Criminal victimization of people with epilepsy: Sixteen criminal judgments in Japan between 1990 and 2019.

Criminal behavior by people with epilepsy (PWE) has often been discussed. However, there are limited studies on criminal victimization of PWE-in particular, how such victimizations occur. We identified criminal cases involving victims with epilepsy using databases containing criminal judgments and found 16 such cases between 1990 and 2019. Seven were homicide cases, including four filicide cases. In the four filicide cases, all the perpetrators had the intention of homicide-suicide; all the victims had intellectual disabilities or cerebral palsy; two of these victims had acted violently toward the family; and two mothers who perpetrated the crime against the victims had depression. It seemed that the comorbidities and problem behaviors of the victims were more strongly related to serious crimes by family caregivers than the epilepsy itself. To prevent victimization caused by family caregivers, reducing their stress levels is important. Defendants sometimes argued against objective evidence of a crime, claiming that epileptic seizure of PWE caused or was related to the death of victims. Legal and medical professionals involved in determining the manner of death need careful evaluation when sudden deaths of PWE occur.

Does cognitive behavioral therapy for anxiety disorders assist the discontinuation of benzodiazepines among patients with anxiety disorders? A systematic review and meta-analysis.

Long-term use of benzodiazepines (BZD) is not recommended for the treatment of anxiety disorders. Cognitive behavioral therapy (CBT) is an effective treatment option for discontinuation of BZD in patients with anxiety disorders. This systematic review and meta-analysis sought to clarify whether CBT is effective for discontinuing BZD anxiolytics in patients with anxiety disorders. This study was preregistered with PROSPERO (registration number: CRD42019125263). A literature search of major electronic databases was conducted in December 2018. Three randomized controlled trials were included in this review, and meta-analyses were performed. The proportion of discontinuing BZD anxiolytics was significantly higher in the CBT plus gradual tapering group than in the gradual tapering alone group, both in the short term (3 months after allocation; number needed to treat: 3.2, 95% confidence interval [CI]: 2.1 to 7.1; risk ratio: 1.96, 95%CI: 1.29 to 2.98, P = 0.002, three studies) and long term (6 to 12 months after allocation; number needed to treat: 2.8, 95%CI: 1.9 to 5.3; risk ratio: 2.16, 95%CI: 1.41 to 3.32, P = 0.0004, three studies). CBT may be effective for discontinuing BZD anxiolytics, both in the short term and in the long term after the allocation. Further studies with larger sample sizes are necessary to draw definitive conclusions regarding the efficacy and safety of CBT for discontinuing BZD anxiolytics in patients with anxiety disorders.

Annual Report of the Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2015: Proposal of urgent measures to reduce maternal deaths.

Perinatal care in Japan has progressed rapidly in recent decades, remarkably reducing maternal, perinatal and neonatal mortality rates. This is attributable not only to the sustained efforts and dedication of past obstetricians and midwives, but also to the collective results achieved by the Japan Society of Obstetrics and Gynecology and healthcare administration, including research on advanced medical care, education, medical care improvements and establishing perinatal care centers. Although the maternal mortality rate was in steady decline until 2007 (3.1/100 000 births), it repeatedly fluctuated thereafter, plateauing at 3.4 per 100 000 births in 2013 and 2.7 per 100 000 births in 2014. Thus, the Perinatology Committee has analyzed the current situation of maternal deaths and has proposed countermeasures to reduce such death. The items deliberated upon by related subcommittees in 2015 are presented herein. The addition of indications for 'fibrinogen concentrate', 'eptacog alfa' and approval of the PGE2 vaginal tablet for cervical ripening were discussed in the subcommittee for unapproved drug review. Thus, a request for approval for health insurance coverage was submitted to the 'Evaluation committee on unapproved or off-label drugs with high medical needs' of the Ministry of Health, Labour and Welfare. Maternal and late-maternal deaths from suicide during the 10 years from 2005 to 2014 in Tokyo's 23 wards were jointly examined with the Tokyo Medical Examiner's Office. The suicide rate in the 23 wards is very high, at 8.7 per 100 000 births. Thus, the subcommittee for the reduction of maternal death discussed countermeasures for the eradication of maternal death and maternal suicide and the revision of death certificates.

Experience with recombinant activated factor VII for severe post-partum hemorrhage in Japan, investigated by Perinatology Committee, Japan Society of Obstetrics and Gynecology.

AIM: To investigate the utility of recombinant activated Factor VII (rFVIIa) for severe post-partum hemorrhage (PPH) in Japan. METHODS: We studied 69 patients treated with rFVIIa for severe PPH; 44 patients were from the registry of Japan Society of Obstetrical, Gynecological and Neonatal Hematology, and 25 were identified by a survey of the Japan Society of Obstetrics and Gynecology. RESULTS: Overall, the mean and median blood loss were 11 835 mL and 8639 mL, respectively. Treatment before rFVIIa included transarterial embolization in 23 patients and hysterectomy in 38. Forty-two patients had a single dose, 17 had two doses, and four had three doses. The mean (± SD) single dose was 81.60 ± 16.25 µg/kg. Sixty-five patients survived, and four died. The cause of PPH in patients who died was uterine rupture plus amniotic fluid embolism in two patients, uterine cervical laceration in one, and placental abruption in one. The amount of blood loss in cases of death was 6428-43 810 mL. This suggested that whether a patient survives or not was more dependent on her general condition before and after rFVIIa treatment than on the amount of blood loss. Four patients had thromboembolic events after rFVIIa treatment (deep vein thrombosis; deep vein thrombosis plus pulmonary embolism; acute myocardial infarction; and pulmonary embolism); all of these patients recovered. CONCLUSION: The present promising results may support the utility of rFVIIa for severe PPH in Japan.

National survey of fibrinogen concentrate usage for post-partum hemorrhage in Japan: investigated by the Perinatology Committee, Japan Society of Obstetrics and Gynecology.

AIM: The aim of this study was to provide basic documents applicable to studying the usefulness of administering fibrinogen concentrate to patients with massive post-partum hemorrhage. We investigated the usage of fibrinogen concentrate at training institutions for specialist physicians of the Japan Society of Obstetrics and Gynecology. MATERIAL AND METHODS: The subjects were women who required fibrinogen concentrate for hemostasis of post-partum hemorrhage during the period between April 2008 and March 2013. The underlying diseases, obstetric disseminated intravascular coagulation scores, blood loss, amount of blood transfusion, dose of fibrinogen concentrate administered, and plasma fibrinogen levels before and after the administration of fibrinogen concentrate were retrospectively investigated. RESULTS: Ninety-nine (98.0%) patients survived and two died after taking fibrinogen concentrate. Of the surviving 99 cases, the average amount of blood loss at the time of initial fibrinogen administration and total blood loss was 3559 ± 2103 mL and 4562 ± 3198 mL, respectively. The dose per administration was 3 g, and the plasma fibrinogen level before the initial administration of fibrinogen concentrate was 70.5 mg/dL, thereafter increasing to 187.0 mg/dL. The increase in the fibrinogen level was 32.9 mg/dL/g of fibrinogen concentrate. It was less than 150 mg/dL after the first administration of fibrinogen concentrate only in patients with amniotic fluid embolism and patients with atonic bleeding showed the smallest increase in fibrinogen per gram of fibrinogen concentrate. No adverse events, including thromboembolism, were reported. CONCLUSION: The results indicated the increase in blood fibrinogen levels to, on occasion, be insufficient even with fibrinogen concentrate use; however, this survey may support the safety and usefulness of fibrinogen concentrate for PPH.

Potential Treat-to-Target Approach for Methamphetamine Use Disorder: A Pilot Study of Adenosine 2A Receptor Antagonist With Positron Emission Tomography.

Introduction: The misuse of stimulant drugs such as methamphetamine is a global public health issue. One important neurochemical mechanism of methamphetamine use disorder may be altered dopaminergic neurotransmission. For instance, previous studies using positron emission tomography (PET) have consistently shown that striatal dopamine D2-type receptor availability (quantified as binding potential; BPND) is lower in methamphetamine use disorder. Further, methamphetamine use is known to induce chronic neuroinflammation through multiple physiological pathways. Upregulation of D2-type receptor and/or attenuation of neuroinflammation may therefore provide a therapeutic effect for this disorder. In vitro studies have shown that blockage of adenosine 2A (A2A) receptors may prevent D2-receptor downregulation and neuroinflammation-related brain damage. However, no study has examined this hypothesis yet. Methods and Analysis: Using a within-subject design, this trial will assess the effect of the selective A2A receptor antagonist, istradefylline, primarily on D2-type BPND in the striatum, and secondarily on neuroinflammation in the whole brain in individuals with methamphetamine use disorder. The research hypotheses are that istradefylline will increase striatal D2-type BPND and attenuate neuroinflammation. Twenty participants with methamphetamine use disorder, aged 20-65, will be recruited to undergo [11C]raclopride PET (for every participant) and [11C]DAA1106 PET (if applicable) once before and once after administration of 40 mg/day istradefylline for 2 weeks. Neuropsychological measurements will be performed on the same days of the PET scans.

Risk factors for the onset of dependence and chronic psychosis due to cannabis use: Survey of patients with cannabis-related psychiatric disorders.

AIM: The objective of the current study was to identify risk factors that affect the onset of dependence and chronic psychosis due to cannabis use. METHODS: We examined clinical genetic factors, psychiatric disorders prior to cannabis use, starting age of cannabis use, duration and frequency of cannabis use, types of cannabis products used, combined use of other psychoactive substances, and the psychiatric diagnosis of 71 patients with cannabis-related psychiatric disorders who underwent treatment at nine mental health hospitals in Japan. Information was collected from cross-sectional interview surveys conducted by each patient's attending psychiatrist. RESULTS: For the diagnosis of dependence syndrome due to the use of cannabis, we found associations with the number of years of cannabis use and the use of cannabis products with a high Δ9-tetrahydrocannabinol (THC) content. However, we found no association between diagnosis of residual and late-onset psychotic disorders and clinical genetic factors, presence of preceding psychiatric disorders, duration and frequency of cannabis use, starting age of cannabis use, or combined use of other psychoactive substances; an association was found only for the absence of use of cannabis products other than dried cannabis. CONCLUSION: The onset of cannabis dependence was related to long-term cannabis use and the use of cannabis products with a high THC content. However, chronic psychosis was not associated with total THC intake or psychiatric vulnerability. Thus, unknown factors appear to be involved in the onset of chronic psychosis.

Opioids for Relief of Dyspnea Immediately Before Death in Patients With Noncancer Disease: A Case Series Study.

BACKGROUND: Dyspnea is commonly found in most conditions among patients with progressive noncancer disease. OBJECTIVE: To clarify the effectiveness and safety of opioid administration for the treatment of dyspnea immediately before death in patients with noncancer disease. METHODS: A retrospective case-series study involving 13 consecutive terminally ill patients who were near death and diagnosed with noncancer disease, and had refractory dyspnea and received opioid therapy, was performed. The authors investigated the route of administration, period, dosage of opioids, intensity of dyspnea-scored according to the Japanese version of the Support Team Assessment Schedule-and clinical course from a review of medical records. RESULTS: The mean age of the patients was 86.5 ± 7.6years (range: 72-98years). The primary causes of dyspnea that led to opioid administration were heart failure (n = 10) and respiratory failure (n = 3). Oxycodone was used in one patient who experienced a complication of chronic renal failure; morphine was used in the other 12 patients. The route of opioid administration was continuous infusions in 11 patients, suppository in one, and oral administration in one. The final dose of oral morphine equivalents was 20.1 ± 8.1 mg/d (range: 5-36 mg [median: 18 mg]). All patients improved in symptom score after opioid administration. The score was significantly decreased from 3.2 ± 0.7 at the beginning of opioid administration to 1.2 ± 0.6 at final estimation (P < .001). No severe adverse events occurred. CONCLUSIONS: Low-dose opioid administration in patients with terminally ill noncancer improved dyspnea and occurred no severe adverse events.

Study of effects of ifenprodil in patients with methamphetamine dependence: Protocol for an exploratory, randomized, double-blind, placebo-controlled trial.

AIMS: Pharmacotherapy for methamphetamine dependence has not yet been developed in Japan or elsewhere in the world. Ifenprodil is a blocker of G protein-activated inwardly rectifying potassium channels that play a key role in the mechanism of action of addictive substances. Our aim is to examine the safety, efficacy, and outcomes of ifenprodil for the treatment of methamphetamine dependence in a randomized, double-blind, placebo-controlled trial. METHODS: The recruitment of outpatients with methamphetamine dependence began in January 2018. The patients will be randomized into three arms: placebo, 60 mg/d ifenprodil, or 120 mg/d ifenprodil. Placebo or ifenprodil will be taken for 84 days. We will use Cerocral fine granule 4%® (ifenprodil tartrate). Follow-up assessments will be conducted for 84 d after the drug administration period. All of the patients will be assessed by self-administered questionnaires and urine tests. The primary outcome will be the presence or absence of methamphetamine use during the 84-day administration period in the 120 mg/d ifenprodil and placebo groups. Secondary outcomes will include the number of days and percentage of days of abstinence from methamphetamine use, positive urine for methamphetamine, relapse risk, and drug craving. DISCUSSION: This study is the first clinical trial of ifenprodil treatment for methamphetamine dependence and is designed as an intervention test with off-label drug use. The present study is expected to provide evidence of the effects of ifenprodil treatment on methamphetamine dependence. TRIAL REGISTRY: This trial was registered in the UMIN clinical trial registry (UMIN000030849; date of registration: January 17, 2018).

Suppressive effect of rice extract on Helicobacter pylori infection in a Mongolian gerbil model.

BACKGROUND: Rice extract has been shown to protect gastric mucosa from stress-induced damage. In this study, the antibiotic effect and the anti-inflammatory effect of orally administered aqueous rice extract on Helicobacter pylori infection and H. pylori-induced gastritis, respectively, in Mongolian gerbils were investigated. METHODS: Fifty specific-pathogen-free male Mongolian gerbils, seven weeks old, were divided into four groups: uninfected, untreated animals (group A); uninfected, rice extract-treated animals (group B); H. pylori-infected, untreated animals (group C); and H. pylori-infected, rice extract-treated animals (group D). Group C and D animals were killed 12 weeks after H. pylori infection (i.e., at 19 weeks of age) and group A and B animals were also killed at age 19 weeks. The stomachs were removed for histopathological examination with hematoxylin-and-eosin staining and anti-5'-bromo-2'-deoxyuridine (BrdU) immunostaining, and to determine the bacterial burden. Serum anti-H. pylori antibody titers were also tested. RESULTS: In groups A and B, the gastric mucosa showed no inflammatory cell infiltration and a few BrdU-reactive cells. Group C animals developed marked chronic active gastritis in the gastric mucosa, and BrdU-labeled cells in the gastric mucosa markedly increased in number. In group D animals, a significant reduction occurred in the degree of neutrophilic polymorphonuclear cell infiltration into the gastric mucosa, in the BrdU-labeling indices of gastric epithelial cells, and in anti-H. pylori antibody titers in the serum (P < 0.01), compared with although H. pylori was not completely eradicated. CONCLUSIONS: The rice extract was effective in suppressing inflammation and epithelial cell proliferation in the gastric mucosa in H. pylori-infected Mongolian gerbils. The rice extract has potential to exhibit a protective effect on H. pylori-related gastric mucosal diseases.

Treatment of benign prostatic hyperplasia using transurethral microwave thermotherapy and dilatation with double-balloon catheter.

PURPOSE: To improve the outcome of transurethral microwave thermotherapy (TUMT) for the treatment of benign prostatic hyperplasia, we combined TUMT and balloon dilatation (BD) with a double-balloon catheter and investigated its effects. PATIENTS AND METHODS: For a short-term trial, 40 patients were divided randomly into two groups: 20 patients received TUMT alone, and the other 20 received TUMT followed by BD. The degrees of symptoms were graded according to the International Prostate Symptom Score and Quality of Life score, and the peak urinary flow rate was measured before and 10 weeks after treatment. A historic control study of 527 patients was also performed to evaluate the long-term re-treatment rate: 98 of the patients received TUMT alone, and the other 429 patients received TUMT followed by BD. RESULTS: The symptom scores improved significantly in both groups. The peak uroflow rate was significantly increased in the group who received TUMT followed by BD (P < 0.01), whereas the change was not significant in the TUMT-alone group. Significant sustainability of long-term effects was more evident in patients receiving TUMT plus BD than in the TUMT-alone group, as judged by the higher proportion of BD-treated patients who required no further treatment during the 5-year study period in comparison with patients who received TUMT alone (66.3% v 28.6%, respectively; P < 0.001). CONCLUSIONS: Combined TUMT and BD achieves sufficient subjective and objective improvement and a sustainable long-term effect. We consider this combination technique to be useful for the treatment of prostatic hyperplasia.

Long-term hormone replacement therapy delays the age related progression of carotid intima-media thickness in healthy postmenopausal women.

OBJECTIVES: Carotid intima-media thickness (IMT) is an appropriate intermediate end point to investigate clinically relevant effects on atherogenesis. The study objective was to clarify whether long-term hormone replacement therapy (HRT) modifies the progress of age-related IMT in healthy postmenopausal Japanese women. METHODS: One hundred and eighty-eight healthy postmenopausal women aged 42-69 years were recruited into the retrospective study. IMT was measured by B-mode real-time ultrasound in the following three groups of patients. One hundred and fifteen women who were prescribed estrogen plus progestin or estrogen alone were classified into two groups according to the HRT treated period: short-term (<2 years of treatment, n = 52) and long-term (> or =2 years, n = 63) HRT groups. The third group consisted an age-matched women (n = 73), who were never treated with HRT (non-HRT group) as a control. RESULTS: Each group was divided into three subgroups according to age: < or =49 years, 50-59 years and 60 years or older. IMT in patients of age > or =60 years in the non-HRT group was 0.607 +/- 0.064 mm and was significantly higher compared with that in the other two age subgroups of non-HRT patients (< or =49 years: [0.495 +/- 0.051 mm; 50-59 years: 0.505 +/- 0.068 mm) (P < 0.05). In the short-term HRT group, IMT of > or =60-year-old-subjects (0.588 +/- 0.074 mm) was also significantly higher compared with that in the other two age subgroups (< or =49 years: 0.480 +/- 0.034 mm; 50-59 years: 0.511 +/- 0.062 mm). However, in the long-term HRT group, IMT was not significantly different among the three age subgroups. There was a significant relationship between IMT and age in non-HRT (r = 0.594, P < 0.0001) and short-term HRT (r = 0.542, P < 0.001) groups, but no significant relationship was observed in the long-term HRT (r = 0.195 , P = 0.1266) group. CONCLUSIONS: In long-term HRT, more than 2 years may delay the age-related increase in IMT in healthy postmenopausal Japanese women.

Distribution of thymidine phosphorylase activity in gastric carcinoma and adjacent normal gastric tissue.

BACKGROUND/AIMS: Thymidine phosphorylase was reported to be identical to the angiogenic factor, platelet-derived endothelial cell growth factor. In this study we investigated the distribution of thymidine phosphorylase activity in human gastric carcinoma or normal gastric tissue using the ELISA system. METHODOLOGY: A longitudinal slice in the center of the gastric carcinoma of resected specimens from 6 patients with gastric carcinoma was used, and thymidine phosphorylase activity was mapped in each case. RESULTS: In all cases, the thymidine phosphorylase activities were significantly higher in tumors than adjacent normal gastric tissues. The amount and distribution of thymidine phosphorylase activity were different between intestinal-type and diffuse-type carcinoma. The thymidine phosphorylase activities in the invasive front of tumor were significantly lower than those in the other part in intestinal-type carcinoma. CONCLUSIONS: The ELISA system used in this study proved useful for the determination of thymidine phosphorylase activities in tissue sections.

[Three cases of recurrent gastric cancer responding to TS-1 therapy following combination therapy with 5-fluorouracil, mitomycin C and cisplatin].

We report three patients with recurrent gastric cancer responding to TS-1 therapy after combination chemotherapy with 5-fluorouracil, mitomycin C and cisplatin. All 3 cases had undergone total gastrectomy with lymphadenectomy for advanced gastric cancer. Postoperative follow-up computed tomography (CT) showed liver metastases (cases 1 and 3), peritoneal dissemination (case 2) and enlargement of paraaortic lymph nodes (case 1) due to cancer recurrence. After 2 to 4 courses of combined treatment with 5-fluorouracil (500-750 mg/body/day, days 1-5, civ), mitomycin C (6-8 mg/body, day 6) and cisplatin (60-80 mg/body, day 7), CT revealed considerable reduction of the metastatic tumors. Subsequently oral administration of TS-1 (80-100 mg/body/day) for 4 weeks was performed. All 3 patients are well without any signs of increase in tumor size.

Gastric small cell carcinoma successfully treated by surgery and postoperative chemotherapy consisting of cisplatin and S-1: report of a case.

We herein report a case of gastric small cell carcinoma (GSCC), which was successfully treated by surgery and postoperative chemotherapy consisting of cisplatin (CDDP) and the fluoropyrimidine S-1. The patient was a 63-year-old man in whom a gastric tumor had been endoscopically detected. The type 1 tumor was located in the gastric body. An abdominal computed tomogram showed many metastasized nodes around the stomach. A total gastrectomy with regional node dissection was performed. The removed tumor was histologically and histochemically diagnosed to be a GSCC with node metastases. Furthermore, washing peritoneal cytology histologically revealed the presence of carcinoma cells. Metastasis was histologically observed in 17 of 24 dissected nodes. After surgery, CDDP was intravenously administered and S-1 was orally administered for 1 year. Consequently, the patient is now well without any recurrence 45 months after surgery. We reviewed 52 Japanese patients with GSCC/endocrine cell carcinoma (EC) reported between 2001 and 2005 with reference to chemotherapy. Chemotherapy using S-1 was performed for 11 of the 52 patients. Four of the 11 patients, including the present case, who were treated with S-1 survived for over 2 years after surgery, although the GSCC/EC of the four patients were staged as III or IV. Therefore, chemotherapy consisting of CDDP and S-1 may provide a survival benefit for patients with GSCC/EC.

Prepregnancy body mass index as an important predictor of perinatal outcomes in Japanese.

OBJECTIVE: The influence of maternal body mass index (BMI) before pregnancy and weight gain during pregnancy on perinatal outcomes in the Japanese population remains to be elucidated. Therefore, we estimated the risk of perinatal morbidity of the mother and infant with respect to maternal prepregnancy BMI and weight gain during pregnancy in Japanese. RESULTS: In the obese before pregnancy group, the risks of cesarean delivery, preeclampsia, and gestational diabetes were significantly elevated compared with the normal group. In the underweight before pregnancy group, the risks of low birth weight infant and hospitalization of infant were elevated significantly. CONCLUSION: However, weight gain during pregnancy did not show any significant influence on the perinatal outcomes of the mother or infant.

Natural history of gastric mucosal cytokine expression in Helicobacter pylori gastritis in Mongolian gerbils.

Data regarding the chronological changes in gastric mucosal cytokines in the different phases of Helicobacter pylori infection are unavailable. We examined Mongolian gerbils for up to 52 weeks after H. pylori (ATCC 43504) inoculation. Levels of mRNAs of mucosal cytokines (interleukin-1beta [IL-1beta], gamma interferon [IFN-gamma], IL-4, IL-6, and IL-10) were assessed using real-time reverse transcription-PCR. Starting 26 weeks after H. pylori inoculation, two clinicohistologic patterns appeared: gastric ulcers in 32% and hyperplastic polyps in 68% of gerbils. High levels of mucosal IL-1beta mRNA were observed early in the infection, reaching maximum at 4 weeks and then rapidly declining. Mucosal IFN-gamma mRNA also reached maximal levels at 4 weeks but remained high thereafter. Both IL-1beta and IFN-gamma mRNA levels were consistently higher in the pyloric mucosa than in the fundic mucosa. In contrast, IL-4, IL-6, and IL-10 mRNA levels peaked at 8 to 26 weeks and levels were similar in the pyloric mucosa and the fundic mucosa. IFN-gamma mRNA levels were significantly higher in gerbils with ulcers than in those with hyperplastic polyps (median IFN-gamma/glyceraldehyde-3-phosphate dehydrogenase ratio x 100,000 = 650 versus 338, respectively [antrum], and 172 versus 40, respectively [corpus]) (P < 0.05). We propose that the different outcomes (e.g., ulcers or hyperplastic polyps) might relate to imbalances among cytokines.

External pneumatic compression does not increase urokinase plasminogen activator after abdominal surgery.

External pneumatic compression (EPC) devices prevent lower extremity deep venous thrombosis (DVT) by reducing stasis. There is a widely held belief that they also enhance endogenous fibrinolysis; however, recent studies of tissue plasminogen activator (the primary activator of fibrinolysis) and plasminogen activator inhibitor-1 (the primary inhibitor of fibrinolysis) failed to confirm this. The hypothesis of this study was that EPC devices increase the level of urokinase plasminogen activator (uPA), a second activator of fibrinolysis. This was a prospective trial in which 44 subjects who underwent major abdominal surgery were randomized to receive unfractionated heparin injections, thigh-length sequential EPC devices, or both for DVT prophylaxis. Prophylaxis was begun immediately before surgical incision and continued until postoperative day 5 or discharge. Venous blood samples were collected from an antecubital vein for measurement of systemic uPA levels and from the common femoral vein for measurement of regional uPA levels. Samples were collected the day before surgery, after induction of anesthesia but before surgical incision, and on postoperative days 1, 3, and 5. uPA levels (ng/mL) were measured with an enzyme-linked immunoassay. Baseline uPA levels (0.41 to 0.56 ng/mL; P >.05, analysis of variance with repeated measures) were similar among the three groups. uPA levels did not change after surgery in systemic or regional blood samples in any group. There were no significant differences in systemic or regional uPA levels in the groups treated with EPC devices relative to those treated with heparin at any time point (P >.05, analysis of variance with repeated measures). Enhancement of fibrinolysis with EPC devices remains unproven; the findings reported here suggest that effective DVT prophylaxis can only be assured when the devices are used in a manner that reduces venous stasis.

Morphologic characteristics of varicose veins: possible role of metalloproteinases.

BACKGROUND: Although varicose veins are a common cause of morbidity, etiologic factors predisposing to dilatation, elongation, and tortuosity of the saphenous vein and its tributaries are poorly understood. We compared histologic features of normal and varicose saphenous veins and investigated the role of enzyme or inhibitor imbalance in development of varicosities. METHODS: Eight normal and 10 varicose (C(2,3)E(P,S)A(S)P(R,O)) vein segments were used for this analysis. Matrix metalloproteinase (MMP) expression and activity were analyzed with Western blotting and zymography. Venous architecture and protein localization were determined with histology and immunohistochemistry. RESULTS: Western blot analysis demonstrated the presence of MMP- 1, MMP-2, MMP-9, and MMP-12, as well as small quantities of tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 in protein isolates from normal and varicose veins. Both vein types demonstrated MMP-2, MMP-9, and MMP-12 activity by gelatin zymography, although varicose vein expressed less MMP-9 activity than normal vein did. Compared with normal veins, changes in varicose veins were not uniformly distributed along the circumference; areas of intimal thickening were often interspersed with focal areas of dilatation. Fragmentation of elastic lamellae and loss of circular and longitudinal muscle fibers were evident in the varicosities. Focal aggregates of macrophages were detected within the media and adventitia of both normal and varicose veins. MMP-1 and MMP-9 were expressed in both types of vein segments; however, their immunohistochemical localization was distinctly different. In normal vein, endothelial cells, occasional smooth muscle cells (SMC), and adventitial microvessels expressed MMP-1, whereas its expression was localized to fibroblasts, SMC, and endothelial cells throughout involved portions of varicose veins. MMP-9 was localized to endothelial cells, medial SMC, and adventitial microvessels in both normal and varicose veins, although varicose veins demonstrated increased medial smooth muscle cell staining. MMP-12 was found in SMC and fibroblasts in both normal and varicose veins. Neither TIMP-1 nor TIMP-2 were detected with immunohistochemistry in any specimens examined. CONCLUSIONS: There are distinct differences in the structural architecture and localization of MMP expression in normal and varicose veins. Although the changes observed are not sufficiently definitive to enable a causal relationship, they do suggest a possible mechanism for the alterations in matrix composition observed between normal and varicose veins.