The Effectiveness of Endovenous Thermal Ablation for the Knee Symptoms of the Osteoarthritis with Varicose Veins.

Patients with varicose veins of the lower extremities with osteoarthritis of the knee often experience improvement in knee joint symptoms after endovascular treatment. We considered that it was important to decide the operation indication of lower extremity varices, to know the correlation between the two diseases in the treatment of varicose veins. To investigate the postoperative improvement of knee symptoms related to varicose veins with knee osteoarthritis, we conducted a questionnaire survey for a total of 12 months, from December 2014 to May 2015 and from October 2018 to March 2019. The participants were 35 patients (7 men and 28 women) with varicose veins complicated with knee osteoarthritis. We classified knee osteoarthritis according to a grading scale and compared the improvement of knee symptoms after endovenous thermal ablation. The higher the knee grade, the lower the degree of improvement. However, the improvement was observed in all knee osteoarthritis grades, and as a whole, 25 patients (71.4%) have experienced improvement of subjective symptoms. For patients with knee osteoarthritis, we strongly recommend surgical treatment of the varicose veins regardless of the progression of knee grade. (This is a translation of Jpn J Phlebol 2019; 30(3): 279-283.).

Supplement of Clinical Practice Guidelines for Endovenous Thermal Ablation for Varicose Veins: Overuse for the Inappropriate Indication.

While endovenous thermal ablation (ETA) become first choice of treatment for varicose veins, overuse of ETA for the inappropriate indication is growing problem. ETA is performed not only on varicose cases without symptom but also non diseased cases with segmental reflux of saphenous veins or no reflux. Indications of ETA was demonstrated in "the Clinical Practice Guidelines for ETA for Varicose Veins 2019" by Japanese Society of Phlebology. Purpose of this supplement is description of basics of correct indication for ETA. We also demonstrate the typical case of overuse of ETA for wrong indication. (This is a translation of Jpn J Phlebol 2020; 31: 39-43.).

Clinicopathological Features of Autoimmune Hepatitis with IgG4-Positive Plasma Cell Infiltration.

BACKGROUND: We aimed to elucidate the characteristics and prognosis of autoimmune hepatitis (AIH) patients with immunoglobulin (Ig) G4-positive plasma cell infiltration. METHODS: We enrolled 84 AIH patients. The number of IgG- and IgG4-positive plasma cells was immunohistochemically counted per high-power field in the portal area. Patients with 3 or more IgG4-positive plasma cells on average and a ratio of IgG4 to IgG-positive plasma cells ≥5% were defined as IgG4-associated AIH (IgG4-AIH), and their clinicopathological characteristics and prognosis were compared to those of the remaining classical-AIH patients. RESULTS: Ten (11.9%) and 74 patients (88.1%) were categorized as IgG4-AIH and classical-AIH patients, respectively. The median age of the IgG4-AIH patients was 67 years, the majority was female (80.0%), and the distribution was similar to that of the classical-AIH patients. The IgG4-AIH patients exhibited significantly more severe phenotypes in portal inflammation, interface hepatitis, fibrosis, and rosette formation. All clinical laboratory data were similar except for serum IgG4 levels, which were higher in IgG4-AIH patients (168.5 vs. 22.9 mg/dL, p = 0.014). During a median follow-up period of 139 months, the relapse rate was significantly lower in the IgG4-AIH group than in the classical-AIH group (11.1 vs. 49.2%; p = 0.048). Twelve (16.2%) and 6 (8.1%) classical-AIH patients underwent liver-related events and liver-related deaths, respectively. In contrast, none of the IgG4-AIH patients progressed to severe liver disease. CONCLUSIONS: The IgG4-AIH patients had more severe inflammation and advanced fibrosis in the liver. However, their prognosis was not poor compared to that of classical-AIH patients. IgG4-AIH may have a phenotype distinct from classical-AIH.

Prevention of Thromboembolic Infarction After Surgery for Traumatic Cervical Fracture with Vertebral Artery Occlusion by Preoperative Endovascular Coil Embolization.

BACKGROUND: Vertebral artery injuries (VAIs) caused by cervical trauma include irregularities with narrowing of the arterial wall, dissection, pseudoaneurysm formation, occlusion, and transection. Although recent guidelines have recommended anticoagulant or antiplatelet therapy to prevent subsequent stroke in patients with traumatic VAIs, regardless of the type of vascular injury, the clinical role of endovascular surgery in the treatment of traumatic VAIs remains to be elucidated. METHODS: We retrospectively evaluated the treatment outcomes of 23 patients with cervical fracture and vertebral artery occlusion (VAO) who had required cervical surgery in the acute stage. RESULTS: No patient received antiplatelet or anticoagulant therapy, because the VAs had already become occluded. After cervical surgery, 5 of the 23 patients developed radiologically confirmed thromboembolic stroke after cervical surgery. None of these 5 patients with postoperative infarction had undergone preoperative VA embolization. Univariate analysis revealed that only the implementation of preoperative VA embolization was associated with the prevention of postoperative infarction (P = 0.004). Factors such as age, reduction, level of VAO, and diabetes mellitus did not correlate with increased risk. CONCLUSIONS: The clinical role of endovascular surgery for traumatic VAI has not been previously established; however, a more specific selection of patients according to the VAI type might be necessary. Our data have indicated that preoperative embolization of the occluded VA significantly reduces the risk of postoperative infarction in a specific cohort of patients with traumatic VAI (i.e., patients with post-traumatic VAO who require cervical surgery).

The clinical utility of serum free light chain and heavy/light chain assays in monitoring disease activity in patients with IgG myeloma after achieving a deep response.

Heavy/light chain (HLC) assay will enable us to evaluate the changes in the concentrations of iHLC and uHLC separately and to better identify whether the change observed is clonal or reactive. It would therefore aid in decision making for earlier implementation or discontinuation of treatment for patients with intact immunoglobulin multiple myeloma (MM).

Early administration of fibrinogen concentrates improves the short-term outcomes of severe pelvic fracture patients.

Aim: Hemorrhage from pelvic fracture is a major cause of mortality after blunt trauma. Several studies have suggested that early fibrinogen supplementation improves outcomes of traumatic hemorrhage. Thus, we revised our massive transfusion protocol (MTP) in April 2013 to include early off-label administration of fibrinogen concentrate. The objective of this study was to evaluate the impact of the revision on the short-term outcomes of pelvic fracture patients. Methods: This was a single-center, retrospective, cohort study. A total of 224 consecutive pelvic fracture patients hospitalized in Saitama Medical Center (Saitama, Japan), 115 before the revision (Group E) and 109 after (Group L), were enrolled. Characteristics of the patients were compared between the groups. Impacts of the revision were evaluated by hazard ratios adjusted for characteristics, injury severity, and coagulation status using Cox's multivariate proportional hazard model. The impact was also evaluated by log-rank test and relative risk of 28-day mortality between the groups. Results: The characteristics were equivalent between the groups. The multivariate analysis revealed that the revision of MTP was significantly related to improved survival with an adjusted hazard ratio (95% confidence interval) of 0.45 (0.07-0.97). The log-rank test gave χ2-test values of 5.2 (P = 0.022) and 6.7 (P = 0.009), and the relative risks were 0.37 (0.15-0.91) and 0.33 (0.13-0.84), in patients with all Injury Severity Scores and Injury Severity Score ≥21, respectively. Conclusion: The revision of MTP to include aggressive off-label treatment with fibrinogen concentrate was related to improved short-term outcomes of severe pelvic fracture patients. However, due to the limitations of the study, the improvement could not be attributed totally to the revision.

Pre-emptive administration of fibrinogen concentrate contributes to improved prognosis in patients with severe trauma.

BACKGROUND: Patients with severe trauma often present with critical coagulopathy, resulting in impaired hemostasis, massive hemorrhage, and a poor survival prognosis. The efficacy of hemostatic resuscitation in correcting coagulopathy and restoring tissue perfusion has not been studied. We assessed a novel approach of pre-emptive administration of fibrinogen concentrate to improve critical coagulopathy in patients with severe trauma. METHODS: We retrospectively compared blood transfusion volumes and survival prognosis between three groups of patients with trauma, with an Injury Severity Score (ISS) ≥26 over three consecutive periods: group A, no administration of fibrinogen concentrate; group B, administration of 3 g of fibrinogen concentrate after evaluation of trauma severity and a plasma fibrinogen level <1.5 g/L; group C, pre-emptive administration of 3 g of fibrinogen concentrate immediately on patient arrival based on prehospital information, including high-severity injury or assessed need for massive transfusion before measurement of fibrinogen. RESULTS: ∼56% of patients with an ISS ≥26 and transfused with red blood cell concentrates ≥10 units, had hypofibrinogenemia (fibrinogen <1.5 g/L) on arrival. Patients who received fibrinogen concentrate in group C showed significantly higher fibrinogen levels after treatment with this agent than those in group B (2.41 g/L vs 1.88 g/L; p=0.01). Although no significant difference was observed in blood transfusion volumes between the groups, the 30-day survival of patients in group C (all, and those with an ISS ≥26) was significantly better than in group A (p<0.05). The 48-hour mortality rate in patients with an ISS ≥26 was significantly lower in group C than in group A (8.6% vs 22.9%; p=0.005). Further, among patients with an ISS ≥41, the overall mortality was significantly lower in group C than in group A (20% vs 50%; p=0.02). CONCLUSION: Pre-emptive administration of fibrinogen concentrate for patients with trauma with critical coagulopathy may contribute to improved survival. LEVEL OF EVIDENCE: Level IV.

[RADIOFREQUENCY ABLATION FOR THE TREATMENT OF VARICOSE VEINS].

Significant advances in the endovenous technique for treating incompetent saphenous veins could change the surgical strategy in patients with varicose veins. Radiofrequency ablation (RFA) was approved as a new technique for the treatment of varicose veins in Japan in June 2014. In RFA, the ablation temperature is controlled by a sensor at the upper end of the catheter. The vein wall is heated with stable conductive power of 120 degrees C, resulting in endothelial denudation. The RFA method was approved in 1998 in Europe and in 1999 in the USA. The ClosurePLUS catheter was developed in 2003 and ClosureFAST in 2006. High occlusion rates and lower postoperative complication rates were reported with ClosureFAST than with ClosurePLUS. It is expected that this new ablation technique will control saphenous vein reflux with less pain and less ecchymosis after surgery. The treatment of varicose veins is less invasive with RFA devices and will become widely accepted as an alternative to conventional surgery for varicose veins in Japan.

The influence of residual below-knee reflux and incompetent perforating veins on venous function after stripping surgery.

Persisting incompetent great saphenous vein (GSV) below the knee and residual incompetent perforating veins (IPV) are often found after selective stripping of GSV from the groin to upper calf. The aim of this study is to evaluate the venous function when the calf GSVs or calf perforating veins are incompetent after stripping surgery. One hundred-thirty-one limbs were treated by stripping from the groin to upper calf with stab avulsion or sclerotherapy of varices. One month and twelve months after surgery, the patients were examined clinically to establish the extent of persisting varices by duplex ultrasonography and air-plethysmography. Venous filling index (VFI) was a little higher in those who had residual calf GSV reflux 12 months later; it was also higher in the group with incompetent perforating veins than the group without. The chief complaints were found to have improved in all groups. The findings suggest that removal of the saphenous vein below the knee is not necessary, but it is important to take care of the incompetent perforating veins. (English Translation of Jpn J Phlebol 2011; 22: 239-244.).

Impact of pitavastatin on high-sensitivity C-reactive protein and adiponectin in hypercholesterolemic patients with the metabolic syndrome: the PREMIUM Study.

BACKGROUND: Inflammatory reactions and oxidative stress, which are important in progression of atherosclerosis, are reported to be increased in individuals with metabolic syndrome (MetS). On the other hand, adiponectin levels are lowered. Since effects of pitavastatin on these parameters have not been reported in hypercholesterolemic patients with MetS, the present study was conducted. PURPOSE: To evaluate the effects of pitavastatin on inflammatory reaction, oxidative stress, and plasma adiponectin levels in hypercholesterolemic MetS patients in a multicenter trial. METHODS: This open-label, single group study was performed at 7 hospitals in Japan. Pitavastatin (2mg/day) was administered to 103 consecutive patients with hypercholesterolemia, subdivided into MetS and non-MetS for 12 weeks. Blood samples were collected after overnight fasting at the start of treatment (baseline) and after 12 weeks. RESULTS: In the patients with MetS (n=69), mean values of plasma high-sensitivity C-reactive protein (hs-CRP) were significantly higher and mean values of plasma high-molecular-weight (HMW)-adiponectin significantly lower than in their counterparts without MetS (n=34). The baseline HMW-adiponectin and high-density lipoprotein cholesterol (HDL-C) values significantly correlated only in the MetS patients (r=0.318; p=0.01). In an effectiveness analysis including 94 patients (62 with MetS, 32 without MetS), the level of hs-CRP was significantly decreased in patients with MetS during the drug treatment, whereas HMW-adiponectin did not change. When patients with MetS were divided into two subgroups according to the percent changes in HDL-C, significantly greater increase in HMW-adiponectin by pitavastatin treatment was observed in the HDL-C ≥10% increase subgroup than in the HDL-C <10% increase subgroup (p=0.009). CONCLUSION: Twelve weeks administration of pitavastatin, in addition to the antihyperlipidemic effects, may be beneficial as an anti-atherosclerotic therapy in hypercholesterolemic patients with MetS, taking changes in hs-CRP and HMW-adiponectin into consideration. ClinicalTrials.gov identifier: NCT00444717.

Effect of L-arginine supplement on liver regeneration after partial hepatectomy in rats.

BACKGROUND: Nitric oxide (NO) has been reported to be a key mediator in hepatocyte proliferation during liver regeneration. NO is the oxidative metabolite of L-arginine, and is produced by a family of enzymes, collective termed nitric oxide synthase (NOS). Thus, administration of L-arginine might enhance liver regeneration after a hepatectomy. Another amino acid, L-glutamine, which plays an important role in catabolic states and is a crucial factor in various cellular and organ functions, is widely known to enhance liver regeneration experimentally. Thus, the present study was undertaken to evaluate the effects of an L-arginine supplement on liver regeneration, and to compared this with supplementation with L-glutamine and L-alanine (the latter as a negative control), using a rat partial hepatectomy model. METHODS: Before and after a 70% hepatectomy, rats received one of three amino acid solutions (L-arginine, L-glutamine, or L-alanine). The effects on liver regeneration of the administered solutions were examined by assessment of restituted liver mass, staining for proliferating cell nuclear antigen (PCNA), and total RNA and DNA content 24 and 72 hours after the operation. RESULTS: At 72 hours after the hepatectomy, the restituted liver mass, the PCNA labeling index and the DNA quantity were all significantly higher in the L-arginine and L-glutamine groups than in the control. There were no significant differences in those parameters between the L-arginine and L-glutamine groups, nor were any significant differences found between the L-alanine group and the control. CONCLUSION: Oral supplements of L-arginine and L-glutamine enhanced liver regeneration after hepatectomy in rats, suggesting that an oral arginine supplement can clinically improve recovery after a major liver resection.

[How should we comprehend the guideline for the revised Organ Transplantation Law?].

In accordance with the revision of the "Organ Transplantation Law", the ordinances and the guideline for the law were also revised. The revision of the guideline, which finds legal basis on the circular notices, raises some issues about its position in the Japanese legislative system. It is quite ambiguous whether we should comprehend the guideline as the interpretation of the law, as the procedural guidance, or as the instruction within the administrative body. Thus, the legal obligation for the healthcare professionals to observe the guideline is also unclear. There are many issues about the transplantation law, the ordinances and the guideline. They include (1) Legal implication of the "brain death" (Is "brain death" absolutely synonymous with "death" ?), (2) Scientific relevance of the criteria for diagnosis of brain death, (3) Definition of the "adequate treatment" which is the prerequisite for diagnosis of brain death, (4) The time of death for the cases who were declared legally brain-dead but did not donate the organs, (5) By whom and when should the organ donation be proposed, and more. The ambiguity about the legal position of the guideline shall cause confusion in the scenes of clinical practice.

Effects of 1-O-hexyl-2,3,5-trimethylhydroquinone on carbon tetrachloride-induced hepatic cirrhosis in rats.

AIM: The present study was undertaken to evaluate the effects of 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), a synthesized vitamin E derivative, on carbon tetrachloride (CCl(4))-induced cirrhosis. METHODS: Rats were treated with hypodermic injections of CCl(4) twice a week to induce the hepatic cirrhosis, and given drinking water containing HTHQ or solvent. Primary cultures of rat hepatocytes were performed to evaluate the effects of HTHQ on the expression of inducible nitric oxide synthase (iNOS). RESULTS: Masson's staining of rat livers showed fibrosis around pseudo-lobules in the CCl(4) group, the lesions being reduced in the CCl(4) HTHQ group. Increases in liver tissue hydroxyproline and alpha(1)(I) collagen, alpha-smooth muscle actin and iNOS induced by CCl(4), were also markedly diminished by HTHQ. Furthermore, both HTHQ and vitamin E attenuated interleukin-1beta-induced iNOS protein expression in cultured hepatocytes, the potency of HTHQ being 10-times higher than that of vitamin E. CONCLUSION: HTHQ may inhibit development of hepatic cirrhosis in rats, more potently than vitamin E, by inhibiting the iNOS expression in hepatocytes. Because vitamin E has a radical scavenging action, roles of NO and peroxynitrite will be discussed in the effects of HTHQ on the fibrosis.

Roles of naofen, a novel WD-repeat-2 protein, in the CCl4-treated livers--a possible relationship to cell proliferation.

Naofen (GenBank accession no. EF613262), a newly found intracellular protein in the WD-repeat-2 protein family, has been cloned as an anti-verotoxin II antibody immunoreactive substance, and the nucleotide- and amino acid-sequences have been clarified. The present study was undertaken to evaluate the roles of naofen especially in carbon tetrachloride (CCl4-induced cirrhosis model of rats, also in partial hepatectomy. Naofen mRNA expressions were observed from the early phases of cirrhosis development and during regenerative phases after partial hepatectomy, more remarkable in the former. Naofen immunoreactive fragments located in the vascular endothelial cells and peri-vascular spaces in normal livers especially in Glisson's areas, being strongly stained in the connective tissues 8 weeks after starting CCl4-injections, besides in the cytoplasm of hepatocytes in pseudo-lobules. In contrast, partial hepatectomy caused a small increase of naofen expressions in the whole hepatocytes, and significantly in the endothelial cells of portal veins and hepatic arterioles. Furthermore, in parallel to the degree of naofen mRNA and protein expressions, the rates of double-nuclei cells to total hepatocytes in the Glisson's areas increased in both cirrhosis and partial hepatectomy, suggesting a relationship between naofen expression and mitosis. In in-vitro studies with cell lines, vascular endothelial growth factor, a cell proliferation stimulant, increased the naofen mRNA expressions in HepG(2) cell lines, whereas paclitaxel, a cytotoxic anti-cancer drug, diminished them in NRK52E, both concentration-dependently. These results indicated that naofen immunoreactive fragments play an important role in the cell proliferation, relevant for analyzing the regenerative phases during cirrhosis developments and after partial hepatectomy.

[A case report of advanced gastric cancer with carcinomatous ascites successfully treated by outpatient chemotherapy].

The patient was a 54-year-old male with peritoneal dissemination and carcinomatous ascites of advanced gastric cancer. Although 4 months of temporary partial responses were obtained by a combination chemotherapy with TS-1 and DOC, retention of ascites appeared. Second-line combination chemotherapy with 5-FU and PTX was not effective, and we attempted to use intraperitoneal chemotherapy of low-dose CDDP. After 100 mg of CDDP had been administered, ascites almost disappeared. Then,intraperitoneal injection of low-dose CDDP and intravenous injection of 5-FU were given. Tumor marker decreased remarkably, and CT revealed reduction of peritoneal dissemination. These regimens seem to be effective in ambulant patients with advanced gastric cancer with peritoneal dissemination and carcinomatous ascites.

[A case report of recurrent gastric cancer in which combination chemotherapy with paclitaxel and 5-fluorouracil made for successful biliary stenting and improvement in QOL].

The patient was a 49-year-old female who had undergone a total gastrectomy for gastric cancer on March 9 2001. Pathological diagnosis revealed sig, T 3 (SE), N 2, H 0, P 1, CY 0, M 0, Stage IV, and the curability was C. 5' DFUR 800 mg/day was administered as adjuvant chemotherapy. CDDP 10 mg/body/week intraperitoneally and 5-FU 500 mg/body/week were added. Retention of ascites, peritoneal dissemination, obstructive jaundice and right hydronephrosis appeared in June, 2003, and we started combination chemotherapy with paclitaxel and 5-fluorouracil. 5-fluorouracil (600 mg/m2/day) was infused continuously for 120-hours (days 1-5), and paclitaxel (80 mg/m2) was infused on days 8, 15, and 22 on an outpatient basis. Ascites and peritoneal dissemination had disappeared, and swollen lymph nodes were reduced after 2 courses of the chemotherapy. Furthermore, billiary stenting was performed and a PTCD tube could be removed after 4 courses. No serious adverse effect was observed, and the patient maintained good QOL through this treatment.

1-O-hexyl-2,3,5-trimethylhydroquinone inhibits IkappaB phosphorylation and degradation-linked inducible nitric oxide synthase expression: beyond antioxidant function.

Inducible nitric oxide (NO) production in macrophages plays an important role in atherosclerosis, the protective effects of vitamin E and its derivatives perhaps being partly mediated by alteration in this parameter. We have investigated the influence of a novel synthesized vitamin E derivative, 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), on NO production in the RAW 264.7 mouse macrophage cell line. HTHQ dose-dependently inhibited lipopolysaccharide (LPS)-induced NO production through reducing LPS-triggered inducible nitric oxide synthase (iNOS) expression. The phosphorylation and subsequent degradation of IkappaB caused by LPS in RAW 264.7 cells was markedly blocked. The free radical scavenging activity of HTHQ was only 2-fold that of vitamin E, whereas its inhibition of NO production was found to be nearly 500-fold stronger. Our results indicated that HTHQ suppressed NO production in macrophages by blocking IkappaB degradation and thus inhibiting iNOS expression. The inhibitory activity of HTHQ on NO production did not parallel its free radical scavenging activity, implying a possible involvement of additional functions.