Effect of renin-angiotensin system inhibitors on pemetrexed plus platinum-induced hematological toxicities: a multicenter retrospective study using three propensity score analyses.

Hematological toxicities induced by pemetrexed plus platinum therapy remain a critical issue in clinical practice. We hypothesized that inhibition of the renin-angiotensin system (RAS) can ameliorate pemetrexed-induced hematological toxicities through drug-drug interactions involving organic anion transporters. Thus, this study aimed to clarify whether RAS inhibitors (RASIs) could prevent pemetrexed plus platinum-induced hematological toxicities. We retrospectively analyzed data from 305 consecutive patients with non-small cell lung cancer or malignant pleural mesothelioma who received their first cycle of a pemetrexed plus platinum regimen and were treated with or without RASIs. The primary endpoint was the incidence of severe myelosuppression after the first cycle. Propensity score (PS)-matched, PS-adjusted, and inverse probability of treatment weighting (IPTW) analyses were used. The number of patients with grade ≥3 hematological toxicities was 27 (8.9%). PS-matched analyses revealed that the concomitant use of RASIs was slightly associated with a lower risk of grade ≥3 hematological toxicities (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.20-2.32; p = 0.536). Additionally, sensitivity analyses using PS-adjusted and IPTW methods demonstrated similar results (OR, 0.63; 95% CI, 0.19-2.15; p = 0.463 and OR, 0.37; 95% CI, 0.11-1.29; p = 0.117, respectively). These findings suggest that RASIs might prevent pemetrexed plus platinum-induced hematological toxicities.

Harvesting epithelial keratinocyte sheets from temperature-responsive dishes preserves basement membrane proteins and improves cell survival in a skin defect model.

Cultured epithelial autograft (CEA) therapy has been used in clinical applications since the 1980s. However, there are some issues related to this treatment that still remain unsolved. Enzymatic treatment is typically used in the collection of epithelial keratinocyte sheets, but it tends to break the adhesion and basement membrane proteins. It is thought that the loss of proteins after enzymatic treatment is responsible for the poor survival of transplanted cell sheets. Our laboratory has developed a temperature-responsive culture dish that does not require enzymatic treatment to harvest the cells. In this study, we compare morphological and survival results from rat epithelial keratinocyte cell sheets harvested by temperature-reducing treatment (TT sheets) against cell sheets harvested by enzymatic (dispase) treatment (DT sheets). TT sheets preserve keratin structure in better conditions and express higher levels of collagen IV and laminin 5 than DT sheets. In order to evaluate cell sheet survival after transplantation, we created an in vivo transplant model. Keratinocyte sheets obtained from GFP-positive animals were transplanted into athymic rats. The survival rate 7 days after transplantation of TT sheet was higher than that of DT sheets. Collagen IV and Laminin 5 expression was observed in the TT sheet transplantation group. These results indicate that the remaining basement membrane proteins are important for initial attachment and cell survival. We believe that the cell sheet harvesting method using temperature-responsive culture dishes provides superior cell survival and can solve one of the roadblocks in CEA therapy. Copyright © 2016 John Wiley & Sons, Ltd.

Linker regions and flexibility around the metalloprotease domain account for conformational activation of ADAMTS-13.

BACKGROUND: Recently, conformational activation of ADAMTS-13 was identified. This mechanism showed the evolution from a condensed conformation, in which the proximal MDTCS and distal T2-CUB2 domains are in close contact with each other, to an activated, open structure due to binding with von Willebrand factor (VWF). OBJECTIVES: Identification of cryptic epitope/exosite exposure after conformational activation and of sites of flexibility in ADAMTS-13. METHODS: The activating effect of 25 anti-T2-CUB2 antibodies was studied in the FRETS-VWF73 and the vortex assay. Cryptic epitope/exosite exposure was determined with ELISA and VWF binding assay. The molecular basis for flexibility was hypothesized through rapid automatic detection and alignment of repeats (RADAR) analysis, tested with ELISA using deletion variants and visualized using electron microscopy. RESULTS: Eleven activating anti-ADAMTS-13 antibodies, directed against the T5-CUB2 domains, were identified in the FRETS-VWF73 assay. RADAR analysis identified three linker regions in the distal domains. Interestingly, identification of an antibody recognizing a cryptic epitope in the metalloprotease domain confirmed the contribution of these linker regions to conformational activation of the enzyme. The proof of flexibility around both the T2 and metalloprotease domains, as shown by by electron microscopy, further supported this contribution. In addition, cryptic epitope exposure was identified in the distal domains, because activating anti-T2-CUB2 antibodies increased the binding to folded VWF up to ~3-fold. CONCLUSION: Conformational activation of ADAMTS-13 leads to cryptic epitope/exosite exposure in both proximal and distal domains, subsequently inducing increased activity. Furthermore, three linker regions in the distal domains are responsible for flexibility and enable the interaction between the proximal and the T8-CUB2 domains.

Electron reemission processes following photoelectron recapture due to post-collision interaction in inner-shell photoionization of water molecules.

Electron reemission following photoelectron recapture due to post-collision interaction has been studied at 0.7 eV the inner-shell photoionization threshold of water molecules, using a multi-electron coincidence method. Electron reemissions after single Auger decay occur from O and OH fragments which are produced by the dissociations of high-n Rydberg H2O(+) states populated through photoelectron recapture. In addition, electron reemissions after double Auger decay are identified in triple coincidence events, where autoionization lines from O and O(+) fragments are observed.

Single photon K(-2) and K(-1)K(-1) double core ionization in C(2)H(2n) (n=1-3), CO, and N(2) as a potential new tool for chemical analysis.

We have observed single photon double K-shell photoionization in the C(2)H(2n) (n=1-3) hydrocarbon sequence and in N(2) and CO, using synchrotron radiation and electron coincidence spectroscopy. Our previous observations of the K(-2) process in these molecules are extended by the observations of a single photon double photoionization with one core hole created at each of the two neighboring atoms in the molecule (K(-1)K(-1) process). In the C(2)H(2n) sequence, the spectroscopy of K(-1)K(-1) states is much more sensitive to the bond length than conventional electron spectroscopy for chemical analysis spectroscopy based on single K-shell ionization. The cross section variation for single photon K(-1)K(-1) double core ionization in the C(2)H(2n) sequence and in the isoelectronic C(2)H(2n), N(2) and CO molecules validates a knock-out mechanism in which a primary ionized 1s photoelectron ejects another 1s electron of the neighbor atom. The specific Auger decay from such states is clearly observed in the CO case.

Communication: Formation of slow electrons in the Auger decay of core-ionized water molecules.

Double Auger decay of O1s(-1) and its satellite states in H(2)O has been studied with a multi-electron coincidence method, and a process leading to autoionizing O* fragments has been revealed. The breaking of the two O-H bonds producing the autoionizing O* fragments occurs for highly excited H(2)O(2+) populated by the initial Auger decay. The O* fragments are more favorably produced in the decay from the satellite states, resulting from the larger population of highly excited H(2)O(2+) states inheriting the valence excitation in the initial state.

Prospective randomised comparative study of visual foam sclerotherapy alone or in combination with ultrasound-guided foam sclerotherapy for treatment of superficial venous insufficiency: preliminary report.

OBJECTIVE: The aim of the study is to compare ultrasound-guided foam sclerotherapy (UGFS: injection of foam sclerosant under ultrasound guidance) of the great saphenous vein (GSV) combined with visual foam sclerotherapy (VFS: injection of foam sclerosant under visual control) for varicose tributary veins and VFS alone in the treatment of GSV reflux. DESIGN AND METHODS: A total of 133 limbs in 97 patients with GSV reflux were randomised to receive either VFS alone or VFS combined with UGFS. In both groups, 1% polidocanol foam was used. Assessments included duplex ultrasonography, evaluation of Venous Clinical Severity Scores (VCSS) and CEAP (clinical, etiologic, anatomic, and pathophysiologic) scores. Ultrasonographic inspection of the foam in the GSV was carried out during 5 min before compression was applied. The primary 'end' point of the study was obliteration of the GSV at 6 months. RESULTS: A total of 51 limbs in 48 patients were treated with UGFS + VFS and the remaining 52 limbs in 49 patients were treated with VFS alone. There were no significant inter-group differences in patient age, male: female ratio, height, weight, body mass index, CEAP clinical scores or VCSS. The GSV diameter was 6.0 ± 1.7 mm (median ± interquartile range) in the UGFS + VFS group and 5.7 ± 1.6 mm in the VFS group (p = 0.419). The mean injected volume of foam for varicose tributary veins was 4 ± 2 ml in the UGFS + VFS group and 6 ± 2 ml in the VFS group, a significantly higher amount of foam being used in the latter (p < 0.001). However, the mean total amount of foam was greater in limbs treated with UFGS + VFS than in those treated with VFS alone (p = 0.017). Ultrasonographic inspection revealed complete vasospasm of the GSV in 37 (72.5%) limbs in the UGFS + VFS group and 29 (55.8%) in the VFS group during sclerotherapy (p = 0.097). At 6-month follow-up, complete occlusion was found in 23 limbs (45.1%) treated with UGFS + VFS and in 22 limbs (42.3%) treated with VFS. The difference between the two groups was not significant (p = 0.775). Reflux was absent in 30 limbs (58.8%) treated with UGFS + VFS and in 37 (71.2%) treated with VFS (p = 0.190). There was no inter-group difference in post-treatment VCSS (p = 0.223). CONCLUSIONS: These results show that UGFS + VFS and VFS are equally effective for the treatment of GSV reflux, despite the lower volume of foam used for VFS alone.

Evidence of single-photon two-site core double ionization of C2H2 molecules.

We observe the formation in a single-photon transition of two core holes, each at a different carbon atom of the C2H2 molecule. At a photon energy of 770.5 eV, the probability of this 2-site core double ionization amounts to 1.6 ± 0.4% of the 1-site core double ionization. A simple theoretical model based on the knockout mechanism gives reasonable agreement with experiment. Spectroscopy and Auger decays of the associated double core hole states are also investigated.

Energy correlation among three photoelectrons emitted in core-valence-valence triple photoionization of Ne.

The direct observation of triple photoionization involving one inner shell and two valence electrons is reported. The energy distribution of the three photoelectrons emitted from Ne is obtained using a very efficient multielectron coincidence method using the magnetic bottle electron spectroscopic technique. A predominance of the direct path to triple photoionization for the formation of Ne3+ in the 1s 2s2 2p4 configuration is observed. It is demonstrated that the energy distribution evolves with photon energy and indicates a significant difference with triple photoionization involving only valence electrons.

Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan.

Upshaw-Schulman syndrome (USS) is an extremely rare hereditary deficiency of ADAMTS13 activity, termed congenital TTP. The clinical signs are usually mild during childhood, often with isolated thrombocytopenia. But their symptoms become more evident when patients have infections or get pregnant. We identified 43 USS-patients in Japan, who ranged in age from early childhood to 79 years of age. Analysing the natural history of these USS patients based on ADAMTS13 gene mutations may help characterise their clinical phenotypes. Severe neonatal jaundice that requires exchange blood transfusion, a hallmark of USS, was found in 18 of 43 patients (42%). During childhood, 25 of 43 patients were correctly diagnosed with USS without gender disparity. These 25 patients were categorised as having 'the early-onset phenotype'. Between 15 and 45 years of age, 15 were correctly diagnosed, and, interestingly, they were all female. The remaining three patients were male and were diagnosed when they were older than 45 years of age, suggesting that they were 'the late-onset phenotype'. Two of these three males developed sudden overt TTP when they were 55 and 63 years old, respectively. These two men had two different homozygous ADAMTS13 gene mutations, p.R193W/p.R193W and p.C1024R/p.C1024R, respectively. Both of which were not discovered in the US or Western countries. In vitro expression studies showed that these two proteins were consistently secreted into the culture medium but to a lesser extent and with reduced activity compared to the wild-type protein. Our results indicate that 'the late-onset phenotype' of USS is formed with ethnic specificity.

Properties of hollow molecules probed by single-photon double ionization.

The formation of hollow molecules (with a completely empty K shell in one constituent atom) through single-photon core double ionization has been demonstrated using a sensitive magnetic bottle experimental technique combined with synchrotron radiation. Detailed properties are presented such as the spectroscopy, formation, and decay dynamics of the N(2)(2+) K(-2) main and satellite states and the strong chemical shifts of double K holes on an oxygen atom in CO, CO2, and O2 molecules.

Factors predicting development of post-thrombotic syndrome in patients with a first episode of deep vein thrombosis: preliminary report.

OBJECTIVE: To investigate the indicative parameters reflecting the progression of post-thrombotic syndrome (PTS) in patients with a first episode of deep vein thrombosis (DVT). DESIGN AND METHODS: The patients' initial risk factors were assessed at presentation. Venous occlusion, and reflux and reflux parameters were evaluated at 6 months using venous duplex scanning. Near-infrared spectroscopy (NIRS) was also used to measure calf muscle deoxygenated haemoglobin levels at 6 months. Clinical manifestations were categorised using the clinical, etiologic, anatomic and pathophysiologic (CEAP) classification for chronic venous insufficiency (CVI), and the patients were divided into those having no PTS (C(0-3S),E(s),A(s,d,p),P(r,o)) and those having PTS (C(4-6S),E(s),A(s,d,p),P(r,o)). RESULTS: Of the 121 patients evaluated, 25 (21%) developed PTS with a mean follow-up period of 66 months. At initial presentation, ilio-femoral DVT (odds ratio (OR) 3.4, 95% confidence interval (CI) 1.4-8.6) was associated with development of PTS. At 6 months, venous occlusion combined with reflux (OR 4.4, 95% CI 2.9-20.7), peak reflux velocity >29.7 cm s(-1) (OR 13.7, 95% CI 4.1-45.7) and mean reflux velocity >8.6 cm s(-1) (OR 4.4, 95% CI 1.5-12.9) in the popliteal vein detected by duplex scanning were strong predictors of PTS. NIRS-derived retention index >3.5 was the strongest predictor of PTS at 6 months (OR 67.4, 95% CI 14.3-318.1). CONCLUSIONS: Ilio-femoral DVT is associated with the development of PTS at initial presentation. By contrast, occlusion and reflux, high reflux velocity in the popliteal vein and increased NIRS-derived retention index are important time-course predictors of PTS progression.

Advanced chronic venous insufficiency is associated with increased calf muscle deoxygenation.

OBJECTIVE: To determine the temporal relationship between changes in calf muscle deoxygenated haemoglobin (HHb) measured by near-infrared spectroscopy (NIRS) during light-intensity exercise and clinical stages of chronic venous insufficiency (CVI). DESIGN AND METHODS: Calf muscle HHb level was obtained in 168 limbs of 158 patients with various clinical stages of CVI. Clinical manifestations were categorised according to the CEAP classification (CEAP, clinical, etiological, anatomical and pathophysiological), and the patients were divided into two groups: early CVI (C(0-3),E(p)(,s),A(s)(,d,p),P(r)(,o)) and advanced CVI (C(4-6),E(p)(,s), A(s)(,d,p),P(r)(,o)). Calf venous blood-filling index (FI-HHb) was calculated on standing, then the calf venous ejection index (EI-HHb) was obtained after one tiptoe movement and the venous retention index (RI-HHb) after 10 tiptoe movements. RESULTS: A total of 116 limbs had early, and 52 had advanced CVI. FI and RI were significantly increased in patients with advanced CVI compared with those with early CVI (P = 0.003, 0.0001, respectively). Similarly, RI was significantly greater in patients who had superficial, combined with deep and/or perforator, insufficiency than in patients with superficial insufficiency alone (P = 0.002). RI showed the strongest correlation with duplex-derived peak reflux velocity in the popliteal vein (r = 0.78, P < 0.0001). Combination of an optimal cut-off point of 0.2 for FI and 2.9 for RI improved the ability to discriminate early from advanced CVI, with a sensitivity of 94% and a specificity of 86%. CONCLUSIONS: These results suggest that FI and RI, as measured by NIRS, may be promising parameters for discriminating early CVI from advanced CVI.

Prognostic impact of calf muscle near-infrared spectroscopy in patients with a first episode of deep vein thrombosis.

BACKGROUND: The risk factors that affect the development of post-thrombotic syndrome (PTS) are not fully recognized, and it is difficult to reliably predict which patients are likely to develop PTS in acute phase of deep vein thrombosis (DVT). AIMS: To investigate changes in calf muscle deoxygenated hemoglobin (HHb) levels after DVT, and to determine the indicative parameters reflecting the progression of PTS. METHODS: Seventy-six consecutive patients with a first episode of unilateral DVT were prospectively enrolled. Clinical manifestations were categorized according to the CEAP (Clinical, Etiologic, Anatomical, and Pathophysiologic) classification, and the patients were divided into no-PTS (C(0-3)E(s),A(s,d,p),P(r,o)) and PTS (C(4-6)E(s),A(s,d,p),P(r,o)) groups. Near-infrared spectroscopy (NIRS) was used to measure calf muscle HHb levels at 6 months after diagnosis of DVT. The calf venous blood filling index (HHbFI) was calculated on standing, and the venous ejection index and the venous retention index (HHbRI) were then obtained after exercise. All patients were followed up for more than 24 months after the diagnosis of DVT. RESULTS: Of 76 patients evaluated, 20 (26.3%) had PTS. The NIRS-derived HHbFI and HHbRI were significantly increased in patients who developed PTS in comparison with those who did not (P = 0.04 and P = 0.0001, respectively). HHbRI was significantly increased in patients with iliofemoral DVT in comparison with patients with calf DVT (P = 0.041). An optimal cut-off point of 2.9 for HHbRI showed the strongest ability to predict the development of PTS, with a sensitivity of 100% and a specificity of 82.1%. CONCLUSIONS: HHbRI as measured by NIRS is significantly increased in patients with iliofemoral DVT as compared with those with calf DVT. Furthermore, HHbRI > 2.9 is a strong predictor of the development of PTS at 6 months.

Great saphenous vein sparing surgery by angioscopic valvuloplasty combined with axial transposition of a competent tributary vein--5-year follow-up.

OBJECTIVE: To evaluate the efficacy and haemodynamic effects of great saphenous vein (GSV) sparing surgery--valvuloplasty combined with axial transposition of a competent tributary vein (A-VACT). MATERIALS AND METHODS: Eighty-five limbs in 74 patients with isolated GSV incompetence were selected for GSV sparing surgery. After angiographic valvuloplasty, the competent tributary vein was exposed and cut 1.5 cm distal to its insertion point on the GSV. The transected vein was anastomosed end-to-side to the GSV, which was ligated between the tributary insertion site and the anastomosis. Venous valve competence were screened by serial postoperative duplex examination, and venous haemodynamic changes were analyzed using venous filling index (VFI) measured by air plethysmograph pre- and postoperatively. The follow-up period was 5-years. RESULTS: Sixty-seven patients were included in whom 76 limbs were treated. There was a statistically significant reduction in the vein diameter at the SFJ after 5-years (0.83 S.D. 0.29 cm to 0.46 S.D. 0.12 cm, p=0.0002, Wilcoxon). Similarly, significant reduction was found in the GSV at the 5-year follow-up point (0.63 S.D. 0.19 cm to 0.39 S.D. 0.11 cm, p<0.0001, Wilcoxon). On the other hand, there was significant increase in the diameter of the competent tributary vein postoperatively (0.22 S.D. 0.13 cm to 0.31 S.D. 0.12 cm, p<0.0001, Wilcoxon). Duplex scanning demonstrated reflux at the SFJ in 12 limbs (16%). Similarly, in the GSV, venous reflux was found in 13 limbs (17%). Reflux in the transposed tributary vein was found in 20 limbs (26%). But only 7 limbs (9%) had minor varicose veins' recurrence. VFI remained normal during the follow-up examination. The preoperative VFI confirmed the presence of venous reflux, but there were significant improvement in the VFI values at all postoperative examinations. CONCLUSIONS: A-VACT procedure improves venous function, resolves varicose veins at 5-years follow-up as well as preserving the GSV for future grafting.

Presence of lower limb deep vein thrombosis and prognosis in patients with symptomatic pulmonary embolism: preliminary report.

OBJECTIVES: To investigate the presence of lower limb deep vein thrombosis (DVT) and prognosis in patients with symptomatic pulmonary embolism (PE). MATERIALS AND METHODS: A total of 203 consecutive referral patients with PE were included. The distribution of DVT was evaluated with compression ultrasound (CUS), and all patients were then followed for 12 months for investigation of recurrence of venous thromboembolism (VTE) and fatal events as adverse outcome. RESULTS: The mean age of the patients was 62.8 years, and 78 (38.4%) were males. DVT was found in 118 (58.1%) patients. Of these patients, 61 (30.0%) had proximal DVT. Multivariate analysis demonstrated that active cancer, inadequate anticoagulation, leg symptoms, male gender, presence of DVT, presence of proximal DVT, and previous DVT were independent risk factors for adverse outcome. A clinical risk score ranging from 0 to 10 points was generated on the basis of multivariate regression coefficients. Receiver operating characteristic curve analysis showed that an appropriate cut-off point for discriminating between the presence and the absence of an adverse event was 4. Using this category, 166 (81.8%) patients were classified as low risk and 37 (18.2%) as high risk for adverse outcome. The adverse event rates were 6.0% for the low-risk group and 59.5% for the high-risk group. CONCLUSIONS: This study has confirmed the clinical significance of surveillance CUS in patients with a first episode of PE. Furthermore, a simple risk score on the basis of available variables can identify patients at risk of an adverse outcome in patients with PE.

Multiple small-dose injections can reduce the passage of sclerosant foam into deep veins during foam sclerotherapy for varicose veins.

OBJECTIVE: To compare the proportion of foam sclerosant that enters deep veins between multiple injections of <0.5 ml foam per injection and a few injections of >0.5 ml foam per injection. DESIGN & METHODS: One hundred and seven patients with superficial venous incompetence were randomised to receive either multiple injections of <0.5 ml 1% polidocanol (POL) -foam (multiple injections) or a few injections of >0.5 ml 1% POL-foam per injection (few injections) for the treatment of varicose tributaries. All patients then received ultrasound-guided foam sclerotherapy for refluxing great saphenous vein (GSV) using 3% POL-foam. Only a single session was allowed per patient in order to standardise treatment. Qualitative ultrasonographic inspection of the foam was carried out during a 5-min period before compression was applied. Post-sclerotherapy surveillance was done at day 3, 2 weeks, 1 month, 3 months, and 6 months. RESULTS: Fifty-six limbs in 53 patients were treated with multiple injections and the remaining 56 limbs in 54 patients were treated with a few injections. There were no significant differences in age or male:female ratio between the groups. The mean volume of 1% POL-foam was 2.2 S.D. 0.6 ml (range: 0.7-4.0 ml) in the multiple injections group and 2.5 S.D. 0.6 ml (range: 1.0-4.0 ml) in the few injections group (p=0.003). The mean volume of 3% POL was 1.5 ml (range: 0.7-3.0 ml) and 1.4 ml (range: 0.7-3.0 ml), respectively (p=0.137). Ultrasonographic inspection immediately after sclerotherapy demonstrated that foam was distributed significantly more commonly in the deep veins of patients treated with a few injections (p=0.0003). Two (4%) of the patients treated with a few injections developed migraine during the procedure, but recovered quickly with no further complications. There was no significant difference in the success rate between the groups at 6 months (p=0.257). CONCLUSIONS: These findings suggest that multiple small-dose injections can reduce the amount of foam sclerosant and the risk of foam sclerosant entering the deep veins in patients with superficial venous insufficiency.

Photosensitization reaction-induced electrical blockade in myocardial tissue.

We proposed the application of photodynamic therapy (PDT) as a new type of atrial fibrillation treatment. PDT is well known as a practical cancer treatment using cytotoxicity of reactive oxygen species generated by the photochemical interaction. We predicted that the photocytotoxic effect induced by PDT might cause electrical blockade in myocardial tissue. We studied the electrical blockade induced by the PDT with talaporfin sodium in vitro, ex vivo, and in vivo. The cell lethality measurement using rat cardiac myocytes confirmed the PDT-induced photocytotoxic effect and its dependence on the loading time of the photosensitizer. In ex vivo experiment using rat right ventricle, the PDT caused a shutdown of the stimulated electrical signal propagation. The long-lasting atrioventricular block induced by the PDT was obtained in vivo experiment with rat heart. These results revealed the possibility of atrial fibrillation treatment with the PDT.

Force-induced IL-8 from periodontal ligament cells requires IL-1beta.

During orthodontic tooth movement, mechanical stresses induce inflammatory reactions in the periodontal ligament (PDL). We hypothesized that chemokines released from PDL cells under mechanical stress regulate osteoclastogenesis, and investigated the profiles and mechanisms of chemokine expression by human PDL cells in response to mechanical stress. In vitro, shear stress and pressure force rapidly increased the gene and protein expressions of IL-8/CXCL8 by PDL cells. Consistently, amounts of IL-8 in the gingival crevicular fluid of healthy individuals increased within 2 to 4 days of orthodontic force application. The PDL cells constitutively expressed low levels of IL-1beta, which were not further increased by mechanical stress. Interestingly, neutralization of IL-1beta abolished IL-8 induction by mechanical stresses, indicating that IL-1beta is essential for IL-8 induction, presumably though autocrine or paracrine mechanisms. Finally, experiments with signal-specific inhibitors indicated that MAP kinase activation is essential for IL-8 induction.

High peak reflux velocity in the proximal deep veins is a strong predictor of advanced post-thrombotic sequelae.

BACKGROUND: The presence of reflux in the femoral vein (FV) and popliteal vein (POPV) after acute deep vein thrombosis (DVT) is considered to contribute to the development of advanced post-thrombotic syndrome (PTS). However, a quantification of reflux has yet to be determined. The purpose of study was to determine the indicative parameters reflecting the progression of PTS. METHODS: Venous abnormalities were evaluated in 131 limbs out of 130 patients who completed a six-year follow-up after an acute DVT. Clinical manifestations were categorized according to the clinical, etiologic, anatomic, and pathophysiologic (CEAP) classification, and the patients were divided into two groups at a six-year follow-up point: group I, C(0-3)E(s),A(s,d,p),P(r,o), early chronic venous insufficiency (CVI); group II, C(4-6)E(s),A(s,d,p),P(r,o), advanced CVI. Venous segments were examined whether they were occluded or recanalized. The reflux parameters assessed were the diameter (cm), the reflux time (RT; s), the peak reflux velocity (PRV; cm s(-1)), and total refluxed volume, and these parameters were assessed especially in the FV and POPV at the two-year (early phase) and subsequent six-year (late phase) follow-up points after DVT. RESULTS: There were 98 limbs in group I and 33 in group II. The frequency of venous reflux was significantly higher in group II (<0.0001). In contrast, the proportion of occlusion did not differ between the groups (P = 0.138). The proportions of FV and POPV incompetence were significantly higher in group II (P < 0.0001 and P < 0.0001, respectively). In these veins, the RT did not improve the discrimination power between the two groups. In contrast, the PRV had significant discrimination power in these veins at both the two- and six-year follow-up points. In the superficial venous system, there were no significant differences in any of the determined parameters between the groups. In group II, 19 patients (58%), who had early symptoms of CVI at the two-year follow-up point, subsequently developed advanced symptoms of PTS. After calculating a suitable cutoff point using receiver operating characteristic curves analysis at the two-year follow-up point, multivariable analysis showed that a PRV of >25.4 cm s(-1) in the POPV was the strongest independent predictor of advanced CVI [odds ratio (OR) 60.32; 95% confidence interval (95CI) 43.1-1238.97, P < 0.0001]. Similarly, in the FV, a PRV of >24.5 cm s(-1) was found to be a strong predictor of advanced CVI (OR 25.77, 95CI 10.56-331.12, P < 0.0001). CONCLUSIONS: These findings suggest that the presence of a high PRV in the proximal deep veins is an independent predictor of advanced symptoms of PTS.