Relationship between donepezil and fracture risk in patients with dementia with Lewy bodies.

AIM: Patients with dementia with Lewy bodies (DLB) are at a high risk for falls and fractures. Although cholinesterase inhibitors reportedly are effective in suppressing the progression of cognitive symptoms in DLB patients, their effects on fracture risk remain unclarified. This study aimed to evaluate the association between donepezil use and hip fracture risk in older patients with DLB. METHODS: Using the Japanese insurance claim database, we collected the data of patients aged ≥65 years with DLB from April 2012 to March 2019. After propensity score matching, we compared the fracture rate over 3 years between DLB patients receiving donepezil and those not receiving antidementia drugs. RESULTS: Altogether, 24 022 239 individuals aged ≥65 years were newly registered from April 2012 to March 2016 and had verifiable information from 6 months before to 3 years after the registration. We identified 6634 pure-DLB patients and analyzed the data of 1182 propensity score-matched pairs. The characteristics, including age, sex, fracture history, osteoporosis, and bone mineral density test rate, of the two groups were well balanced by propensity score matching. The incidence rate of hip fracture was significantly lower in DLB patients receiving donepezil than in those not receiving antidementia drugs (0.60 vs. 1.44/100 person-years, P < 0.001), whereas that of vertebral fractures was the same. CONCLUSIONS: Donepezil administration in Japanese people aged ≥65 years with DLB was significantly associated with a decreased risk of hip fracture. Donepezil may provide new benefits to DLB patients. Geriatr Gerontol Int 2024; ••: ••-••.

Early-onset dementia and risk of hip fracture and major osteoporotic fractures.

INTRODUCTION: There is limited knowledge about early-onset dementia (EOD) on fracture risk. METHODS: Individuals ages 50 to 64 were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (2012 to 2019). The association between EOD and fractures and the association between cholinesterase inhibitors for EOD and fractures were evaluated using logistic regression analyses. RESULTS: We identified 13,614 EOD patients and 9,144,560 cognitively healthy individuals. The analysis revealed that EOD was associated with an increased risk of hip fractures (adjusted odds ratio, 95% confidence interval: 8.79, 7.37-10.48), vertebral fractures (1.73, 1.48-2.01), and major osteoporotic fractures (2.05, 1.83-2.30) over 3 years. The use of cholinesterase inhibitors was significantly associated with a reduction in hip fractures among EOD patients (0.28, 0.11-0.69). DISCUSSION: EOD patients have a higher risk of osteoporotic fractures than cognitively healthy individuals. The use of cholinesterase inhibitors may reduce the risk of hip fracture among EOD patients. HIGHLIGHTS: It is unknown whether early-onset dementia (EOD) increases the risk of fractures. We identified 13,614 individuals with EOD using a nationwide administrative database. Patients with EOD have a higher risk of hip, vertebral, and major osteoporotic fractures. The use of cholinesterase inhibitors may reduce hip fracture among patients with EOD.

Association between pharmacotherapy and secondary vertebral fracture managed with a brace in a real-world setting: A nationwide database study in Japan.

AIM: This retrospective cohort study assessed the association between the incidence of secondary vertebral fracture managed with a brace (SVF) and pharmacotherapy. METHODS: The association between the incidence of SVF and the presence, type, and medication possession ratio (MPR) of pharmacotherapy was investigated using medical insurance data acquired from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. RESULTS: The data of female patients (n = 637 303) were analyzed. The 2-year incidence of SVF was 73.5 per 10 000 patients (n = 4687). Approximately 0.73% of patients without medications and 0.74% with medications had SVF. Patients taking bisphosphonates (0.87), denosumab (0.77), and selective estrogen receptor modulators (0.88) had significantly lower standardized incidence ratios (SIRs) than patients not taking medications after the occurrence of primary fracture; meanwhile, patients taking parathyroid hormone medications had considerably higher SIRs than those not taking medications. The non-SVF group (59.1%) had a significantly higher mean MPR than the SVF group (55.5%). Patients taking denosumab in the non-SVF group (68.2%) had the highest mean MPR. The proportion of patients taking denosumab with an MPR of ≥80% in the non-SVF group was significantly higher than that in the SVF group. CONCLUSION: Patients taking medications were at a lower risk of developing SVF than those not taking medications. Although this study did not compare the medications' SVF prevention effects, patients taking denosumab had a 0.77 SIR of SVF in Japan. The effect of pharmacotherapy on SVF prevention might be affected by the MPR of each medication. Geriatr Gerontol Int 2024; 24: 390-397.

Average daily glucocorticoid dose, number of prescription days, and cumulative dose in the initial 90 days of glucocorticoid therapy are associated with subsequent hip and clinical vertebral fracture risk: a retrospective cohort study using a nationwide health insurance claims database in Japan.

PURPOSE: Fracture risk assessment is recommended at three months after glucocorticoid (GC) therapy initiation. This study aimed to assess whether GC exposure in the initial 90 days of GC therapy is associated with subsequent hip and clinical vertebral fracture risk using the nationwide health insurance claims database of Japan (NDBJ). METHODS: Patients aged ≥ 50 years who were prescribed GC (≥ 70 mg prednisolone or equivalent; PSL) in the initial 90 days of GC therapy and were followed for hip and clinical vertebral fracture incidences for the subsequent 1080 days were selected from NDBJ. Associations of GC exposure with hip or clinical vertebral fracture risk were evaluated by Cox regression analysis adjusted for potential confounders. RESULTS: We selected 316,396 women and 299,871 men for the GC-exposed group and 43,164 women and 33,702 men for the reference group. Higher GC doses and longer prescription days in the initial 90 days of GC therapy were significantly and dose-dependently associated with increased fracture risk relative to the reference group. Patients receiving GC ≥ 5 mg PSL/day had a significantly increased fracture risk in the stratum of 30-59 days of GC prescription. In addition, female patients who received GC (≥ 1 and < 2.5 mg PSL/day) for 90 days in the initial 90 days of GC therapy had a significantly increased fracture risk. CONCLUSIONS: GC exposure in the initial 90 days of GC therapy was dose-dependently associated with hip and clinical vertebral fracture risk. GC may increase fracture risk with lower doses for shorter durations than previously reported. Fracture risk assessment three months after glucocorticoid (GC) therapy initiation is recommended. We found that GC exposure in the initial 90 days of GC therapy at lower daily doses for shorter durations than previously reported were significantly and dose-dependently associated with fracture risk using a nationwide health insurance claims database.

Prescription of vitamin D was associated with a lower incidence of hip fractures.

Patients with osteoporosis are prone to fragility fractures. Evidence of the effects of active forms of vitamin D on hip fracture prevention is insufficient. We examined the association between vitamin D prescription and incidence of new fractures using the data of osteoporotic patients from the nationwide health insurance claims database of Japan. The follow-up period was 3 years after entry. The untreated patients were never prescribed vitamin D during follow-up (n = 422,454), and the treated patients had a vitamin D medication possession ratio of ≥ 0.5 at all time points (n = 169,774). Propensity score matching was implemented on these groups, yielding 105,041 pairs, and subsequently, the control and treatment groups were established and analyzed. The incidence of new fractures was significantly lower in the treatment group compared with the control group (6.25% vs. 5.69%, hazard ratio 0.936 [95% confidence interval 0.904-0.970], p < 0.001*). By site, hip fractures significantly decreased (0.89% vs. 0.42%, p < 0.001), but not vertebral and radial fractures. Subgroup analysis by vitamin D type showed a significantly lower incidence of total fractures only in alfacalcidol (hazard ratio 0.676 [95% confidence interval 0.628-0.728], p < 0.001*). The results suggest that vitamin D prescription was associated with a reduced incidence of hip fractures.

Relationship between antidementia medication and fracture prevention in patients with Alzheimer's dementia using a nationwide health insurance claims database.

This retrospective study aimed to evaluate the association between antidementia medication use and incidence of new vertebral, hip, and radial fractures in patients with Alzheimer's dementia (AD). We used the nationwide health insurance claims database of Japan from 2012 to 2019 and identified 12,167,938 patients aged ≥ 65 years who were newly registered from April 2012 to March 2016 and had verifiable data receipt from half-year before to 3 years after the registration. Among these patients, 304,658 were diagnosed with AD and we showed the prescription status of antidementia and osteoporosis medication among them. Propensity score matching was conducted for AD group with and without antidementia medication use, and 122,399 matched pairs were yielded. The incidence of hip fractures (4.0% vs. 1.9%, p < 0.001) and all clinical fractures (10.5% vs. 9.0%, p < 0.001) significantly decreased and that of radial fractures increased (0.6% vs. 1.0%, p < 0.001) in AD patients with antidementia medication use compared with AD patients without antidementia medication use. No significant difference was found in vertebral fractures (6.6% vs. 6.5%, p = 0.51). Overall, these results suggest a positive relationship between antidementia medication use and fracture prevention in patients with AD.

Association between pharmacotherapy and secondary hip fracture in a real-world setting: a nationwide database study.

INTRODUCTION: This study aimed to assess the association between pharmacotherapy and secondary hip fracture incidence. MATERIALS AND METHODS: The correlation between secondary hip fracture incidence and the presence, type, and medication possession ratio (MPR) of pharmacotherapy was investigated using medical insurance data acquired from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. RESULTS: Data collected from female patients (n = 1,435,347) were analyzed. The 2-year secondary hip fracture incidence was 3.48% (n = 49,921). Secondary hip fracture was significantly more common in patients without medications (3.80%) than in those with medications (3.00%). Patients receiving selective estrogen receptor modulators (SERMs) had the lowest average age. The crude incidence of secondary hip fracture was the lowest in patients receiving SERMs (n = 2088 [2.52%]), followed by those taking bisphosphonates (n = 11,355 [2.88%]), denosumab (n = 1118 [2.90%]), no medications (n = 32,747 [3.80%]), and parathyroid hormone (PTH: n = 2163 [4.55%]), whereas the age-adjusted incidence was the lowest in patients administered denosumab (2.27%), followed by those taking bisphosphonates (2.47%), SERMs (2.55%), PTH (3.67%), and no medications (3.80%). The mean MPR was the highest in patients taking denosumab (64.9%), followed by those receiving bisphosphonates (58.7%), SERMs (58.2%), and PTH (40.6%) in the no hip fracture group. CONCLUSION: Secondary hip fractures were less likely to occur with medication versus no medication. Differences in the crude incidence of secondary hip fracture based on medications usage might be attributed to background characteristics.

Hip and vertebral fracture risk after initiating antidiabetic drugs in Japanese elderly: a nationwide study.

INTRODUCTION: We aimed to clarify the risks of initiating antidiabetic drugs for fractures using a nationwide health insurance claims database (NDBJ). MATERIALS AND METHODS: Patients aged ≥ 65 years initiating antidiabetic drugs at the outpatient department were enrolled after a 180-day period without prescribed antidiabetic drugs and followed with during 2012-2018 using NDBJ. The adjusted hazard risks (HRs) of each antidiabetic drug (thiazolidine, alpha-glucosidase inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, glinide, and insulin) for fractures compared with biguanide were obtained adjusting for age, gender, polypharmacy, dementia, and the other antidiabetic drugs. RESULTS: The DPP-4 inhibitor was the most often prescribed antidiabetic drug followed by biguanide with prescribed proportions of 71.7% and 12.9%. A total of 4,304 hip fractures and 9,388 vertebral fractures were identified among the 966,700 outpatient participants. Compared with biguanide, insulin, alpha-glucosidase inhibitor, and DPP-4 inhibitor were related to increased hip fracture risks. Vertebral fracture risk was higher in outpatients prescribed with insulin, thiazolidine, and DPP-4 inhibitor compared with biguanide. Patients prescribed insulin for hip and vertebral fractures' adjusted HRs were 2.17 (95% CI 1.77-2.66) and 1.45 (95% CI 1.24-1.70), respectively. Those prescribed DPP-4 inhibitor for hip and vertebral fractures' adjusted HRs were 1.27 (95% CI 1.15-1.40) and 1.20 (95% CI 1.12-1.28), respectively. CONCLUSIONS: Initiating insulin increased the risk of not only hip fractures but also vertebral fractures. Patients initiating antidiabetic drugs had increased risks of hip and vertebral fractures compared with those initiating biguanide independently for age, gender, polypharmacy, and dementia in the Japanese elderly.

Real-world effectiveness of anti-osteoporosis medications for the prevention of incident hip and clinical vertebral fractures in patients on long-term glucocorticoid therapy: A nationwide health insurance claims database study in Japan.

PURPOSE: Early initiation of anti-osteoporosis medications (AOMs) is recommended for patients on long-term glucocorticoid (GC) therapy. This study aimed to clarify the real-world effectiveness of AOMs against incident hip and vertebral fractures in patients undergoing GC therapy using the nationwide health insurance claims database of Japan (NDBJ). METHODS: Patients aged ≥50 years who were prescribed GC (≥5 mg/day prednisolone or equivalent) for ≥90 days and who were followed up regarding AOM prescription and hip and clinical vertebral fracture incidences for the subsequent 1080 days between 2012 and 2018 were selected from NDBJ. Associations of AOMs prescribed within 90 days since GC therapy initiation with hip or vertebral fracture risk were evaluated by Cox proportional hazards regression using propensity score inverse probability weighting (IPW) for receiving any AOM or individual AOMs. RESULTS: In total, 96,475 women and 98,385 men were included in the analysis; 38.0 % of women and 27.6 % of men received AOMs. Patients who received any AOM and those who received bisphosphonates or denosumab had a significantly lower risk of hip and clinical vertebral fractures than those who received no AOM in both sexes after propensity score IPW. Teriparatide was associated with an increased risk of both fractures in women and an increased risk of clinical vertebral fractures in men. Selection biases such as confounding by indication might have caused an underestimation of AOMs' protective effects. CONCLUSIONS: Bisphosphonates and denosumab were associated with a lower fracture incidence in patients on long-term GC therapy in real-world settings.

Association of pharmacotherapy with the second hip fracture incidence in women: A retrospective analysis of the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

AIM: Second hip fractures worsen the quality of life and are associated with increased mortality. We clarified the association between the pharmacotherapy and second hip fracture prevention. METHODS: The relationship between the incidence of second hip fracture and the presence, type and medication possession ratio (MPR) of pharmacotherapy was investigated using medical insurance data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan during April 2012 to March 2019. RESULTS: Data of 776 040 female patients were analyzed. The 2-year rate of second hip fractures was 3.31% (n = 25 684). Bisphosphonates (n = 148 138, 19.1%) were the most commonly used medications after primary hip fracture. Patients receiving selective estrogen receptor modulators (SERMs) had the lowest age, followed by those receiving bisphosphonates, denosumab and parathyroid hormone (PTH). The second hip fracture crude incidence was lowest in patients administered SERMs (n = 859, 2.44%), followed by those administered bisphosphonates (n = 4451, 3.00%), denosumab (n = 484, 3.19%), no medication (n = 19 017, 3.39%) and PTH (n = 873, 5.35%); however, the age-adjusted incidence was the lowest in patients administered denosumab (2.22%), followed by those administered bisphosphonates (2.35%), SERMs (2.39%), no medications (3.39%) and PTH (3.67%). The MPR was highest in patients administered denosumab (60.0%). Among patients without a second hip fracture, the rate of patients with MPR ≥80% was highest among those administered SERMs (40.8%), followed by those administered bisphosphonates (38.0%), denosumab (35.4%) and PTH (12.2%). CONCLUSION: Differences in patient background characteristics and the rate of patients with MPR ≥80% might underlie the observed differences in the crude incidence of second hip fracture among the medication groups. Geriatr Gerontol Int 2022; 22: 930-937.

Delayed initiation of anti-osteoporosis medications increases subsequent hip and vertebral fractures in patients on long-term glucocorticoid therapy: A nationwide health insurance claims database study in Japan.

PURPOSE: Early initiation of anti-osteoporosis medications (AOMs) is recommended for patients on long-term glucocorticoid (GC) therapy. This study aimed to examine whether physicians prescribe AOMs as soon as GC therapy is initiated, and whether a delay in AOM initiation affects hip and vertebral fracture incidence, using the nationwide health insurance claims database of Japan (NDBJ). METHODS: Patients aged ≥50 years who were prescribed GC (≥5 mg/day prednisolone or equivalent) for ≥90 days and who were followed for AOM use and hip and vertebral fracture events for the subsequent 1080 days in 2012-2018 were selected from NDBJ. Delay in AOM initiation was defined as the number of days without AOMs following GC therapy initiation. Associations between delay in AOM initiation and hip and vertebral fracture risk were evaluated by Cox proportional hazards regression. RESULTS: In total, 92,143 women and 94,772 men were included in the analysis, of which only 39.3% of women and 28.5% of men received AOMs within 90 days from GC therapy initiation. Approximately, 15% of hip fractures and 30% of vertebral fractures occurred before AOM initiation in patients with delayed AOM initiation. HRs of both fractures were significantly greater in patients with a longer delay in AOM initiation (p value for trend<0.001). After excluding patients who had fractures before AOM initiation, the magnitude of HRs significantly decreased, and HR trends for hip fracture became insignificant. CONCLUSIONS: Delayed initiation of AOMs may result in increased fracture events, which may be reduced by early initiation of AOMs.

Insufficient persistence to pharmacotherapy in Japanese patients with osteoporosis: an analysis of the National Database of Health Insurance Claims and Specific Health Checkups in Japan.

In Japan, persistence and the 2-year MPR were inadequate in increasing fracture control efficacy despite a high adherence rate during the treatment period. Both factors were higher in females and those with polypharmacy but worsened with increasing age. PURPOSE: Only a few large-scale studies have examined the care gap between the patients who need osteoporosis treatment and those who receive them in Japan. The aim of this study was to investigate the persistence and adherence to osteoporosis pharmacotherapy in Japan. METHODS: Continuation (persistence) rates and adherence to osteoporosis pharmacotherapy were investigated using medical insurance data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan, between April 2012 and March 2019. RESULTS: The study included 528,806 male and 3,064,410 female patients. Persistence proportions were 56.6% in the first year and 46.3% in the second year. The medication possession ratio (MPR) from start to discontinuation of treatment (MPRdiscon) was 94.5%, and 92.7% of patients had an MPRdiscon ≥ 80%. The 2-year MPR (MPR730) was 61.9%, and 49.6% of patients had an MPR730 ≥ 80%. Both the persistence proportion and MPR730 were higher in females than in males, whereas MPRdiscon was higher in males. The persistence proportion and MPR730 were highest in the 70-79 years age group, whereas MPRdiscon improved with increasing age. The MPRdiscon and MPR730 were higher in the mixed-fracture and vertebral-fracture groups, respectively. The persistence proportion, MPRdiscon, and MPR730 were higher in patients with polypharmacy than in those without. CONCLUSION: In Japan, persistence and the 2-year MPR were inadequate in increasing fracture control efficacy despite a high adherence rate during the treatment period. To bridge the care gap following osteoporosis pharmacotherapy, improvements are required for males, the elderly, and those without polypharmacy.

Insufficient increase in bone mineral density testing rates and pharmacotherapy after hip and vertebral fracture: analysis of the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

Test and treatment rates for osteoporosis in Japan aimed at preventing secondary fragility fractures were insufficient. Those who suffered hip fractures had approximately half the rates of those who suffered vertebral fractures, with such rates being lower among those over 80 years old and males. PURPOSE: The present study aimed to examine the care gap for secondary fracture prevention in Japan given the few large-scale studies regarding the matter. METHODS: Changes in bone mineral density testing (test rate) and osteoporosis pharmacotherapy administration (treatment rate) rates before and after hip and vertebral fracture registration were examined using medical insurance data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan issued from April 2012 to March 2019. RESULTS: The hip fracture group comprised 677,480 women and 264,003 men, the vertebral fracture group comprised 703,247 women and 251,542 men, and the mixed fracture group comprised 3614 women and 1055 men. Test rates were 14.1%, 25.3%, and 17.6% prior to fracture registration (pre-registration) and 22.3%, 43.6%, and 28.1% after fracture registration (post-registration) in the hip, vertebral, and mixed fracture groups, respectively. Moreover, pre-registration treatment rates were 21.2%, 33.5%, and 30.7%, while post-registration rates were 31.6%, 61.7%, and 46.6% in the hip, vertebral, and mixed fracture groups, respectively. All fracture groups showed a tendency for decreased post-registration test and treatment rates among those aged over 80 years old, with men having lower rates. Moreover, 184,180 (19.4% of whom received new treatment) and 707,263 (23.8% of whom received new treatment) patients with and without polypharmacy underwent treatment after registration, respectively. CONCLUSION: To bridge the care gap following fractures, medical professionals should change their perception regarding osteoporosis treatment in patients with hip fractures, elderly individuals undergoing polypharmacy, and males.

Incidence of fractures among patients receiving medications for type 2 diabetes or chronic obstructive pulmonary disease and glucocorticoid users according to the National Claims Database in Japan.

According to information from the National Health Insurance and Claims database, the risk for hip, radius, and clinical vertebral fractures was higher among patients receiving medication for type 2 diabetes, COPD, or glucocorticoids than among the whole Japanese population after middle age. PURPOSE: The aim of this study was to determine the incidence of fractures among patients receiving medications for type 2 diabetes or chronic obstructive pulmonary disease (COPD) and using glucocorticoids (GC) according to the National Database of Health Insurance Claims (NDB) in Japan. METHODS: We obtained data on the number of fractures and patients receiving medications for type 2 diabetes, COPD, or GC from the NDB. The claims data included sex, age group, injury/illness name, hospitalization, outpatient, surgery/medical treatment, and drugs used between January and December 2017. RESULTS: The risk of hip fracture was higher among patients receiving medications for diabetes or COPD and GC users than in the Japanese population, with standardized incidence ratios (SIRs) of 1.71 (95% confidence interval [CI]1.6-1.75), 1.35 (95% CI 1.28-1.42), and 1.62 (95% CI 1.53-1.71) in men and 1.81 (95% CI 1.79-1.84), 1.67 (95% CI 1.54-1.80), and 1.71 (95% CI 1.66-1.76) in women, respectively. There was also a significantly higher incidence of radial fractures in women and clinical vertebral fractures in both men and women. A greater risk of hip fracture was found among diabetic patients starting in their late 40 s. CONCLUSIONS: Real-world data revealed that the incidence of hip, radius, and clinical vertebral fractures was significantly higher among patients receiving medications for diabetes or COPD and GC users than in the Japanese population after middle age.

Clinical outcome and complications of temporary inferior vena cava filter placement.

OBJECTIVE: We evaluated the current clinical experience of temporary inferior vena cava (IVC) filter placement and its related complications. METHODS: From January 2000 to December 2005, we enrolled 33 patients (8 men and 25 women) who underwent percutaneous insertion of a temporary IVC filter in the Department of Vascular Surgery of Tokyo University Hospital. Deep vein thrombosis (DVT) was proven in 78.8% of the patients. The indications for filter insertion were contraindication to anticoagulation therapy (9.1%), thrombolytic therapy (12.1%), perioperative prophylactic implantation (84.8%), pregnancy with DVT (3.0%), and prophylactic implantation in the absence of DVT (15.2%). A Neuhaus Protect was used in 13 patients, and an Antheor was used in 20 patients. RESULTS: The mean +/- SD duration of filter placement was 10.6 +/- 7.0 days. There was no case of pulmonary embolism during filter protection and retraction. Filter thrombosis (capture of thrombus) was observed in four patients (12.1%), who then received additional thrombolytic therapy. Thrombi were dissolved by thrombolysis in three, one of whom had replacement with a permanent filter. The thrombus was not dissolved in one patient and was removed under venotomy at the insertion site. Major filter-related complications occurred in nine patients (27.3%), including filter dislocation in four patients (12.1%), catheter fracture in three (9.1%), and catheter-related infection in one (3.0%). In a patient with giant ovarian cancer, the IVC was nearly occluded with massive thrombus around the filter 2 days after operation, and the vena cava was then ligated under open laparotomy. No patients died during filter protection and retraction. CONCLUSIONS: Temporary IVC filters were effective for the prevention of fatal pulmonary embolism. However, our experience of a high incidence of complications related to temporary filters suggests that this device has limited indications and supports the need for innovative design of temporary filters.

Popliteal arterial aneurysm associated with Klippel-Trénaunay syndrome: case report and literature review.

A 35-year-old woman with Klippel-Trénaunay syndrome developed a popliteal artery aneurysm in the affected extremity. The aneurysm was successfully treated by aneurysmectomy and bypass grafting with autologous saphenous vein. In Klippel-Trénaunay syndrome, angiodysplasia in the venous system is common. However, reports of an arterial aneurysm in a patient with Klippel-Trénaunay syndrome are extremely rare.

Long-term outcome after surgical treatment of arterial lesions in Behçet disease.

OBJECTIVE: Surgical treatment of arterial lesions associated with Behçet disease (BD) is often complicated by graft occlusion and recurrence of aneurysms. The purpose of this study was to clarify the long-term outcome of surgical intervention for arterial involvement in BD. METHODS: Ten patients with BD (9 men, 1 woman) who underwent surgical treatment for arterial aneurysms between 1980 and 2004 were included in the study. The age of patients at the first operation ranged from 36 to 69 years (mean, 50.4 +/- 9.0 years). The mean period between the onset of BD and that of arterial manifestations was 8.0 +/- 5.0 years. We retrospectively reviewed their postoperative courses, including survival, graft occlusion, formation of anastomotic false aneurysms, and the development of aneurysms at different sites. The Kaplan-Meier method was used to calculate the chronologic incidence of complications after surgery. RESULTS: The mean follow-up period was 133 +/- 92 months, ranging from 5 to 285 months. One patient died of rupture of a dissecting aortic aneurysm after undergoing several surgical interventions for multiple aneurysms. There were five graft occlusions among 21 grafts. The cumulative primary graft patency rate in the infrainguinal region was 83.9% at 3 years. Five anastomotic false aneurysms formed among 49 anastomoses between grafts and host arteries. The overall cumulative incidence of formation of anastomotic pseudoaneurysm was 12.9% at 5 and 10 years. All of them formed within 18 months after surgery. Development of new aneurysms in different arteries was observed in two patients. CONCLUSIONS: Early occurrence of anastomotic false aneurysm is characteristic of BD. Further investigation is necessary to establish effective postoperative treatment.

In vivo electroporation enhances plasmid-based gene transfer of basic fibroblast growth factor for the treatment of ischemic limb.

BACKGROUND: Angiogenic therapy for ischemic tissues using angiogenic growth factors has been reported on an experimental and a clinical level. Electroporation enhances the efficiency of plasmid-based gene transfer in a variety of tissues. The purpose of this study was to evaluate the angiogenic effects of plasmid-based gene transfer using basic fibroblast growth factor (bFGF) in combination with electroporation. MATERIALS AND METHODS: The transfection efficiency of in vivo electroporation in rabbit skeletal muscles was evaluated using pCAccluc+ encoding luciferase. To evaluate the angiogenic effects of bFGF gene in ischemic limb, we constructed a plasmid, pCAcchbFGFcs23, containing human bFGF cDNA fused with the secretory signal sequence of interleukin (IL)-2. Then, 500 microg of pCAcchbFGFcs23 or pCAZ3 (control plasmid) was injected into the ischemic thigh muscles in a rabbit model of hind limb ischemia with in vivo electroporation (bFGF-E(+) group and LacZ-E(+) group). Other sets of animals were injected with pCAcchbFGFcs23 (bFGF-E(-) group) or pCAZ3 (LacZ-E(-) group) without electroporation. Then 28 days later, calf blood pressure ratio, angiographic score, in vivo blood flow, and capillary density in the ischemic limb were measured. RESULTS: Gene transfer efficiency increased markedly with the increase in voltage up to 100 V. Regarding angiogenic responses, calf blood pressure ratio, in vivo blood flow, and capillary density only in the bFGF-E(+) group were significantly higher than those in LacZ-E(-) group. Angiographic scores in the bFGF-E(+) and bFGF-E(-) groups were significantly higher than that in the LacZ-E(-) group. CONCLUSION: These data suggest that in vivo electroporation enhances bFGF gene transfer for the treatment of ischemic limb muscles.

Appropriate control of ex vivo gene therapy delivering basic fibroblast growth factor promotes successful and safe development of collateral vessels in rabbit model of hind limb ischemia.

PURPOSE: In our previous study, adenovirus-mediated ex vivo gene transfer of basic fibroblast growth factor promoted significant collateral vessel development in a rabbit model of hind limb ischemia. The present study examined how to control the efficacy and safety of this gene therapy, and also evaluated the feasibility of repeat application of this procedure. METHODS: Modified hFGF gene with the secretory signal sequence was adenovirally transferred to cultured autologous fibroblasts, and various numbers of the cells (2 x 10(5), 1 x 10(6), 5 x 10(6), or 2.5 x 10(7)) or vehicle was injected through the left internal iliac artery in rabbits in whom the left femoral artery had been excised 21 days previously. Twenty-eight days after cell administration, calf blood pressure ratio, angiographic score, blood flow in the internal iliac artery, and capillary density of muscle tissue were measured to analyze collateral vessel development and tissue perfusion in the ischemic limb. To assess delivery efficiency and viral contamination, the distribution of injected cells and the time course of blood anti-adenovirus antibody titer were examined in rabbits treated with various numbers of gene-transduced cells. In addition, animals received two injections, 21 days apart, of fibroblasts infected with adenovirus vector containing the luciferase gene, and luciferase expression was measured to evaluate whether the present therapy is repeatable. RESULTS: At 28 days after cell administration, significant collateral vessel development without detectable side effects was observed in rabbits who received 5 x 10(6) or 2.5 x 10(7) cells, compared with those who received vehicle, and no significant development was detected in animals with fewer than 5 x 10(6) cells (P <.01 for calf blood pressure ratio and capillary density, P <.05 for angiographic score and maximum blood flow). There was no difference in collateral augmentation between rabbits with 5 x 10(6) and 2.5 x 10(7) cells. However, in animals with 2.5 x 10(7) cells a large number of injected cells accumulated in the lungs, anti-adenovirus antibody titer increased significantly, and calf blood pressure in the left hind limb of two rabbits decreased immediately after injection. Luciferase analysis showed very low gene expression after repeated administration. CONCLUSION: These findings suggest that 5 x 10(6) is a suitable number of cells to induce appropriate collateral vessel development and minimize potential side effects of this procedure. Despite use of ex vivo gene transfer, repeat administration of the cells was not feasible. Clinical relevance Since the present study determined the appropriate conditions for effective and safe stimulation of collateral vessels, the clinical relevance of the ex vivo therapy might be carried forward. However, the findings raised another issue that should be resolved before clinical application; that is, the number of gene-transduced cells able to be injected was strictly limited. To estimate the therapeutic range of cell number in humans, additional experiments using large animals are desirable.