Study of charged particle activation analysis (II): Determination of boron concentration in human blood samples.

Boron Neutron Capture Therapy (BNCT) is a radiotherapy for the treatment of intractable cancer. In BNCT precise determination of 10B concentration in whole blood sample before neutron irradiation of the patient, as well as accurate neutron dosimetry, is crucial for control of the neutron irradiation time. For this purpose ICP-AES and neutron induced prompt γ-ray analysis are generally used. In Ibaraki Neutron Medical Research Center (iNMRC), an intense proton beam will be accelerated up to 8 MeV, which can also be used for Charged Particle Activation Analysis (CPAA). Thus, in this study, we apply the CPAA utilizing the proton beam to non-destructive and accurate determination of 10B concentration in whole blood sample. A CPAA experiment is performed by utilizing an 8 MeV proton beam from the tandem accelerator of Nuclear Science Research Institute in Japan Atomic Energy Agency. The 478 keV γ-ray of 7Be produced by the 10B(p, α)7Be reaction is used to quantify the 10B in human blood. The 478 keV γ-ray intensity is normalized by the intensities of the 847 keV and 1238 keV γ-rays of 56Co originating from Fe in blood. The normalization methods were found to be linear in the range of 3.27 µg 10B/g to 322 µg 10B/g with correlation coefficients of better than 0.9999.

Terahertz Dynamics of a Topologically Protected State: Quantum Hall Effect Plateaus near the Cyclotron Resonance of a Two-Dimensional Electron Gas.

We measure the Hall conductivity of a two-dimensional electron gas formed at a GaAs/AlGaAs heterojunction in the terahertz regime close to the cyclotron resonance frequency using highly sensitive Faraday rotation measurements. The sample is electrically gated, allowing the electron density to be changed continuously by more than a factor of 3. We observe clear plateaulike and steplike features in the Faraday rotation angle vs electron density and magnetic field (Landau-level filling factor) even at fields or frequencies very close to cyclotron resonance absorption. These features are the high frequency manifestation of quantum Hall plateaus-a signature of topologically protected edge states. We observe both odd and even filling factor plateaus and explore the temperature dependence of these plateaus. Although dynamical scaling theory begins to break down in the frequency region of our measurements, we find good agreement with theory.

A phase II study of metronomic paclitaxel/cyclophosphamide/capecitabine followed by 5-fluorouracil/epirubicin/cyclophosphamide as preoperative chemotherapy for triple-negative or low hormone receptor expressing/HER2-negative primary breast cancer.

PURPOSE: Better treatments for triple-negative breast cancer (TNBC) are needed. To address this need, we studied the effects of preoperative metronomic paclitaxel/cyclophosphamide/capecitabine (mPCX) followed by 5-fluorouracil (FU)/epirubicin/cyclophosphamide (FEC) as preoperative chemotherapy in TNBC patients. METHODS: Forty primary TNBC patients received four cycles of metronomic paclitaxel (80 mg/m(2) on Days 1, 8, and 15), cyclophosphamide (50 mg/body daily), and capecitabine (1,200 mg/m(2) daily), followed by four cycles of 5-FU (500 mg/m(2)), epirubicin (100 mg/m(2)), and cyclophosphamide (500 mg/m(2)) every 3 weeks. The primary end point was the pathological complete response (pCR) rate. RESULTS: Forty patients formed the intent-to-treat population. The median dose intensities of paclitaxel, cyclophosphamide, and capecitabine were 89.7, 92.1, and 89.8%, respectively. Five patients discontinued mPCX and two discontinued FEC, primarily because of adverse events, resulting in a per-protocol population (PPS) of 33 patients. The pCR (ypT0/Tis ypN0) rate was 47.5% (19/40) in the intent-to-treat population and 54.5% (18/33) in the PPS. The clinical response rates were 36/40 (90.0%) and 31/33 (93.9%) in the intent-to-treat and PPS, respectively. The breast conservation rate was 72.7% (24/33), and 5/13 patients underwent partial resection instead of pre-planned total mastectomy. Grade 3-4 adverse events included neutropenia (35%), leukopenia (25%), and hand-foot syndrome (8%). CONCLUSIONS: Metronomic PCX followed by FEC chemotherapy was associated with a high pCR rate and low toxicity in TNBC patients. Further studies of this regimen in larger numbers of patients are warranted.

Feasibility of marrow harvesting from pediatric sibling donors without hematopoietic growth factors and allotransfusion.

We retrospectively studied 108 marrow harvests from 105 pediatric sibling donors. The median age of donors was 8 years (range: 1-15) and the median body weight was 27 kg (range: 10-100). The volumes of aspirated marrow were 5.0-23.8 mL/kg donor body weight, and harvested bone marrow volume exceeded 15 mL/kg in 42% of the donors. A total of 100 autologous blood donations were performed, and eight donors had red cells salvaged from their harvests reinfused. The median Hb levels before and after harvests were 12.3 g/dL (range: 10.0-14.7) and 11.0 g/dL (range: 8.9-13.8), respectively. None of the donors received allogeneic blood transfusions or hematopoietic growth factors such as EPO and G-CSF before or after collection. Transplanted dose was 1.4-10.8 × 10(8) cells/kg recipient body weight without differences due to donor age. Higher concentrations of nucleated and CD34(+) cells were obtained from younger donors. All donors tolerated the procedures well, with no serious complications. Thus, children may safely donate marrow for allogeneic transplantation, and the yields of nucleated cells for engraftment are substantial.

Feasibility of 2nd generation STS retinal prosthesis in dogs.

We developed a 2(nd) generation suprachoroidal transretinal stimulation (STS) system with a 49 channel electrode array and implanted in 2 dogs. One month after surgery, all electrodes were functioning and the ocular fundus was normal in both dogs. The results indicate the 2(nd) generation STS retinal prosthesis is feasible and can be considered for clinical use.

Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil­ epirubicin­cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy.

This randomized, multicenter study compared the efficacy of docetaxel with or without capecitabine following fluorouracil/epirubicin/cyclophosphamide (FEC) therapy in operable breast cancer and investigated the role of Ki67 as a predictive biomarker. Patients were randomized to 4 cycles of docetaxel/capecitabine (docetaxel: 75 mg/m2 on day 1; capecitabine: 1,650 mg/m2 on days 1­14 every 3 weeks) or docetaxel alone (75 mg/m2 on day 1 every 3 weeks) after completion of 4 cycles of FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks). The primary endpoint was the pathological complete response (pCR) rate. Predictive factor analysis was conducted using clinicopathological markers, including hormone receptors and Ki67 labeling index (Ki67LI). A total of 477 patients were randomized; the overall response in the docetaxel/capecitabine and docetaxel groups was 88.3 and 87.4 %, respectively. There were no significant differences in the pCR rate (docetaxel/capecitabine: 23 %; docetaxel: 24 %; p = 0.748), disease-free survival, or overall survival. However, patients with mid-range Ki67LI (10­20 %) showed a trend towards improved pCR rate with docetaxel/capecitabine compared to docetaxel alone. Furthermore, multivariate logistic regression analysis showed pre-treatment Ki67LI (odds ratio 1.031; 95 % CI 1.014­1.048; p = 0.0004) to be a significant predictor of pCR in this neoadjuvant treatment setting. Docetaxel/capecitabine (after 4 cycles of FEC) did not generate significant improvement in pCR compared to docetaxel alone. However, exploratory analyses suggested that assessment of pre-treatment Ki67LI may be a useful tool in the identification of responders to preoperative docetaxel/capecitabine in early-stage breast cancer.

High incidence of fatty liver and insulin resistance in long-term adult survivors of childhood SCT.

Overweight/obesity among adult survivors of childhood SCT has been considered to be predictive of eventual development of metabolic abnormalities. Fatty liver is increasingly recognized as a major cause of liver-related morbidity and mortality in the general population. However, the real incidence of fatty liver in adult survivors of SCT has not been fully elucidated. We determined whether adult survivors are at risk for overweight/obesity, metabolic abnormalities and fatty liver and whether these risks are associated with cranial radiotherapy (CRT) before SCT. Among the 51 patients (30 males), only two male patients were overweight/obese at the last evaluation. On the other hand, 9 male (30%) and 15 female (71%) patients were underweight. Fatty liver was diagnosed in 11 male (37%) and 10 female (48%) patients during the follow-up period, although patients who had fatty liver did not tend to be overweight/obese. Significantly more patients who received CRT before SCT developed fatty liver with insulin resistance than those who did not (P<0.05). Even patients who are not overweight/obese may develop fatty liver and metabolic abnormalities. We recommend that healthcare professionals recognize these risks and give life-long attention to detecting, preventing and treating late complications after SCT.

Subunit-specific and homeostatic regulation of glutamate receptor localization by CaMKII in Drosophila neuromuscular junctions.

For the efficient transfer of information across neural circuits, the number of synaptic components at synapses must be appropriately regulated. Here, we found that postsynaptic calcium/calmodulin dependent protein kinase II (CaMKII) modulates the localization of glutamate receptors (GluRs) at Drosophila larval neuromuscular junctions (NMJs). Expression of an inhibitory peptide of CaMKII, Ala, in muscle cells enhanced the density of GluRIIA, which is a major and calcium-permeable subunit of GluR, at synapses of third instar larval NMJs. On the other hand, postsynaptic expression of a constitutively active form of CaMKII (T287D) reduced synaptic GluRIIA. These results suggest that CaMKII regulates GluRIIA at NMJs. Moreover, postsynaptic expression of T287D abolished the accumulation of the scaffolding protein discs large (DLG) at synapses, while exerting no significant effects on the presynaptic area and the localization of cell adhesion molecule fasciclin II (FasII). The amplitude of excitatory junctional potentials (EJPs) was enhanced in Ala-expressing larvae, whereas it was unaffected in T287D-expressing larvae in spite of the prominent loss of GluRIIA. The amplitude of miniature EJPs (mEJPs) was significantly reduced and quantal content was significantly increased in T287D-expressing larvae. Notably, another class of GluR containing GluRIIB was enhanced by the postsynaptic expression of T287D. These results suggest that the homeostatic mechanism in T287D larvae works to maintain the level of synaptic responses. Thus, the Drosophila larval NMJs have several regulatory systems to ensure efficient muscle excitability which is necessary for proper larval movement.

[Bentall operation in left sinus of valsalva aneurysm with anomalous origin of left coronary artery and severe aortic regurgitation].

We report a successful Bentall operation in a 74-year-old man with an unruptured left sinus of Valsalva aneurysm and aortic regurgitation. The coronary angiogram showed an absent left main trunk (split origination of left coronary arteries from the same left sinus of Valsalva). We implanted a stented bovine pericardial valve and a Valsalva tube graft as a composite graft. To reconstruct the coronary arteries, we made one left coronary button including both ostia of the left anterior descending coronary artery and circumflex artery, and reimplanted the coronary button with interposition of a short small synthetic graft. Excessive tension of the coronary ostia can be avoided and a new left main trunk can also be created in this manner. Postoperative course was uneventful.

Clinical and radiological evaluation of revision hip arthroplasty using the cement-in-cement technique.

We reviewed 44 consecutive revision hip replacements in 38 patients performed using the cement-in-cement technique. All were performed for acetabular loosening in the presence of a well-fixed femoral component. The mean follow-up was 5.1 years (2 to 10.1). Radiological analysis at final follow-up indicated no loosening of the femoral component, except for one case with a continuous radiolucent line in all zones and peri-prosthetic fracture which required further revision. Peri-operative complications included nine proximal femoral fractures (20.4%) and perforation of the proximal femur in one hip. In five hips wiring or fixation with a braided suture was undertaken but no additional augmentation was required. There was an improvement in the mean Japanese Orthopaedic Association score from 55.5 (28 to 81) pre-operatively to 77.8 (40 to 95) at final follow-up (p < 0.001). Revision using a cement-in-cement technique allows increased exposure for acetabular revision and is effective in the medium term. Further follow-up is required to assess the long-term results in the light of in vitro studies which have questioned the quality of the cement-in-cement bond.

Tonsillectomy in the treatment of pediatric Henoch-Schönlein nephritis.

The exact pathophysiology of HSN remains to be elucidated. Hence, a therapeutic strategy that enables curative treatments for all the various grades of HSN patients has yet to be established. We report our experience performing tonsillectomy combined with steroid therapy for 16 pediatric proteinuric Henoch-Schönlein nephritis (HSN) patients. All patients exhibited hematuria and proteinuria in their first HSN attack with the mean age of onset 7.7 years (range 4.75 - 13.9 years). Nine patients were diagnosed with clinically severe HSN presenting with massive proteinuria (> 1 g/m(2)/day). Renal biopsy findings performed in 6 patients were Grade II (3), Grade III (2) and Grade IV (1) according to the International Study of Kidney Diseases in childhood classification. Tonsillectomy was performed after 1-4 cycles of methylprednisolone pulses during oral prednisolone (0.5 - 1.5 mg/kg/day) therapy. In 2 patients, oral cyclophosphamide therapy was added before the tonsillectomy. The interval between the onset of HSN and tonsillectomy was 97.4 +/- 24.5 days (range 27 424 days). In all patients, proteinuria had disappeared by 6 months after the tonsillectomy and the urine findings had normalized. The interval between therapy initiation and complete remission was 9.6 +/- 2.0 months (range 2 - 26 months). Over follow-up periods of 4.9 +/- 0.6 years (range 2.2 - 9.3 years), no recurrences of Henoch-Schonlein purpura or HSN were observed. There was a significant correlation between early tonsillectomy performance and decreased time until normalization of the urine findings, indicating that the tonsils may have pivotal roles in the initiation and progression of HSN. Their elimination might promote the reversal of nephritis. Although this study is retrospective, we suggested that tonsillectomy at an early stage of HSN may be beneficial by shortening the period of illness and contributing to clinical recovery. Randomized controlled trials will be needed to confirm this supposition.

Gonadal shielding to irradiation is effective in protecting testicular growth and function in long-term survivors of bone marrow transplantation during childhood or adolescence.

An increasing number of long-term surviving bone marrow transplantation (BMT) recipients have recovered from their primary disease but are at risk of developing failure of endocrine organs. We investigated 30 recipients who underwent allogeneic BMT during childhood or adolescence. Testicular growth and function were evaluated by serial measurement of testicular volume, basal luteinizing hormone (LH), basal follicle-stimulating hormone (FSH) and testosterone levels and by gonadotropin-releasing hormone (GnRH) provocative test. Puberty started spontaneously in all patients. However, all except four patients had normal testosterone levels with elevated LH, indicating partial Leydig cell dysfunction. Standard deviation scores of testicular volume at last evaluation were statistically lower in those who had received irradiation without gonadal shield compared to those with (-2.04+/-0.45 vs -0.30+/-1.17, respectively, P<0.005), suggesting damage of testicular germinal epithelium owing to gonadal irradiation. Serial measurement of testicular volume showed a tendency of growth to stop at 10 ml in those without gonadal shield. Among the 30 patients, only one patient has fathered a child after reaching spontaneous puberty. These results suggest that gonadal shield is effective to protect testicular growth and function, although the attainment of fertility is difficult to achieve.

Cost-effectiveness analysis of antifungal treatment for patients on chemotherapy.

Invasive fungal infections are fatal complications for patients on chemotherapy, and antifungal prophylactic treatment has been commonly recommended. Because its clinical and economic impact is not well known, we evaluated cost-effectiveness of anti-fungal treatment for patients who were neutropoenic as a result of chemotherapy. We constructed a hypothetical cohort of 40-year-old patients with acute myelogenic leukemia to evaluate years of life survived (YLS), costs (US$), and incremental cost-effectiveness ratio (US$/YLS). The following treatment strategies for fungal infections were compared: (1) prophylactic fluconazole strategy: oral fluconazole administration concurrently with chemotherapy; (2) empirical amphotericin B strategy: empirical intravenous amphotericin B administration at the point where fever is detected; and (3) no prophylaxis strategy: intravenous micafangin administration at the point where fungal infections is diagnosed. Baseline analyses showed that prophylactic fluconazole strategy involved higher costs but also longer YLSs (25,900 US$ and 24.08 YLS). The incremental cost-effectiveness ratio of prophylactic fluconazole strategy was 625 US$/YLS compared to no prophylaxis strategy, and 652 US$/YLS compared to empirical amphotericin B strategy. Baseline result was found to be robust through sensitivity analyses. Our study showed that concurrent administration of oral fluconazole during induction chemotherapy appears to ensure clinical benefits together with acceptable cost-effectiveness.

Association between patient education and health-related quality of life in patients with Parkinson's disease.

BACKGROUND: Providing patients with disease- and treatment-related information is an important role of medical staff and is now reimbursed in Japan by the national health insurance system under the rubric 'patient education'. Evaluation of the effectiveness of patient education programs is necessary to ensure that limited health care resources are used efficiently. OBJECTIVE: The objective is to determine whether educating patients with Parkinson's disease (PD) is related to better health-related quality of life (HRQOL). DESIGN: A cross-sectional study was conducted. SETTING: Members of the Japan Association of Patients with Parkinson's disease were randomly selected. PARTICIPANTS: A total of 1200 patients with PD were asked to fill in written questionnaires and replies from 762 (63.5%) were analyzed. MEASUREMENTS: The questionnaire inquired about clinical characteristics, comorbidity, symptoms of PD, complications of therapy, HRQOL, and patient education. SF-36 was used to assess HRQOL. The section on patient education comprised one question each on patient-perceived satisfaction with information provided on (1) disease condition and pathophysiology, (2) effectiveness of drug therapy, (3) adverse drug reactions, (4) publicly available financial and social resources, and (5) rehabilitation and daily activities. Patient education score was defined as the sum of the individual scores for these five questions. The relationships between scores on the SF-36 subscales and the patient education score were examined. RESULTS: More satisfaction with patient education was associated with higher scores in all SF-36 subscales except physical functioning and bodily pain. The difference in score between the most satisfied and the least satisfied patients ranged from 8.4 points on the subscales of general health and 16.7 points on the subscale of role limitation due to emotional problems. CONCLUSION: The conclusion that patient education is associated with better HRQOL in patients with PD is drawn.

Hard-food mastication suppresses complete Freund's adjuvant-induced nociception.

The effect of food hardness during mastication on nociceptive transmission in the spinal cord was studied by analyzing complete Freund's adjuvant (CFA) induced nocifensive behavior and Fos expression. The behavioral study showed that the shortening of the withdrawal latency following CFA injection into the hind paw was depressed after a change in the given food hardness from soft to hard. The depression of nocifensive behavior in the rats with hard food was reversed after i.v. injection of naloxone. Fos protein-like immunoreactive cells (Fos protein-LI cells) were expressed in the superficial and deep laminae of the L4-6 spinal dorsal horn after s.c. injection of CFA into the hind paw during soft food mastication. The number of Fos protein-LI cells was decreased in the rats with hard food mastication followed by soft food. This reduction of Fos protein-LI cells following change in food hardness was reversed after i.v. application of naloxone. Furthermore, the depression of Fos protein-LI cells following hard food intake was significantly inhibited after bilateral inferior alveolar nerve transection or bilateral ablation of the somatosensory cortex. These findings suggest that the change in food hardness during mastication might drive an opioid descending system through the trigeminal sensory pathway and somatosensory cortex resulting in an antinociceptive effect on chronic pain. However, IAN transection and cortical ablation did not induce 100% reversal of Fos expression, suggesting other than trigeminal sensory system may be involved in this phenomena, such as the pathway through the brainstem reticular formation.

A new model of experimental parotitis in rats and its implication for trigeminal nociception.

A rat model of chronic parotitis was developed following a direct injection of Complete Freund's adjuvant (CFA) into the unilateral parotid gland via the parotid duct without skin incision. The nocifensive behavior, plasma extravasation in the parotid gland, and trigeminal Fos protein expression, a marker of neuronal activation, were analyzed in this model and compared to that of the saline-injected rats. A significant reduction of the escape threshold to mechanical stimulation of the lateral face on the ipsilateral side to the CFA injection was observed at 1-6 days after CFA injection as compared to that of the pre-CFA control ( P<0.01). The lateral face region contralateral to the CFA injection also showed mechanical hyperalgesia at 1-6 days after injection ( P<0.05). The plasma extravasation was significantly increased in the parotid gland ipsilateral to CFA injection as compared to that of the parotid gland with saline injection at 3 days after injection as shown by Evans' blue dye extravasation ( P<0.05). Bilateral expression of Fos protein-like immunoreactive cells was observed in the transition zone between the trigeminal spinal nucleus interpolaris (Vi) and caudalis (Vc) and paratrigeminal nucleus (Pa5). On the other hand, a significant unilateral expression of Fos protein-positive cells was observed on the ipsilateral side of the upper cervical (C2) dorsal horn ( P<0.05). This model of parotitis can be used to study trigeminal pain mechanisms associated with sialadenitis. A unique feature of this preparation is that the inflammation was limited to the parotid gland after intraductal injection of CFA, allowing analysis of peripheral input from a defined orofacial region. The model will be useful in developing new strategies to treat chronic orofacial pain.