference (P=0.014). In Rutherford 5 patients, HGF achieved a significantly higher improvement rate (100% [11/11]) than placebo (40% [2/5]; P=0.018). HGF plasmid also improved QOL. There were no major safety problems. HGF gene therapy is safe and effective for CLI.

Three-year cardiovascular events and disease progress in patients with peripheral arterial disease: results from the Japan Medication Therapy for Peripheral Arterial Disease (J-METHOD).

AIM: To investigate the current status of peripheral arterial disease (PAD) drug treatment in Japan, and the effects of drug treatment, risk factors, and complications on disease progress and onset of cardiovascular events in PAD patients. METHODS: In this prospective observational cohort study, 557 PAD patients were followed up for 3 years, and the current status of PAD treatment, risk factors, and cardiovascular events were monitored. RESULTS: Three drugs, i.e., beraprost sodium, cilostazol, and aspirin, were most frequently used. The patients who had undergone vascular reconstruction of the lower limbs before enrollment showed significant improvement in ABI. Among the patients who had not undergone vascular reconstruction before enrollment, there was a significant improvement in ABI after treatment with beraprost. During the observation period, cardiovascular deaths occurred in 35 patients (6.3%), heart diseases in 63 (11.3%), brain diseases in 39 (7.0%), and events in the lower limbs in 94 (16.9%). The factors affecting the increase of the cardiovascular events were explored by multivariate analysis (Cox regression analysis). As a result, age (75 years or older), ischemic heart disease and increase in severity on the Fontaine classification were identified as significant factors for cardiovascular deaths, whereas kidney disorders and increase in severity on the Fontaine classification were identified for heart diseases, the number of oral drugs for treating PAD was identified for brain diseases, and age (younger than 75 years), dialysis, ABI (less than 0.7) and aspirin were identified for the events in the lower limbs. CONCLUSION: As a result of the three-year follow-up on the Japanese PAD cohort, the current status of PAD treatment, risk factors, and cardiovascular events could be identified.

Prostaglandin receptors EP2 and IP are detectable in atherosclerotic arteries and plaques.

AIM: Prostaglandin (PG) receptor agonists are frequently used for the pharmacological treatment of arteriosclerosis obliterans (ASO). In particular, the PG receptors EP2 and IP stimulate vasodilation and inhibit platelet aggregation, biological processes thought to be protective against ASO and important for physiological homeostasis. However it is uncertain whether EP2 and IP exist in diseased arteries, or what their distribution within the artery might be. In this study, we analyzed the distribution of these PG receptors in patients with severe ASO to determine the potential application of stimulation of these receptors as targets for pharmacological treatment. METHODS: We collected segments of atherosclerotic femoral arteries during femoropopliteal bypass surgery and determined the expression levels of EP2 and IP receptors by western blotting. Immunofluorescence was used to observe receptor localization. RESULTS: Findings of western blotting showed an increased Cox-2 expression in patients with ASO. The EP2 as well as IP receptors were each induced approximately 3-fold in comparison to normal samples. The expression of these receptors was increased in the intimal layer as well as the medial layer; their expression was also detectable within the atherosclerotic plaque. CONCLUSION: We observed induction of the PG receptors EP2 and IP in atherosclerotic femoral arteries in the arterial intima, medial layer, as well as the associated atherosclerotic plaque. These results suggest that receptor-selective PG agonists specifically target atherosclerotic arteries and therefore, may find potential application in the pharmacological management of patients with ASO.

The education system to master endovascular aortic repair in Japan - the Japanese Committee for Stentgraft Management.

OBJECTIVE: The Japanese Committee for Stentgraft Management (JACSM) was established with the aim of ensuring the safe and proper reach of commercial stent grafts following their regulatory approval. This study examines the validity of the practice standards developed by JACSM. METHODS: JACSM comprises 10 associations related to endovascular treatment. Based on the practice standards developed by JACSM, the status of practising institutions, practising surgeons, supervising surgeons and the results of follow-up surveys were analysed. RESULTS: In the 2.5 years following the establishment of JACSM, 298 institutions have fulfilled the practice standards. The number of practising surgeons reached 493, and the number of supervising surgeons reached 177. There were 3089 registered cases up to June 2009. The present study analysed 1570 cases registered in the 2 years from July 2006 to June 2008. The hospital mortality rate was low (0.4%) in the follow-up surveys. CONCLUSIONS: Early results following the introduction of stent grafts were generally good. The procedure spread safely without the learning curve seen in the initial stages following introduction of new medical materials, indicating that the practice standards were appropriate.

Cell sheet injection as a technique of osteogenic supply.

We previously reported a new cell transplantation method utilizing injections of mesenchymal stem cell (MSC) sheets that have osteogenic potential. After subcutaneous transplantation without any scaffold, the sheet demonstrated in vivo bone formation. In the present study, we transplanted such sheets by injection into implanted ceramics and assessed whether the injectable MSC sheets could stimulate osteogenic integration of the ceramics. To fabricate MSC sheets, bone marrow cells cultured from femur shafts of 7-week-old rats were subcultured in regular 10-cm dishes containing dexamethasone and ascorbic acid phosphate until confluent. Each cell sheet was then lifted using a scraper. Porous ß-tricalcium phosphate (ß-TCP) disks (5 mm Φ×2 mm) were transplanted subcutaneously into the backs of the rats. Immediately following implantation, the sheets were injected around the disks via a 16G needle (immediate group). Cell sheets were also injected into the remaining implanted disks 1 week after disk implantation (1-wk group). Four weeks following sheet injection, radiography and histology revealed calcification and bone tissue around the harvested disks of the immediate group (eight disks exhibited bone formation/eight implanted disks), whereas calcification and bone tissue were observed in 50% of the samples in the 1-wk group (four disks exhibited bone formation/eight implanted disks). The present study indicates that injected cell sheets can supply osteogenic potential to implanted ceramics. Owing to the usage of a needle for cell sheet transplantation, such an injection method can be applied as a minimally invasive technique of osteogenic supply to implanted ceramics.

Clinical comparison of two different types of bifurcated graft for postoperative baPWV and ABI.

AIM: A newly-designed bifurcated graft with the distal end larger than the conventional type has been developed. The purpose of this study was to evaluate the early results of graft replacement using this new graft, and to compare whether the new graft is more advantageous than the conventional graft in terms of peripheral blood flow and arterial stiffness. METHODS: Records of 36 patients who underwent bifurcated graft replacement for infrarenal abdominal aortic aneurysm (AAA), from May 2003 to September 2006 were reviewed after excluding peripheral arterial disease (ABI > 0.9). Subjects were divided into two groups: group C (N.=20), with implantation of the conventional type and group N (N.=16), with implantation of the new type. We investigated changes in brachial-ankle pulse wave velocity (baPWV) and ankle-brachial pressure index (ABI), measurements being performed preoperatively and postoperatively. RESULTS: baPWV in the postoperative group as a whole was significantly higher than in the preoperative group (P<0.05), while ABI in the postoperative group was lower than in the preoperative group (P<0.05). In group C, baPWV increased (P<0.05) and ABI decreased (P<0.05) after bifurcated graft replacement, whereas in group N, there were no significant differences in changes of baPWV and ABI. CONCLUSIONS: This study shows that the new graft reduces the development of arterial stiffness postoperatively compared with the conventional type. These results may predict the new type graft decrease in the risk of morbidity and mortality caused by atherosclerotic disease.

[Adequate size of elephant trunk in the procedure of total arch replacement for acute aortic dissection].

Total aortic arch replacement using the 'elephant trunk (ET)' procedure has commonly been applied to acute aortic dissection, but enlargement of a residual false lumen of the descending thoracic aorta sometimes occurs. We performed endovascular stent-grafting to close the entry as the second operation and obtained successful outcomes. From April 1997 to January 2004, we performed the modified ET procedure for acute aortic dissection in 29 patients and evaluated postoperative changes of the false lumen. In many cases of the residual false lumen, kinks and wrinkles were observed at the site of the ET grafts in the descending aorta. An adequate length of ET would be about 8 cm long to prevent kinking, and a diameter about 20 mm to prevent wrinkles.