OBJECTIVE: The aim of this study was to confirm the prognostic value of (201)Tl scintigraphy in the midcourse of preoperative chemotherapy in patients with osteosarcoma. METHODS: The 28 patients with biopsy-proven osteosarcoma were enrolled retrospectively in this study. Planar scintigraphy was performed 15 min after injection of 111 MBq (201)Tl before preoperative chemotherapy and after third course (midcourse) of chemotherapy in all patients. The (201)Tl uptake ratio was calculated by dividing the count density of the lesion by that of the contralateral normal area. The percentage reduction of the (201)Tl uptake ratio calculated by 100 × [(pre-chemotherapy ratio - mid-chemotherapy ratio)/pre-chemotherapy ratio] was compared with the histopathological response and long-term survival rate. RESULTS: Good histopathological response was observed in 16 patients. Mean follow-up period was 58.0 ± 41 months. Both overall and event-free survival rates of histopathologically good responders were significantly higher than that of poor responders (P = 0.018 and P = 0.0076). There was also significant correlation between pre-chemotherapeutic effect evaluated with (201)Tl scintigraphy and overall and event-free survival rate in all patients (P = 0.045 and P = 0.017, respectively), and in patients without metastasis at initial diagnosis (P = 0.043 and P = 0.031, respectively). CONCLUSION:(201)Tl scintigraphy performed in the middle of neoadjuvant chemotherapy can predict overall survival and event-free survival in patients with osteosarcoma.

To examine the effects of firefighters' self-contained breathing apparatus'(SCBA) weight and its harness design on the physiological and subjective responses, eight male students performed treadmill exercise under four conditions: the 8 kg firefighter protective clothing (PC)(Control), the PC + an 11 kg SCBA with an old harness (Test A), the PC + a 6.4 kg SCBA with an old harness (Test B) and the PC + a 6.4 kg SCBA with a new harness (Test C), at ambient temperatures (T (a)) of 22°C and 32°C. Besides highlighting the fact that a heavy SCBA had a significant effect on the oxygen consumption and metabolic rate, this experiment also found that in a T (a) of 32°C, in particular, the combined effect of 4.7 kg lighter SCBA and new harness design could reduce metabolic rate and improved subjective muscle fatigue and thermal discomfort. Practitioner Summary An effort to alleviate the physiological and subjective burden of firefighters by reducing the weight of SCBA and by using the new harness design has provided satisfactory results in reduced oxygen consumption and in improved subjective responses in a hot air environment.

Background: Advancement in chemotherapy has significantly improved the prognosis of cancer patients. However, many anticancer drugs have serious cardiovascular side effects. We assessed doxorubicin-induced cardiac toxicity (DCT) during and after preoperative chemotherapy using gated (99m)Tc-hexakis-2-methoxyisobutylisonitrile (MIBI) single photon emission computed tomography (SPECT) in patients with malignant bone and soft tissue tumors. Methods and Results: Gated (99m)Tc-MIBI SPECT was performed before, and after the middle and final courses of preoperative chemotherapy. Gated (99m)Tc-MIBI SPECT was quantitatively analyzed with QGS/QPS software. We also assessed the reproducibility of measurements of global and regional functions from gated SPECT images. Twenty-eight patients (19 males and 9 females), eligible for preoperative chemotherapy, were included. All patients had normal myocardial perfusion images based on QPS during preoperative chemotherapy. Wall thickening (WT) and motion (WM) decreased after the middle course of preoperative chemotherapy compared to baseline. After the final course of preoperative chemotherapy, significant decreases of ejection fraction, WT and WM, and one-third mean filling rate were observed compared to baseline. By regression analysis, correlation coefficients of inter- and intra-observer reproducibility of global and regional functions were excellent (r≥0.95). Conclusions: Gated (99m)Tc-MIBI SPECT can monitor the deterioration of cardiac function in asymptomatic patients with possible DCT. WT and WM might be useful as early markers of ventricular dysfunction due to DCT.

Factor (F)VIII can be activated to FVIIIa by FXa following cleavages at Arg372, Arg740 and Arg1689. FXa also cleaves FVIII/FVIIIa at Arg336 and Arg562 resulting in inactivation of the cofactor. These inactivating cleavages occur on a slower time scale than the activating ones. We assessed the contributions to cleavage rate and cofactor function of residues flanking Arg336, the primary site yielding FVIII(a) inactivation, following replacement of these residues with those flanking the faster-reacting Arg740 and Arg372 sites and the slower-reacting Arg562 site. Replacing P4-P3(') residues flanking Arg336 with those from Arg372 or Arg740 resulted in ~4-6-fold increases in rates of FXa-catalyzed inactivation of FVIIIa which paralleled rates of proteolysis at Arg336. Examination of partial sequence replacements showed a predominant contribution of prime residues flanking the scissile bonds to the enhanced rates. Conversely, replacement of this sequence with residues flanking the slow-reacting Arg562 site yielded inactivation and cleavage rates that were ~40% that of the WT values. The capacity for FXa to activate FVIII variants where cleavage at Arg336 was accelerated due to flanking sequence replacement showed marked reductions in peak activity, whereas reducing the cleavage rate at this site enhanced peak activity. Furthermore, plasma-based thrombin generation assays employing the variants revealed significant reductions in multiple parameter values with acceleration of Arg336 cleavage suggesting increased down-regulation of FXase. Overall, these results are consistent with a model of competition for activating and inactivating cleavages catalyzed by FXa that is modulated in large part by sequences flanking the scissile bonds.

BACKGROUND: Breast cancer has the potential to metastasize to bone, causing debilitating symptoms. Although many tumor cells have thrombin-generating systems originating from tissue factor (TF), therapy in terms of the coagulation system is not well established. To elucidate the efficacy of the thrombin inhibitor, argatroban, on bone metastasis, we investigated TF activation and vascular endothelial growth factor (VEGF) secretion on treatment with thrombin and argatroban. METHODS: MDA-231 breast cancer cells were treated with thrombin in presence or absence of argatroban, and TF activity was measured in the form of activated factor X. Enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF concentrations in the medium. MDA-231 cells were injected into the left heart ventricle of mice, and then argatroban or saline was administered intraperitoneally for 28 days. After 28 days, incidence of bone metastasis was evaluated in the limbs by radiography. RESULTS: TF activity and VEGF secretion were upregulated by thrombin. Argatroban inhibited the enhancement of TF activity and VEGF secretion induced by thrombin. In vivo analysis revealed that the number of metastasized limbs in the argatroban group was significantly lower compared with the saline group (P < 0.05). CONCLUSIONS: Thrombin not only enhances VEGF secretion but also has a positive feedback mechanism to reexpress TF. These results indicate that inhibition of thrombin is of great value in suppression of tumor metastasis. Argatroban is a noteworthy and useful thrombin inhibitor because it has already been used in the clinical setting and has antimetastatic effects in vivo.

Seventy-five patients underwent unilateral metal-on-metal total hip arthroplasty using a large-diameter head. Serum levels of cobalt and chromium were determined. Significant increases in both cobalt and chromium were observed at 3 months (cobalt, 1.4 μg/L; chromium, 1.4 μg/L) compared with preoperative values (P <.001). At 1 year, the median cobalt and chromium levels were 2.3 and 2.1 μg/L, respectively, and the levels had increased significantly compared with 3 months (P <.001). There were no significant differences between levels of either metal at 1 or 2 years (cobalt, 2.3 μg/L; chromium, 1.6 μg/L). Pseudotumor occurred in 2 hips. Patients with large-diameter metal-on-metal total hip arthroplasty had higher circulating metal ion levels at 3 months and 1 year, with no additional significant increases at 2 years.

Breast milk (BM) is the main source of human cytomegalovirus (HCMV) infection. We examined whether the number of HCMV DNA copies in BM is related to HCMV infection in very low birth weight (VLBW) infants. We identified 11 pairs of VLBW infants and mothers. BM samples were collected every week until 10 weeks postpartum. Urine samples were collected from the infants within 1 week, at 6 to 8 weeks, at discharge, and whenever HCMV infection was suspected. HCMV DNA in BM was positive in 7 of 11 mothers and reached a peak at 4 to 5 weeks postpartum. Of the 11, 5 infants were determined to be infected from positive HCMV DNA in the urine, despite the fact that BM was used after being frozen. Of the five, four infected infants exhibited symptoms between 35 and 60 days of age. Symptomatic infants had longer stays and slower weight gain. The HCMV infection rate is high in very preterm infants. A new strategy to prevent HCMV infection other than freezing should therefore be established.

The purpose of this study was to explore whether there is evidence of heat acclimatization in the words used to express thermal sensation. A total of 458 urban Japanese and 601 Indonesians participated in a questionnaire. In addition, in a preliminary survey, 39 native English speakers in the UK participated. Our results showed that (1) for Indonesians, the closest thermal descriptor of a feeling of thermal comfort was 'cool'(75%) followed by 'slightly cool'(7%),'slightly cold'(5%) and 'cold'(5%), while Japanese responses were distributed uniformly among descriptors 'cool','slightly cool','neither','slightly warm', and 'warm';(2) the closest thermal descriptors of a feeling of discomfort for Indonesians were less affected by individual thermal susceptibility (vulnerability) than those for Japanese;(3) in the cases where 'cool' and 'slightly cold' were imagined in the mind, the descriptors were cognized as a thermal comfortable feeling by 97% and 57% of Indonesians, respectively;(4) the most frequently voted choice endorsing hot weather was 'higher than 32°C' for Indonesians and 'higher than 29°C' for Japanese respondents; for cold weather,'lower than 15°C' for Japanese and 'lower than 20°C' for Indonesians. In summary, the descriptor 'cool' in Indonesians connotes a thermally comfortable feeling, but the inter-zone between hot and cold weather that was judged in the mind showed a upward shift when compared to that of Japanese. It is suggested that linguistic heat acclimatization exists on a cognitive level for Indonesians and is preserved in the words of thermal descriptors.

We evaluated hemostatic markers in patients who underwent major orthopedic surgery, including total hip and total knee arthroplasty, and were treated for the prophylaxis of deep vein thrombosis (DVT) with or without fondaparinux (anti-Xa group, n = 98 and without anti-Xa group, n = 20). The frequency of DVT was significantly higher in the without anti-Xa group than in the anti-Xa group, but the reduction of hemoglobin and fibrinolytic marker levels was significantly lower in the without anti-Xa group than in the anti-Xa group. Eighteen patients in the anti-Xa group showed a reduction in hemoglobin of more than 2 g/dl, and those individuals were considered to be the increased bleeding (IB) group. The concentration of fibrinolytic markers in the anti-Xa group was significantly higher in the IB group than in the non-IB group. There were also no significant differences in the levels of anti-Xa activity, plasminogen activator inhibitor-I, soluble fibrin and antithrombin between the IB and non-IB groups. In conclusion, elevated fibrinolysis induced by increased bleeding may lead to further increases in bleeding in patients receiving thromboprophylaxis with fondaparinux following major orthopedic surgery.

Factor (F) VIII functions as a cofactor in FXase, markedly accelerating the rate of FIXa-catalyzed activation of FX. Earlier work identified a FX-binding site having µM affinity within the COOH-terminal region of the FVIIIa A1 subunit. In the present study, surface plasmon resonance (SPR), ELISA-based binding assays and chemical cross-linking were employed to assess an interaction between FX and the FVIII light chain (A3C1C2 domains). SPR and ELISA-based assays showed that FVIII LC bound to immobilized FX (Kd = 165 nM and 370 nM, respectively). Furthermore, active site-modified activated protein C (DEGR-APC) effectively competed with FX in binding FVIII LC (apparent Ki = 82.7 nM). Western blotting revealed that the APC-catalyzed cleavage rate at Arg336 was inhibited by FX in a concentration-dependent manner. A synthetic peptide comprising FVIII residues 2007-2016 representing a portion of an APC-binding site blocked the interaction of FX and FVIII LC (apparent Ki = 152 µM) and directly bound to FX (Kd = 7.7 µM) as judged by SPR and chemical cross-linking. Ala-scanning mutagenesis of this sequence revealed that the A3C1C2 subunit derived from FVIII variants Thr2012Ala and Phe2014Ala showed 1.5- and 1.8-fold increases in Kd for FX, whereas this value using the A3C1C2 subunit from a Thr2012Ala/Leu2013Ala/Phe2014Ala triple mutant was increased >4-fold. FXase formed using this LC triple mutant demonstrated an ~4-fold increase in the Km for FX. These results identify a relatively high affinity and functional FX site within the FVIIIa A3C1C2 subunit and show a contribution of residues Thr2012 and Phe2014 to this interaction.