Temporal Profiles of Symptom Scores After Palliative Radiotherapy for Bleeding Gastric Cancer With Adjustment for the Palliative Prognostic Index: An Exploratory Analysis of a Multicentre Prospective Observational Study (JROSG 17-3).

AIMS: Although palliative radiotherapy for gastric cancer may improve some symptoms, it may also have a negative impact due to its toxicity. We investigated whether symptoms improved after radiotherapy with adjustment for the Palliative Prognostic Index (PPI) considering that patients with limited survival tend to experience deterioration of symptoms. MATERIALS AND METHODS: This study was an exploratory analysis of the Japanese Radiation Oncology Study Group study (JROSG 17-3). We assessed six symptom scores (nausea, anorexia, fatigue, shortness of breath, pain at the irradiated area and distress) at registration and 2, 4 and 8 weeks thereafter. We tested whether symptoms linearly improved after adjusting for the baseline PPI. Shared parameter models were used to adjust for potential bias in missing data. RESULTS: The present study analysed all 55 patients enrolled in JROSG 17-3. With time from registration as the only explanatory variable in the model, a significant linear decrease was observed in shortness of breath, pain and distress (slopes, -0.26, -0.22 and -0.19, respectively). Given that the interaction terms (i.e. PPI × time) were not significantly associated with symptom scores in any of the six symptoms, only PPI was included as the main effect in the final multivariable models. After adjusting for the PPI, shortness of breath, pain and distress significantly improved (slope, -0.25, -0.19 and -0.17; P < 0.001, 0.002 and 0.047, respectively). An improvement in fatigue and distress was observed only in patients treated with a biologically effective dose ≤14.4 Gy. CONCLUSION: Shortness of breath, pain and distress improved after radiotherapy. Moreover, a higher PPI was significantly associated with higher symptom scores at all time points, including baseline. In contrast, PPI did not seem to influence the improvement of these symptoms. Regardless of the expected survival, patients receiving radiotherapy for gastric cancer can expect an improvement in shortness of breath, pain and distress over 8 weeks. Multiple-fraction radiotherapy might hamper the improvement in fatigue and distress by its toxicity or treatment burden.

Serum αKlotho as a Predictor of Graft Dysfunction After Kidney Transplantation.

OBJECTIVE: To improve the long-term survival rate after kidney transplantation (KTx), allograft injury should be identified as soon as possible. Regardless of aggressive immunosuppressive therapies, recipients of kidney transplants still have a significant risk of graft failure. No specific predictor for the progression of chronic kidney disease (CKD) after KTx has yet been found. Aberrant molecular mechanisms involving the αKlotho-fibroblast growth factor (FGF) 23 axis may be a useful determinant of renal impairment and graft failure over time. METHODS: Plasma and spot urine samples were collected from 47 patients 1 year after KTx. Evaluation of renal function after KTx was performed using levels of biomarkers including serum intact FGF23, soluble αKlotho, 25(OH) vitamin D (25(OH)D), and the difference in the estimated glomerular filtration rate (eGFR) between the first and third year after KTx (ΔeGFR). RESULTS: The median serum αKlotho, intact FGF23, and 25(OH)D were 516.3 pg/mL, 58.7 pg/mL, and 5.7 ng/mL, respectively. No marked changes in the standard biomarkers that regulate phosphate homeostasis were found. Serum αKlotho levels were associated with ΔeGFR. Multivariate regression analysis revealed that serum αKlotho levels significantly predicted a decrease in eGFR in the graft kidney 2 years after KTx, but serum 25(OH)D and FGF23 levels were not significant. Serum αKlotho levels showed an inverse correlation with fractional excretion of magnesium, which reflects tubular injury in the early stage of CKD. CONCLUSION: Measurement of serum αKlotho may serve as a useful predictor of KTx patients who require initiation of pre-emptive medication.

Plasma CD147 reflects histological features in patients with lupus nephritis.

OBJECTIVE: A glycosylated transmembrane protein, CD147, has been implicated in regulating lymphocyte responsiveness and leukocyte recruitment. As lupus nephritis (LN) often follows a relapsing-remitting disease course, accurate understanding of the disease activity would be extremely helpful in improving prognosis. Unfortunately, neither clinical nor serological data can accurately reflect the histological features of LN. The present study investigated whether CD147 can accurately predict pathological features of LN. METHODS: Plasma and spot urine samples were collected from 64 patients who underwent renal biopsy between 2008 and 2011. Disease activity for LN tissues was evaluated using the biopsy activity index, and compared to levels of biomarkers including CD147. RESULTS: In LN tissues, CD147 induction was striking in injured glomeruli and infiltrating inflammatory cells, but not in damaged tubules representing atrophy. Plasma CD147 levels accurately reflected the histological disease activity. However, prediction using a single molecule would be quite difficult because of the complex pathogenesis of LN. The diagnostic accuracy of multiplex parameters indicated that the combination including plasma CD147 might yield excellent diagnostic abilities for guiding ideal LN therapy. CONCLUSION: Plasma CD147 levels might offer useful insights into disease activity as a crucial biomarker in patients with LN.

Accurate determination of patient-specific boundary conditions in computational vascular hemodynamics using 3D cine phase-contrast MRI.

In the patient-specific vascular CFD, determination of the inlet and outlet boundary conditions (BCs) is an important issue for a valid diagnosis. The 3D cine phase-contrast MRI (4D Flow) velocimetry is promising for this issue; yet, its measured velocities contain relatively large error and are not admissible as the BCs without any correction. This paper proposes a novel correction method for determining the BCs accurately using the 4D Flow velocimetry. First, we reveal that the error of the velocity measured by the 4D Flow at each measurement voxel is large but is distributed symmetrically. Secondly, our method pays attention to the incompressibility of the blood and the fact that the volume flow rate (VFR) in each vessel is constant on any cross sections. We reveal that the average of the cross-sectional VFRs integrated from many measurement voxel in each vessel is accurate despite the large error. Finally, we propose the novel correction method, which applies a smoothing to the measured velocities on each inlet or outlet boundary with a low-pass filter and then corrects them with the VFR. The results of the several phantom studies are presented to validate the accuracy of our method. A demonstrative analysis for an actual aneurysm is also presented to show the feasibility and effectiveness of our method.

Minimally invasive removal of a recurrent lumbar herniated nucleus pulposus by the small incised microendoscopic discectomy interlaminar approach.

In this report, we introduce two cases of recurrent herniated nucleus pulposus (HNP) at L5-S1 that were successfully removed using the small incised microendoscopic discectomy (sMED) technique, proposed by Dezawa and Sairyo in 2011. sMED was performed via the interlaminar approach with a percutaneous endoscope. The patients had previously underdone microendoscopic discectomy for HNP. For the recurrent HNP, the sMED interlaminar approach was selected because the HNP occurred at the level of L5-S1; the percutaneous endoscopic transforaminal approach was not possible for anatomical reasons. To perform sMED via the interlaminar approach, we employed new, specially made devices to enable us to use this technique. In conclusion, sMED is the most minimally invasive approach available for HNP, and its limitations have been gradually eliminated with the introduction specially made devices. In the near future, percutaneous endoscopic surgery could be the gold standard for minimally invasive disc surgery.

Endoscopic removal of herniated nucleus pulposus migrated dorsally to the dural sac.

A herniated nucleus pulposus (HNP) migrated dorsally to the dural sac is a rare condition. Here, we present a case, in which the HNP was removed with minimally invasive spinal endoscopy. A 54-year-old man presented complaining of left leg pain and paresis. Neurologic findings and an MRI suggested an epidural tumor or a dorsally migrated HNP compressing the S1 nerve root and dural sac. With a spinal endoscope, careful laminotomy of caudal L5 and cranial S1 was made. En bloc flavectomy exposed a mass covered with a thin capsule. The mass was identified as a dorsally migrated HNP. After complete HNP fragment removal, the dural sac and S1 nerve root were decompressed. Immediately postoperative, the leg pain subsided and motor function normalized, although the patient complained of numbness at the S1 dermatome area. In summary, a large HNP that had migrated dorsally to the dural sac was successfully removed endoscopically.

Visualization of hemodynamics in a silicon aneurysm model using time-resolved, 3D, phase-contrast MRI.

We performed time-resolved 3D phase-contrast MR imaging by using a 1.5T MR scanner to visualize hemodynamics in a silicon vascular model with a middle cerebral aneurysm. We ran an aqueous solution of glycerol as a flowing fluid with a pulsatile pump. Time-resolved images of 3D streamlines and 2D velocity vector fields clearly demonstrated that the aneurysm had 3D complex vortex flows within it during systolic phase. This technique provided us with time-resolved 3D hemodynamic information about the intracranial aneurysm.

Aberrant expression of beta- and gamma-catenin is an independent prognostic marker in oral squamous cell carcinoma.

Alteration in expression of E-cadherin and catenins is associated with loss of differentiation, acquisition of an invasive phenotype and poor clinical outcome in many types of cancer. To identify molecular prognostic markers, membrane expression levels of E-cadherin, and alpha-, beta- and gamma-catenin in biopsy samples (n=135) of oral squamous cell carcinoma (OSCC) were evaluated immunohistochemically in relation to preoperative tumour-related features, clinical course and prognostic value, and were found to be significantly correlated with an endophytic growth pattern and pathologically proved lymph-node metastasis. Alteration of expression of E-cadherin, and alpha-, beta- and gamma-catenin was also significantly correlated with poor disease-specific 5-year survival (P=0.0096, 0.0434, 0.0005 and 0.0005, respectively). Multivariate Cox proportional hazard regression analysis showed that alteration of beta- and gamma-catenin expression was a significantly independent prognostic parameter for survival (P=0.0112 and 0.0088, respectively), as was the case with endophytic growth pattern and advanced N-category. These results indicate that patients with OSCC and absent or reduced membrane expression of beta- and gamma-catenin should be considered a high-risk group for regional lymph-node metastasis and poor prognosis.

Bound thrombin-induced upregulation of myosin heavy chain isoform, SMemb messenger RNA expression in cultured rabbit vascular smooth muscle cells.

To investigate whether bound thrombin can induce modulation of SMemb expression in vascular smooth muscle (VSM) cells, messenger RNA (mRNA) expression was measured by in situ hybridization (ISH) and reverse transcription-polymerase chain reaction (RT-PCR) in cultured rabbit aortic VSM cells. To test the concentration- and time-dependent effect of bound thrombin on the expression of SMemb, confluent VSM cells were incubated for 48 h in 10% FBS-DMEM containing 0, 3, 10 and 30 units/ml of bound thrombin. In addition, the confluent VSM cells were incubated for 6, 12, 24 and 48 h in 10% FBS-DMEM containing 10 units/ml of bound thrombin. Consequently, bound thrombin significantly increased SMemb mRNA in a concentration- and time-dependent manner. When compared with the effect of rabbit fibrinogen (10 microg/ml) and native thrombin (10 units/ml), SMemb mRNA was significantly increased by bound thrombin and was slightly increased by native thrombin, but not by fibrinogen. Other myosin heavy chain (MHC) isoform (SM1 and SM2) mRNA expressions were not changed by fibrinogen, native thrombin or bound thrombin. ISH revealed that there was no significant difference in the expression of MHC mRNAs among fibrinogen, native thrombin or bound thrombin. Western blot analysis demonstrated that the SMemb protein level was significantly increased by 2.5-fold by bound thrombin. When the clot-forming activities in cultured medium containing native thrombin or bound thrombin were measured from 0.5 to 48 h, the activity of bound thrombin declined more slowly than that of native thrombin. In conclusion, bound thrombin could upregulate the expression of SMemb mRNA and protein in cultured VSM cells and the activity of bound thrombin was maintained for longer than that of native thrombin in culture medium.

Isolation of bound thrombin consisting of thrombin and fibrin N-terminal fragment from clot lysate.

It has been reported that thrombin is liberated from fibrin clots by the action of fibrinolytic enzymes. It has also been reported that the liberated thrombin complexes with fibrin fragment E or (DD)E, which are denoted as bound thrombin. However, bound thrombin has not been isolated from clot lysate, and the structural characteristics of isolated bound thrombin have not been specified. In this study, we attempted to isolate the bound thrombin from clot lysate and to clarify its structural features. Rabbit fibrinogen was clotted with bovine thrombin, and clot lysate was prepared with urokinase. The bound thrombin was isolated from clot lysate by serial chromatography using a Sepharose 4B column immobilizing an anti-bovine thrombin antibody and a Sepharose 4B column immobilizing an anti-rabbit fibrinogen antibody. SDS-PAGE under unreduced conditions demonstrated that there were two different protein bands in the isolated bound thrombin. On a C4 reverse-phase HPLC, the bound thrombin from clot lysate was resolved by 4 M urea into alpha-thrombin and a fibrin fragment, the N-terminal regions of which were identified as alpha-, beta- and gamma-chains. Thus, in the bound thrombin, thrombin molecule would bind to rabbit fibrin fragment consisting of N-terminal central domain.

Analysis of IgE turnover in non-sensitized and sensitized rats.

BACKGROUND: Although the levels of immunoglobulin E (IgE) in the circulating blood are often elevated in patients with allergic diseases, such levels cannot always be considered as pathognomonic signs of allergy. The induction of allergic reactions in the tissue was inferred to be related to the amount of IgE passing through the vascular wall. AIMS: We attempted to clarify which compartment, the intravascular or extravascular, plays an important role in the regulation of the turnover of rat IgE. METHODS: The level of DNP-specific rat IgE in the serum was estimated by IgE-capture enzyme-linked immunosorbent assay, and the turnover of IgE was analyzed from its pharmacokinetic parameters. RESULTS: The transfer rate constants from the central to tissue compartment (Kct) were larger than those from the tissue to central compartment (Ktc) irrespective of the sensitized state. The value of the distribution volume of the tissue compartment (Vt) was larger than that of the distribution volume of the central compartment (Vc) irrespective of the sensitized state. CONCLUSIONS: These Findings suggest that the short half-life of rat IgE in the circulation could be attributable to the distribution of IgE from the intravascular to the extravascular compartment.

Expression of p16, nm23-H1, E-cadherin, and CD44 gene products and their significance in nasopharyngeal carcinoma.

OBJECTIVE: The present study was aimed to determine whether p16/MTS1, nm23-H1, E-cadherin, and CD44 proteins were expressed in nasopharyngeal carcinoma (NPC) and whether those expressions were pathologically significant in the progress of NPC. METHOD: We examined non-cancerous nasopharyngeal mucosa (20 cases) and NPC (80 cases) using immunohistochemistry with six different types of monoclonal antibodies against p16, nm23-H1, E-cadherin, CD44H, CD44v3, and CD44v6 proteins. RESULTS: The results showed that 1) the rates of positive p16 protein expression and of preserved E-cadherin protein expression in NPC were significantly lower than those in non-cancerous tissue (P <.01); 2) no significant difference in the rate of positive expression of nm23-H1, CD44H, CD44v3, and CD44v6 proteins were observed between non-cancerous nasopharyngeal mucosa and NPC; 3) no significant difference in the expression of those proteins were found by respective correlation analyses of sex, stage, and size of primary tumor in NPC; and 4) no significant difference in the rates of positive expression of CD44H, CD44v3, and CD44v6 proteins were observed in NPC between with and without lymph node metastasis, indicating that those gene products did not correlate with lymph node metastasis in NPC. However, there were inverse correlations between the expression of p16, nm23-H1, or E-cadherin protein and lymph node metastasis (P <.05), indicating that the expression of p16, nm23-H1, and E-cadherin gene were related to the carcinogenesis and tumor progression of NPC. CONCLUSION: Detecting the expressions of those gene products may provide clinically valuable information for therapeutic strategy and for predicting the prognosis of patients with NPC.

Lack of tyrosine protein kinase regulation of L-type Ca2+ channel current in transfected cells stably expressing alpha1C-b Subunit.

Tyrosine protein kinase (Tyr-PK) regulation of L-type Ca2+ channel (CaL) current was studied in COS-7 cells expressing vascular smooth muscle-type alpha1C-b with no auxiliary subunit by using a whole-cell voltage clamp. The averaged peak amplitude of CaL currents was -0.33 +/- 0.03 at holding potential of -60 mV. Na(3)VO(4), genistein and phosphorylated p60(c-src) peptide had no effect on the current. Thus the alpha1C-b subunit may not be involved in Tyr-PK regulation of CaL current.

An autopsy case of the schizophrenic 32 years after lobotomy.

An autopsy case is reported here of a 69-year-old patient with schizophrenia, who was known retrospectively to have had a prefrontal lobotomy 32 years previously. The patient was diagnosed as schizophrenic at the age of 24 and the lobotomy was undertaken 13 years later. The patient was recently found outside in a dehydrated condition and admitted to a general hospital, where he died of respiratory failure. Bilateral cystic lesions were found in the deep white matter of the frontal lobe. The cyst walls consisted of glial fibrous tissues, and severe demyelination with axonal destruction was diffusely observed in the white matter of the frontal lobe. In the thinner frontal cortex without arcuate fibers (U fibers) close to the cavities, cytoarchitectural abnormalities were observed. In the thalamic nuclei marked retrograde degeneration and astrocytic gliosis were observed. The detailed neuropathological findings of a lobotomized schizophrenic brain are reported here. It is proposed that one should be reminded of a lobotomized brain if bilateral cysts are found.

Hematological studies on DIC-like findings observed in patients with snakebite in south China.

To clarify the characteristics of the hematological disturbances evoked by snakebite, we measured the antithrombin III (AT-III) activity, alpha2-plasmin inhibitor (alpha2-PI) activity, fibrinogen concentration (Fg) and level of fibrin degradation products (FDP) in 21 patients envenomed by several snakes in south China between August 1998 and October 1999. The hematological changes observed were as follows: the mean activities of AT-III were decreased in patients bitten by Ophiophagus hannah (Oh.), Bungarus fasciatus (Bf.), Hydrophis cyanocinctus (Hc.), Rhabdophis subminiatus (Rs.), and Trimeresurus stejnegeri (Ts.), while those of alpha2-PI were decreased in all patients in the present study; Fg was not detectable in the case of Rs. bite, and the Fg concentration after Ts., Oh., Hc. and Bf. bites also decreased markedly thereby increasing the mean levels of FDP in all patients. It thus appeared that DIC-like syndrome was caused in patients envenomed by snakebite. In the present study, we found that patients who were bitten by Rs., which is still being classified as a non-venomous snake, exhibited complete defibrinogenation and severe hemorrhage without any evidence of severe multiple organ damage. We also found that patients with Ts. bite showed marked hemostatic disturbance without severe multiple organ damage. It is considered that such a discrepancy between the hematological findings and clinical symptoms could be a characteristic phenomenon of the DIC-like syndrome induced by snakebite, especially by Rs. and Ts. bites.

Nanosized Ni/SiO2 catalyst prepared by homogeneous precipitation in wet silica gel.

A Ni/SiO2 catalyst was prepared by homogeneous precipitation of nickel hydroxide in a sol-gel-derived wet silica gel. The preparation process consists of two successive steps: gelation of silica in the presence of nickel nitrate and urea at 50 degrees C, followed by aging at higher temperature, typically at 80 degrees C, to decompose the urea. The decomposition of urea increases the pH of the solution in the wet gel, leading to the concurrence of structural rearrangement of silica gel and deposition of nickel species. As a result, the structure of the silica changes from a ramified polymeric network into particle aggregates that entrap the nickel cations in the particles. The resulting Ni/SiO2 contains large mesopores that have high thermal stability up to 1000 degrees C and highly dispersed Ni metal particles with typical crystallite size of 4 nm even at high Ni content at 20 wt%.

The nucleotide sequence of dinitrophenyl-specific IgE and Fc(epsilon)RI alpha-subunit obtained from FE-3 hybridoma cells.

FE-3 cells were established by Hanashiro et al. by hybridizing mouse myeloma cells (Sp2/0-Ag14/SF) with rat spleen cells that were freshly isolated from Brown-Norway rats sensitized with DNP-As. FE-3 cells can constitutively secrete IgE without stimulation by cytokines. Our preliminary experiments demonstrated that the IgE secretion was decreased at 3 days after start of culture and the addition of exogenous IgE into culture media depressed the secretion of IgE. Thus, we hypothesized that the IgE production in FE-3 cells may be regulated by a signal transduction through the binding of IgE to its high affinity receptor (Fc(epsilon)RI) or to an IgE binding protein on the cell surface. In this study, we aimed to identify the nucleotide sequence of IgE FE-3 and compared with those of mouse IgE and IgE IR162 to find a structural heterogeneity in the Fc region of IgE FE-3. We also tested if the mRNA of Fc(epsilon)RI was expressed in FE-3 cells using the reverse transcriptase-polymerase chain reaction (RT-PCR) method with the combination of sequencing analysis. Consequently, the cDNA sequence of IgE FE-3 was identical to that of the CH3 and CH4 domains in the epsilon-chain of rat IgE IR162, whereas the cDNA of Fc(epsilon)RI was identical to that of mouse, suggesting that the genes of IgE FE-3 and Fc(epsilon)RI was derived from that of rat spleen cells and mouse myeloma cells, respectively.

A monoclonal antibody against bovine thrombin reacting to the C-terminal side of thrombin.

We succeeded in producing a monoclonal antibody (MAb) against bovine thrombin. The MAb belonged to mouse IgG(1), and its light chain consisted of kappa-chain. The MAb reacted with bovine and human thrombins, which were coated by coupling to poly-lysine-coated wells with glutaraldehyde, but did not react with the thrombin-like enzyme, habutobin. Furthermore, the MAb did not react with thrombin which was coated to plates without poly-lysine and glutaraldehyde. The concentration of thrombin in ovalbumin solution (10 mg/mL) could be measured by means of the enzyme-linked immunosorbent assay (ELISA) double sandwich method using the MAb and polyclonal antibody. Thrombin added to defibrinated plasma could not be detected by means of the ELISA double sandwich method using the present MAb, and this may be due to the AT-III activity in the defibrinated plasma. Postclotting thrombin could be detected by means of the ELISA-double sandwich method using the MAb. It is suggested, from the results of our experiments, that the MAb obtained reacted in a limited fashion to the C-terminal of bovine thrombin.