A possible role for inducible arginase isoform (AI) in the pathogenesis of chronic venous leg ulcer.

Chronic venous ulcer (CVU) is a major cause of chronic wounds of lower extremities and presents a significant financial and resource burden to health care systems worldwide. Defects in the vasculature, matrix deposition, and re-epithelialization are the main histopathological changes believed to impede healing. Supplementation of the amino acid arginine that plays a crucial role in the interactions that occur during inflammation and wound healing was proven clinically to improve acute wound healing probably through enhancing activity of inducible arginase (AI) locally in the wounds. However, the possible mechanism of arginine action and the potential beneficial effects of AI/arginine in human chronic wounds remain unclear. In the present study, using biopsies, taken under local anesthesia, from adult patients (n = 12, mean age 55 years old) with CVUs in lower extremities, we investigated the correlation between AI distribution in CVUs and the histopathological changes, mainly proliferative and vascular changes. Our results show a distinct spatial distribution of AI along the ulcer in the epidermis and in the dermis with the highest level of expression being at the ulcer edge and the least expression towards the ulcer base. The AI cellular immunoreactivity, enzymatic activity, and protein levels were significantly increased towards the ulcer edge. Interestingly, a similar pattern of expression was encountered in the proliferative and the vascular changes with strong correlations between AI and the proliferative activity and vascular changes. Furthermore, AI cellular distribution was associated with increased proliferative activity, inflammation, and vascular changes. Our findings of differential expression of AI along the CVU base, edge, and nearby surrounding skin and its associations with increased proliferative activity and vascular changes provide further support to the AI implication in CVU pathogenesis. The presence of high levels of AI in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.

Vitamin D intervention does not improve vascular regeneration in diet-induced obese male mice with peripheral ischemia.

Vitamin D appears to either promote or inhibit neovascularization in a disease context-dependent manner. The effects of vitamin D, alone or in combination with niacin, on endothelial cell (EC) angiogenic function and on revascularization in obese animals with peripheral ischemia are unknown. Here, we report that supplementation of high palmitate medium with vitamin D, niacin or both vitamins increased EC tube formation, which relies primarily on cell migration, and also maintained tube stability over time. Transcriptomic analyses revealed that both vitamins increased stress response and anti-inflammatory gene expression. However, vitamin D decreased cell cycle gene expression and inhibited proliferation, while niacin induced stable expression of miR-126-3p and -5p and maintained cell proliferation in high palmitate. To assess vascular regeneration, diet-induced obese mice received vitamin D, niacin or both vitamins following hind limb ischemic injury. Niacin, but not vitamin D or combined treatment, improved recovery of hind limb use. Histology of tibialis anterior sections revealed no improvements in revascularization, regeneration, inflammation or fibrosis with vitamin D or combined treatment. In summary, although both vitamin D and niacin increased angiogenic function of EC cultures in high fat, only niacin improved recovery of hind limb use following ischemic injury in obese mice. It is possible that inhibition of cell proliferation by vitamin D in high-fat conditions limits vascular regeneration and recovery from peripheral ischemia in obesity.

Modelling of intracranial behaviour on occiput impact in judo.

Acute subdural hematoma (ASDH) sometimes occurred in judo because of the bridging veins' failure by rotation of the brain in the skull. However, the relationship between intracranial behaviour and the motion of the body on occiput impact has not yet been clarified. In this study, we developed an intracranial mechanical model based on multibody dynamics and compared it with experimental results. The results show the importance of modelling bridging veins and cerebral spinal fluid to the relative displacement between brain and skull. The proposed model will contribute to accident analyses or the optimum design of supporting devices.

A randomised controlled trial comparing venous stenting with conservative treatment in patients with deep venous obstruction: research protocol.

INTRODUCTION: Deep venous obstruction (DVO) has a great impact on quality of life (QoL) comparable to angina pectoris or chronic pulmonary disease. Post-thrombotic scar formation and May-Thurner syndrome (MTS) are the most common causes of DVO. Conventional treatment of DVO focuses on reducing pain or leg swelling by use of (pain) medication and therapeutic elastic stockings. In the past, a venous bypass was offered in severe post-thrombotic cases, but this procedure showed bad clinical and patency outcomes. With the introduction of percutaneous angioplasty and dedicated venous stents new opportunities were created. Deep venous stenting has been shown to be effective in retrospective case series. However, there is no prior research in which QoL after interventional treatment is compared with QoL after conventional treatment. Currently, there is a debate about the true additional value of interventional treatment. We investigate whether those patients who are treated with stenting experience a change in short form 36 (SF-36) and the Veines-QoL/Sym questionnaires compared with conventionally treated patients. METHODS AND ANALYSIS: This is a randomised trial comparing conservative deep venous management to interventional treatment. A total of 130 patients with post-thrombotic syndrome (PTS) or MTS, eligible for interventional percutaneous treatment, who did not have previous deep venous intervention will be included. Patients will be randomised to conservative treatment or venous stenting and stratified for the PTS or MTS subgroup. Conservative treatment consists of either one or a combination of pain medications, manual lymphatic drainage, compression stockings and regular post-thrombotic anticoagulant therapy.The primary outcome is the QoL change after 12 months compared with baseline QoL. Secondary outcomes are QoL changes at 6 weeks, clinical assessment of DVO, recurrence rate of deep venous thrombosis at 6 weeks and 12 months, and the total amount of working days lost. Intervention-specific outcomes include complications and patency. ETHICS AND DISSEMINATION: The protocol is approved by the Medical Ethics Committee of Academisch ziekenhuis Maastricht/Universiteit Maastricht, The Netherlands (protocol number NLNL55641.068.15 / METC 161008).We aim to publish the results of this study in a peer reviewed journal and present our findings at national or international conferences. TRIAL REGISTRATION NUMBER: The study protocol was registered at www.clinicaltrials.gov (registration number: NCT03026049) on 17 January 2017.

Hyperbaric oxygen inhibits venous neointimal hyperplasia following arteriovenous fistulization.

Hypoxia following arteriovenous fistulization results in venous neointimal hyperplasia (VNH), potentially causing early arteriovenous fistula (AVF) dysfunction. In this study, we used hyperbaric oxygen (HBO) in a rabbit model of AVF to determine whether it could ameliorate early AVF failure. Chronic renal failure was induced by adenine in 96 adult rabbits randomly divided into 3 groups (n=32 in each group). The sham + HBO group underwent sham operation and received HBO. The AVF alone group underwent fistulization, but did not receive HBO. The AVF + HBO group underwent fistulization and received HBO. Each group was further divided into 4 subgroups of 8 rabbits each that were euthanized at 1, 7, 14 or 28 days post-operatively. At each time point, blood flow changes in the AVF venous segment were detected using a high-frequency duplex ultrasonography system. Immunohistochemical staining for proliferating cell nuclear antigen (PCNA), and hematoxylin and eosin staining were performed to evaluate VNH. Western blot analysis was performed to confirm the expression of hypoxia-inducible factor (HIF)-1α. At 14 and 28 days following HBO treatment, blood flow in the AVF + HBO group was greater than that at day 0. The AVF + HBO group had a smaller ratio of intima to media area, a lower HIF-1α protein expression, and a smaller percentage of PCNA-positive cells in the proximal vein than did the AVF alone group. Our results thus suggest that continuous HBO treatment following AVF significantly inhibits VNH and promotes blood flow. Therefore, early AVF failure may be prevented by the use of HBO therapy.

In vivo biodistribution, biocompatibility, and efficacy of sorafenib-loaded lipid-based nanosuspensions evaluated experimentally in cancer.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. In this study, sorafenib-loaded lipid-based nanosuspensions (sorafenib-LNS) were first developed as an intravenous injectable formulation to increase the efficacy of sorafenib against HCC. LNS were used as nanocarriers for sorafenib owing to their desired features in increasing the solubility and dissolution velocity, improving the bioavailability of sorafenib. Sorafenib-LNS were prepared by nanoprecipitation and consisted of spherical particles with a uniform size distribution (164.5 nm, polydispersity index =0.202) and negative zeta potential (-11.0 mV). The drug loading (DL) was 10.55%±0.16%. Sorafenib-LNS showed higher in vitro cytotoxicity than sorafenib against HepG2 cells (P<0.05) and Bel-7402 cells (P<0.05). The in vivo biodistribution, biocompatibility, and antitumor efficacy of sorafenib-LNS were evaluated in H22-bearing liver cancer xenograft murine model. The results showed that sorafenib-LNS (9 mg/kg) exhibited significantly higher antitumor efficacy by reducing the tumor volume compared with the sorafenib oral group (18 mg/kg, P<0.05) and sorafenib injection group (9 mg/kg, P<0.05). Furthermore, the results of the in vivo biodistribution experiments demonstrated that sorafenib-LNS injected into H22 tumor-bearing mice exhibited increased accumulation in the tumor tissue, which was confirmed by in vivo imaging. In the current experimental conditions, sorafenib-LNS did not show significant toxicity both in vitro and in vivo. These results suggest that sorafenib-LNS are a promising nanomedicine for treating HCC.

Effects of pulsed electromagnetic fields on peripheral blood circulation in people with diabetes: A randomized controlled trial.

Cutaneous blood flow provides nourishment that plays an essential role in maintaining skin health. We examined the effects of pulsed electromagnetic fields (PEMFs) on cutaneous circulation of dorsal feet. Twenty-two patients with diabetes mellitus (DM) and 21 healthy control subjects were randomly allocated to receive either PEMFs or sham PEMFs (0.5 mT, 12 Hz, 30 min). Blood flow velocity and diameter of the small vein were examined by using ultrasound biomicroscopy; also, microcirculation at skin over the base of the 1st metatarsal bone (Flux1) and distal 1st phalange (Flux2) was measured by laser Doppler flowmetry before and after intervention. Results indicated that PEMFs produced significantly greater changes in blood flow velocity of the smallest observable vein than did sham PEMFs (both P < 0.05) in both types of subjects. However, no significant difference was found in changes of vein diameter, nor in Flux1 and Flux2, between PEMFs and sham PEMFs groups in subjects with or without DM. We hypothesized that PEMFs would increase blood flow velocity of the smallest observable vein in people with or without DM. Bioelectromagnetics. 37:290-297, 2016. © 2016 Wiley Periodicals, Inc.

Venous Invasion in Colorectal Cancer: Impact of Morphologic Findings on Detection Rate.

PURPOSE: Venous invasion (VI) is widely accepted as a poor prognostic factor in colorectal cancer (CRC), and is indicated as a high-risk factor determining the use of adjuvant chemotherapy in CRC. However, there is marked interobserver and intraobserver variability in VI identification and marked variability in the real prevalence of VI in CRC. MATERIALS AND METHODS: We investigated the detection rate of VI in 93 consecutive cases of T3 or T4 CRC based on the following: original pathology report, review of hematoxylin and eosin (H&E) slides with attention to the "protruding tongue" and "orphan arteriole" signs, and elastic stain as the gold standard. RESULTS: Overall, the detection rate of VI was significantly increased as follows: 14/93 (15.1%) in the original pathology report, 38/93 (40.9%) in review of H&E slides with attention to the "protruding tongue" and "orphan arteriole" signs, and 45/93 (48.4%) using elastic stain. VI detection based on morphologic features showed 77.8% sensitivity and 91.1% specificity and showed a linear correlation (Spearman correlation coefficient, 0.727; p < 0.001) with VI detected by elastic stain. In addition, improved agreement between detection methods (detection on the basis of morphologic features, κ=0.719 vs. original pathology report, κ=0.318) was observed using kappa statistics. CONCLUSION: Slide review with special attention to the "protruding tongue" and "orphan arteriole" signs could be used for better identification of VI in CRC in routine surgical practice.

Idiopathic mesenteric phlebosclerosis associated with long-term use of medical liquor: two case reports and literature review.

A 62-year-old woman was admitted to our hospital in 2011 because of recurrent abdominal pain, nausea and constipation for six months. Computed tomography enterography (CTE) showed tortuous thread-like calcifications in the ileocolic vein and right colic vein, while colonoscopy revealed purple-blue mucosa extending from the cecum to the splenic flexure. Based on the results of these tests, the patient was diagnosed with idiopathic mesenteric phlebosclerosis (IMP). She had a history of Chinese medical liquor intake for one and a half years and her symptoms subsided after conservative treatment. In 2013, a 63-year-old male patient who presented with recurrent lower right abdominal pain, bloating, melena and diarrhea for fifteen months was admitted to our institution. Colonoscopy and CTE led to the diagnosis of IMP. He also used Chinese medical liquor for approximately 12 years. The patient underwent total colectomy and the postoperative course was uneventful. We searched for previously published reports on similar cases and analyzed the clinical data of 50 cases identified in PubMed. As some of these patients admitted use of Chinese medicines, we hypothesize that Chinese medicines may play a role in the pathogenesis of IMP.

Iatrogenic venous thrombosis secondary to supplemental medicine toxicity.

OBJECTIVE: We described a case of cerebral venous sinus thrombosis in a patient taking multiple supplements as part of a naturopathic anti-aging regimen. METHODS: Case report. RESULTS: The patient presented with a thalamic infarct associated with a thrombus in the vein of Galen. He reported no previous history of endocrinopathy and no known hypercoagulability risk factors. He was treated with therapeutic anticoagulation resulting in improvement. Diagnostic workup revealed hyperthyroidism and gonadotrophic deficiency attributed to significant supplement medicine usage. CONCLUSION: This case highlights a potential risk of dietary supplements. Use of these supplements may be a risk factor for idiopathic cerebral venous thrombosis.

Development of intravenous lipid emulsion of α-asarone with significantly improved safety and enhanced efficacy.

Severe adverse events have been frequently associated with taking the commercially available formulation of α-asarone injection (α-asarone-I). Hence, we sought to develop an intravenous lipid emulsion of α-asarone (α-asarone-LE), where we hypothesized that these adverse events could be prevented. Using a central composite design-response surface methodology, we developed and optimized an emulsion formulation of α-asarone-LE that composed of 10.0% (w/v) soybean oil, 0.4% (w/v) α-asarone, 1.2% (w/v) soybean lecithin, 0.3% (w/v) F68, and 2.2% (w/v) glycerol. The mean particle size of α-asarone-LE was 226±11 nm, the ζ-potential was -25.6±1.2 mV, the encapsulation efficiency was 99.2±0.1% and the drug loading efficiency was 3.45%. Stability, safety, and efficacy studies of α-asarone-LE were systematically investigated and compared to those of α-asarone-I. The α-asarone-LE not only showed a desired stability, but also exhibited excellent safety and improved efficacy in vivo, indicating its great potential for clinical application in the future.

[Characteristics of sublingual vein and expressions of vascular endothelial growth factor and hypoxia-inducible factor 1alpha proteins in sublingual tissues of Beagle dogs with portal hypertension].

OBJECTIVE: To observe sublingual vein characteristics and the expressions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha (HIF-1alpha) proteins in sublingual tissues of Beagle dogs with cirrhotic portal hypertension. METHODS: Twelve Beagle dogs were randomly divided into normal control group and cirrhotic portal hypertension group. There were 6 dogs in each group. A canine model of cirrhosis portal hypertension was established by injecting dimethylnitrosamine (DMN) into portal vein once a week for 7 weeks. The characteristics of sublingual vein were observed. Portal venous pressure was measured by using bioelectric recording techniques. The expressions of VEGF and HIF-1alpha proteins in sublingual vein were detected by immunohistochemical method. RESULTS: The shape and color of sublingual vein in beagle dogs in the cirrhotic portal hypertension group changed obviously as compared with the normal control group. Immunohistochemical results showed that there were almost no expressions of VEGF and HIF-1alpha proteins in sublingual tissues in the normal control group; however, the expressions of VEGF and HIF-1alpha proteins in sublingual tissues in the cirrhotic portal hypertension group significantly increased. CONCLUSION: Changes of portal pressure may lead to the formation of the abnormal sublingual vein by increasing the expressions of VEGF and HIF-1alpha proteins in sublingual tissues in Beagle dogs with portal hypertension.

Histological results of sclerotherapy, phototherapy, and pulsed 980-nm laser irradiation of the dorsal rabbit ear vein.

OBJECTIVE: To compare the histological changes occurring after three different treatment modalities for telangiectasias. MATERIALS AND METHODS: Thirty 16-week-old New Zealand white rabbits weighing 2.4-3.1 kg were enrolled in the study. The rabbits were divided into three groups. The group 1 received sclerotherapy, he group 2 received phototherapy, and group 3 received high-power diode laser treatments. All animals were treated on the right dorsal marginal ear vein. Biopsies were taken on days 1, 2, 7, and 30 post-treatment, and histopathogical evaluation was performed. RESULTS: Clinical and histological thrombosis occurred between days 1 and 7 in all groups. Superficial necrosis, neutrophil infiltration, and recanalization were mostly seen in group 3, whereas thrombosis was prominent in groups 1 and 2. CONCLUSIONS: All of the methods tested appear to have similar mechanisms of action, but had differing clinical and histological results. Phototherapy and laser treatment are non-invasive and do not require an exact, pinpoint technique, in contrast to sclerotherapy. However, sclerotherapy and phototherapy showed better results, especially with regard to recanalization.

A lipid microsphere vehicle for vinorelbine: Stability, safety and pharmacokinetics.

A lipid microsphere vehicle for vinorelbine (VRL) was designed to reduce the severe venous irritation caused by the aqueous intravenous formulation of VRL. Lipid microspheres (LMs) were prepared by high pressure homogenization. The physical stability was monitored by the appearance, particle size and zeta potential changes while the chemical stability was achieved by using effective antioxidants and monitored by long-term investigations. Safety tests were performed by testing rabbit ear vein irritation and a guinea pig hypersensitivity reaction. A pharmacokinetic study was performed by determining the drug levels in plasma up to 24h after intravenous administration of VRL-loaded LMs and conventional VRL aqueous injection separately. The VRL-loaded LMs had a particle size of 180.5+/-35.2nm with a 90% cumulative distribution less than 244.1nm, while the drug entrapment efficiency was 96.8%, and it remained stable for 12 months at 6+/-2 degrees C. The VRL-loaded LMs were less irritating and toxic than the conventional VRL aqueous injection. The pharmacokinetic profiles were similar and the values of AUC(0-t) were very close for the two formulations. A stable and easily mass-produced VRL-loaded LM preparation has been developed. It produces less venous irritation and is less toxic but has similar pharmacokinetics in vivo to the VRL aqueous injection currently commercially available.

Formulation and evaluation of nimodipine-loaded lipid microspheres.

The purpose of this study was to develop an alternative, improved and better tolerated formulation and investigate the pharmacokinetic profile of the new formulation of nimodipine (NM) compared with nimodipine ethanol solutions. Lipid microspheres (LMs) prepared using lecithin and vegetable oils have attracted a lot of interest owing to their versatile properties, such as non-immunogenicity, being easily biodegradable and exhibiting high entrapment efficiency. NM incorporated in LMs could reduce irritation by avoiding the use of ethanol as a solubilizer. The solubility of NM was also increased by dissolving it in the oil phase. The particle size distribution, zeta potential, entrapment efficacy and assay of the NM-loaded LMs were found to be 188.2+/-5.4 nm, -31.6 mV, 94.2% and 1.04 mg mL(-1), respectively. The preparation was stable for 1 year at 4-10 degrees C. The formulation and some physicochemical properties of NM-loaded LMs were investigated. The pharmacokinetic and biodistribution studies were performed in rats at a dose of 1.2 mg kg(-1). From the observed data, there is no obvious retention of NM-loaded LMs in plasma. Moreover, incorporation of NM in LMs did not alter the tissue distribution significantly except for the relatively greater drug accumulation in the liver and spleen. The stimulation studies demonstrate that LMs of NM reduce irritation markedly compared with NM solutions. These results suggest that the LM system is a promising option to replace NM ethanol solutions as an intravenous treatment.

[Correlation between the width of lingual vein and the changes of hemodynamics of portal system in patients with primary liver cancer].

OBJECTIVE: To explore the correlation between the width of lingual varix and changes of hemodynamics of portal system in patients with primary liver cancer so as to supply the data for the forecast of portal hypertension by observing lingual varix. METHODS: The diameter of lingual vein (Dlv) was measured by vernier caliper as dependent variable, and the diameters and indexes of hemodynamics of portal vessels were measured by Doppler as independent variables, then a multipe stepwise analysis was performed. RESULTS: The diameters of portal vein (Dpv) and splenic vein (Dsv) entered the formula Dlv (mm) = 0.185 + 0.311 Dsv (mm) + 0.236 Dpv (mm) when the entry and removal values were alpha(in)=0.10 and alpha(out)=0.15, respectively. CONCLUSION: The width of lingual vein is closely correlated with the diameters of portal vein and splenic vein in patients with primary liver cancer.

[Characteristics of sublingual venae in primary liver cancer patients in different clinical stages].

OBJECTIVE: To explore the characteristics of the sublingual venae in patients with primary liver cancer (PLC). METHODS: The shape, color and the red, green and blue values of the sublingual venae were analyzed quantitatively for PLC patients in different clinical stages by analysis system for comprehensive information of tongue diagnosis. RESULTS: With the aggravating of the disease, the patients' sublingual venae became wide and tortuous, and their color became blue and purple. The abnormality of the sublingual venae was more serious in clinical stage III than in stages I and II (P < 0.05). CONCLUSION: The shape, color and abnormality degree of the sublingual venae in patients with PLC in different clinical stages are distinct.