To examine the environmental effects on cytosine methylation of preterm infant's DNA, because early life experiences are considered to influence the physiological and mental health of an individual through epigenetic modification of DNA.
A prospective cohort study, comparison of epigenetic differences in the glucocorticoid receptor (GR) gene between healthy term and preterm infants.
Neonatal Intensive Care Unit in a Japanese University Hospital.
A cohort of 40 (20 term and 20 preterm) infants was recruited on the day of birth, and peripheral blood was obtained from each infant at birth and on postnatal day 4.
Main outcome measures
The methylation rates in the 1-F promoter region of the GR gene using the Mquant method.
The methylation rate increased significantly between postnatal days 0 and 4 in preterm infants but remained stable in term infants. Thus, the methylation rate was significantly higher in preterm than in term infants at postnatal day 4. Several perinatal parameters were significantly correlated with this change in the methylation rate. Logistic regression analysis revealed that methylation rates at postnatal day 4 predicted the occurrence of later complications that required glucocorticoid administration during the neonatal period. No gene polymorphism was detected within the GR promoter region analysed.
Although further large-scale studies are needed to detect the environmental factors that explain the difference in epigenetic modification among infants after birth, our data show that the postnatal environment influences epigenetic programming of GR expression through methylation of the GR gene promoter in premature infants, which may result in relative glucocorticoid insufficiency during the postnatal period.
NEONATOLOGY; MOLECULAR BIOLOGY
The aim of this report is to present the preliminary results of a Phase II study of high-dose (74 Gy RBE) proton beam therapy (PBT) with concurrent chemotherapy for unresectable locally advanced non-small-cell lung cancer (NSCLC). Patients were treated with PBT and chemotherapy with monthly cisplatin (on Day 1) and vinorelbine (on Days 1 and 8). The treatment doses were 74 Gy RBE for the primary site and 66 Gy RBE for the lymph nodes without elective lymph nodes. Adapted planning was made during the treatment. A total of 15 patients with Stage III NSCLC (IIIA: 4, IIIB: 11) were evaluated in this study. The median follow-up period was 21.7 months. None of the patients experienced Grade 4 or 5 non-hematologic toxicities. Acute pneumonitis was observed in three patients (Grade 1 in one, and Grade 3 in two), but Grade 3 pneumonitis was considered to be non-proton-related. Grade 3 acute esophagitis and dermatitis were observed in one and two patients, respectively. Severe ( ≥ Grade 3) leukocytopenia, neutropenia and thrombocytopenia were observed in 10 patients, seven patients and one patient, respectively. Late radiation Grades 2 and 3 pneumonitis was observed in one patient each. Six patients (40%) experienced local recurrence at the primary site and were treated with 74 Gy RBE. Disease progression was observed in 11 patients. The mean survival time was 26.7 months. We concluded that high-dose PBT with concurrent chemotherapy is safe to use in the treatment of unresectable Stage III NSCLC.
proton therapy; radiotherapy; lung cancer; Phase II study; chemo–proton therapy
Surgical resection is the first choice for treatment of a thymic carcinoid tumor and radiotherapy is often performed as adjuvant therapy. Here, we report a case of an unresectable and chemoresistant thymic carcinoid tumor that was treated successfully using standalone proton beam therapy (PBT). The patient was a 66-year-old woman in whom surgical resection of the tumor was impossible because of cardiac invasion. Therefore, chemotherapy was administered. However, the tumor grew to 15 cm in diameter and she developed severe superior vena cava (SVC) syndrome. She was referred to our hospital and received PBT at a dose of 74 GyE in 37 fractions. PBT was conducted without severe early toxicities. After PBT, the tumor mildly shrunk to 13 cm in diameter and SVC syndrome almost disappeared. Subsequently, the tumor has continued to decrease in size slowly over the last 2 years and late toxicities have not been observed. Our experience with this case suggests that PBT may be effective for an unresectable thymic carcinoid tumor.
thymic carcinoid tumor; proton beam therapy; radiation; superior vena cava syndrome; mediastinal tumor
Radiation therapy (RT) has become particularly important recently for treatment of liver tumors, but there are few experimental investigations pertaining to radiation-induced liver injuries over long-term follow-up periods. Thus, the present study examined pathological liver features over a 10-month period using an intraoperative whole-liver irradiation model. Liver function tests were performed in blood samples, whereas cell death, cell proliferation, and fibrotic changes were evaluated pathologically in liver tissues, which were collected from irradiated rats 24 h, 1, 2, 4 and 40 weeks following administration of single irradiation doses of 0 (control), 15 or 30 Gy. The impaired liver function, increased hepatocyte number, and decreased apoptotic cell proportion observed in the 15 Gy group, but not the 30 Gy group, returned to control group levels after 40 weeks; however, the Ki-67 indexes in the 15 Gy group were still higher than those in the control group after 40 weeks. Azan staining showed a fibrotic pattern in the irradiated liver in the 30 Gy group only, but the expression levels of alpha smooth muscle actin (α-SMA) and transforming growth factor-beta 1 (TGF-β1) in both the 15 and 30 Gy groups were significantly higher than those in the control group (P < 0.05). There were differences in the pathological features of the irradiated livers between the 15 Gy and 30 Gy groups, but TGF-β1 and α-SMA expression patterns supported the gradual progression of radiation-induced liver fibrosis in both groups. These findings will be useful in the future development of protective drugs for radiation-induced liver injury.
radiation-induced liver injury; liver fibrosis; transforming growth factor-beta 1; alpha smooth muscle actin; apoptosis
The hallmark of neuronopathic Gaucher disease (GD) is oculomotor abnormalities, but ophthalmological assessment is difficult in uncooperative patients. Chromatic pupillometry is a quantitative method to assess the pupillary light reflex (PLR) with minimal patient cooperation. Thus, we investigated whether chromatic pupillometry could be useful for neurological evaluations in GD. In our neuronopathic GD patients, red light-induced PLR was markedly impaired, whereas blue light-induced PLR was relatively spared. In addition, patients with non-neuronopathic GD showed no abnormalities. These novel findings show that chromatic pupillometry is a convenient method to detect neurological signs and monitor the course of disease in neuronopathic GD.
To evaluate the efficacy of proton beam therapy (PBT) for pediatric patients with advanced neuroblastoma.
PBT was conducted at 21 sites in 14 patients with neuroblastoma from 1984 to 2010. Most patients were difficult to treat with photon radiotherapy. Two and 6 patients were classified into stages 3 and 4, respectively, and 6 patients had recurrent disease. Seven of the 8 patients who received PBT as the initial treatment were classified as the high risk group. Twelve patients had gross residual disease before PBT and 2 had undergone intraoperative radiotherapy before PBT. Five patients received PBT for multiple sites, including remote metastases. Photon radiotherapy was used in combination with PBT for 3 patients. The PBT doses ranged from 19.8 to 45.5 GyE (median: 30.6 GyE).
Seven patients are alive with no evidence of disease, 1 is alive with disease progression, and 6 died due to the tumor. Recurrence in the treatment field was not observed and the 3-year locoregional control rate was 82%. Severe acute radiotoxicity was not observed, but 1 patient had narrowing of the aorta and asymptomatic vertebral compression fracture at 28 years after PBT, and hair loss was prolonged in one patient.
PBT may be a better alternative to photon radiotherapy for children with advanced neuroblastoma, and may be conducted safely for patients with neuroblastoma that is difficult to manage using photon beams.
Neuroblastoma; Proton therapy; Radiotherapy; Late toxicity; Pediatrics
A polymer-ceramic pressure-sensitive paint (PC-PSP) is a fast responding and sprayable PSP which has been applied for capturing global unsteady flows. The luminophore application process is studied to enhance the characterization of the PC-PSP. A dipping deposition method is used to apply a luminophore on a polymer-ceramic coating. The method selects a solvent by its polarity index. The characterization includes the signal level, pressure sensitivity, temperature dependency, and response time. It is found that the luminophore application process affects the steady-state characterizations, such as the signal level, pressure sensitivity, and temperature dependency. A range of change for each characterization, which is based on the minimum quantity, is a factor of 4.7, 9, and 3.8, respectively. A response time on the order of ten microseconds is shown. The application process is not a dominant factor for changing the response time, which is within the uncertainty of the thickness variation. Comparisons of the effects on the luminophore application process and the polymer content are made to discuss the PC-PSP characterization results.
pressure-sensitive paint; polymer ceramic; luminophore application
Minimally invasive follicular thyroid carcinoma (MI-FTC) is characterized by limited capsular and/or vascular invasion with good long-term outcomes. However, some cases of MI-FTC show a poor prognosis because of severe distant metastasis (i.e., metastatic MI-FTC). Nonetheless, no method has been established for predicting the prognosis of MI-FTC. This study was conducted to identify novel prognostic factors for metastatic MI-FTC by the use of microRNA (miRNA). Thirty-four patients with MI-FTC were categorized into two groups: the metastatic group, M(+) (n=12) and the non-metastatic group, M(−) (n=22). In the M(+) group, distant metastasis was recognized after the initial operation established the diagnosis of MI-FTC. In the M(−) group, no distant metastasis was recognized postoperatively for ≥10 years. Using laser micro-dissection followed by quantitative real-time PCR and PCR arrays, we performed a comprehensive expression profiling of 667 miRNAs in formalin-fixed, paraffin-embedded samples from the initial MI-FTC operation. Furthermore, we assessed the potential use of miRNAs as novel biomarkers for the metastatic potential of MI-FTC by logistic regression analysis. Comprehensive quantitative analysis of miRNA expression in MI-FTC samples revealed that the miR-221/222 cluster (i.e., miR-221, miR-222 and miR-222*), miR-10b and miR-92a were significantly upregulated in the M(+) group compared with the M(−) group. Interestingly, the expression levels of these miRNAs were also shown to be upregulated in widely invasive FTC (WI-FTC; n=13) that has distant metastasis and worse prognosis, indicating a close similarity in the miRNA expression between metastatic MI-FTC and WI-FTC. Logistic regression analysis revealed that miR-10b made a significant contribution to prognosis (OR 19.759, 95% CI 1.433–272.355, p= 0.026). Our findings suggest that miR-10b is a potential prognostic factor for evaluating the metastatic potential of MI-FTC at an initial operation stage.
microRNA; minimally invasive follicular thyroid carcinoma; thyroid surgery; metastasis; prognostic factor
Esophageal cancer patients are often associated with multiple primary cancers (MPC). The aim of this study is to evaluate the effect of MPC on prognosis in esophageal cancer patients treated by radiotherapy. Between 2001 and 2008, esophageal cancer patients treated by definitive radiotherapy at Gunma Cancer Center were retrospectively reviewed. Exclusion criteria were preoperative or postoperative radiotherapy, palliative radiotherapy, follow-up of <6 months, radiation dose of <50 Gy and no information on MPC. We analyzed 167 esophageal cancer patients and 56 (33.5%) were associated with MPC. Gastric cancer was the most frequent tumor (38.2%), followed by head and neck cancer (26.5%). Median follow-up time was 31.5 months (range 6.1–87.3 months). Patients with MPC included more stage I/II esophageal cancer than those without MPC (66.1% vs. 36.9%, P < 0.01). The 5-year overall survival rate for esophageal cancer with MPC was relatively better than those without MPC (46.1% vs. 26.7%), although the difference did not reach statistical significance in univariate analysis (P = 0.09). Stage I/II esophageal cancer patients had a significantly better overall survival than stage III/IV patients (P < 0.01). Among esophageal cancer patients with MPC, there was no difference in overall survival between antecedent and synchronous cancer (P = 0.59). Our study indicated that the prognosis of esophageal cancer patients treated by radiotherapy was primarily determined by the clinical stage itself, but not the presence of MPC.
esophageal cancer; radiotherapy; multiple primary cancers; synchronous cancer;
Malignant pleural mesothelioma was once a rare finding but its incidence is increasing worldwide, most likely because of widespread exposure to asbestos. Although complete surgical resection is considered the only curative treatment, the results of surgery have shown a median survival time of only one year. In inoperable cases, chemotherapy, radiotherapy, and a combination of both have been considered as palliative therapy. Therefore, outcomes for inoperable cases have been poor. Here, we report the case of a long-term survivor treated with hyperthermia and chemotherapy.
A 61-year-old Japanese man with a performance status of 1 due to chest pain was referred to our hospital. He had a history of asbestos exposure for approximately five years. A computed tomography scan showed diffuse extensive right pleural thickening with small nodular lesions, and video-assisted thoracoscopy revealed tumor invasion of the ipsilateral chest wall muscles. The histopathologic findings were consistent with a diagnosis of malignant pleural mesothelioma (sarcomatoid type). The tumor was diagnosed as being stage cT3N0M0. Our patient refused any invasive therapies including surgery and radiotherapy, and was therefore treated with hyperthermia and systemic chemotherapy with agents such as cisplatin and irinotecan. He underwent three hyperthermia sessions and a single course of chemotherapy without any severe complications. One month after treatment, a follow-up computed tomography scan showed no definitive abnormality in the thoracic space. Our patient has subsequently survived without any evident disease for more than seven years.
The combination of hyperthermia and chemotherapy may be a novel and safe therapeutic option for malignant pleural mesothelioma, and can be considered for patients ineligible for radical treatment. Further clinical studies of the combination of hyperthermia and chemotherapy are needed to confirm the effects of this treatment on malignant pleural mesothelioma.
Chemotherapy; Hyperthermia; Long-term survivor; Malignant pleural mesothelioma
The purpose of this study was to determine the risk factors for rectal bleeding after prostate brachytherapy. Between April 2005 and September 2009, 89 patients with T1c-2cN0M0 prostate cancer were treated with permanent I-125 seed implantation alone. The prostate prescription dose was 145 Gy, and the grade of rectal bleeding was scored according to the Common Terminology Criteria for Adverse Events version 4.0. Post-treatment planning was performed with fusion images of computerized tomography and magnetic resonance imaging 4–5 weeks after brachytherapy. Patient characteristics and dosimetric parameters were evaluated to determine risk factors for bleeding. The calculated parameters included the rectal volume in cubic centimeters that received >50–200% of the prescribed dose (RV50–200) and the minimal doses received by 1–30% of the rectal volume (RD1–30). The median follow-up time was 42 months (ranging 18–73 months). Grade 1 rectal bleeding occurred in 24 (27.0%) patients, but no Grade 2 or severe bleeding was observed. Usage of anticoagulants had a significant correlation with the occurrence of bleeding (P = 0.007). The RV100–150 and RD1–10 were significantly higher in patients with rectal bleeding than in those without bleeding. The RV100 was identified as a possible threshold value; the 3-year rectal bleeding rate in patients with an RV100 > 1.0 cm3 was 36%, whereas that with an RV100 ≤ 1.0 cm3 was 14% (P < 0.05). Although no Grade 2 morbidity developed in this study, the RV100 should be kept below 1.0 cm3, especially in additional dose-escalated brachytherapy.
prostate cancer; brachytherapy; rectal bleeding; dose-volume-histogram; anticoagulant
The treatment strategy of central lung tumors is not established. Intraluminal brachytherapy (ILBT) is widely used for palliative treatment of endobronchial tumors, however, it is also a promising option for curative treatment with limited data. This study evaluates the results after ILBT for endobronchial carcinoma.
Sixteen-endobronchial carcinoma of 13 patients treated with ILBT in curative intent for 2000 to 2008 were retrospectively reviewed. ILBT using high dose rate 192 iridium thin wire system was performed with 5 Gy/fraction at mucosal surface. The patient age ranged from 57 to 82 years old with median 75 years old. The 16 lesions consisted of 13 central endobronchial cancers including 7 roentgenographically occult lung cancers and 3 of tracheal cancers. Of them, 10 lesions were treated with ILBT of median 20 Gy combined with external beam radiation therapy of median 45 Gy and 6 lesions were treated with ILBT alone of median 25 Gy.
Median follow-up time was 32.5 months. Two-year survival rate and local control rate were 92.3% and 86.2%, respectively. Local recurrences were observed in 2 lesions. Three patients died due to lung cancer (1 patient) and intercurrent disease (2 patients). Complications greater than grade 2 were not observed except for one grade 3 dyspnea.
ILBT combined with or without EBRT might be a curative treatment option in inoperable endobronchial carcinoma patients with tolerable complication.
Lung cancer; Radiation therapy; High dose rate; Intraluminal brachytherapy; Curative intent
A pressure-sensitive paint (PSP) with fast response characteristics that can be sprayed on a test article is studied. This PSP consists of a polymer for spraying and a porous particle for providing the fast response. We controlled the polymer content (%) from 10 to 90% to study its effects on PSP characteristics: the signal level, pressure sensitivity, temperature dependency, and time response. The signal level and temperature dependency shows a peak in the polymer content around 50 to 70%. The pressure sensitivity was fairly constant in the range between 0.8 and 0.9 %/kPa. The time response is improved by lowering the polymer content. The variation of the time response is shown to be on the order of milliseconds to ten seconds. A weight coefficient is introduced to optimize the resultant PSPs. By setting the weight coefficient, we can optimize the PSP for sensing purposes.
pressure-sensitive paint; polymer ceramic; optimization
We describe a high-speed long-depth range optical frequency domain imaging (OFDI) system employing a long-coherence length tunable source and demonstrate dynamic full-range imaging of the anterior segment of the eye including from the cornea surface to the posterior capsule of the crystalline lens with a depth range of 12 mm without removing complex conjugate image ambiguity. The tunable source spanned from 1260 to 1360 nm with an average output power of 15.8 mW. The fast A-scan rate of 20,000 per second provided dynamic OFDI and dependence of the whole anterior segment change on time following abrupt relaxation from the accommodated to the relaxed status, which was measured for a healthy eye and that with an intraocular lens.
(170.4500) Optical coherence tomography; (170.3880) Medical and biological imaging; (170.4470) Ophthalmology
To calculate the pattern deviation for identifying abnormal points of pupil perimetry, and also to evaluate the grayscale display for distinguishing glaucomatous pupil field loss (abnormal test points) from normal pupil field (normal test points).
Fourteen patients ranging in age from 51 to 80 years, who had normal-tension glaucoma (6 eyes) and primary open-angle glaucoma (8 eyes) were tested. Pupil perimetry (Kowa & Hamamatsu, Japan) was used to objectively measure the visual field. Also, to obtain a subjective visual field, the analysis was performed with a Humphrey Field Analyzer (30-2, Full threshold program, Carl Zeiss Meditec, Dublin). Of the 76 test points, the 22 surrounding points and the 3 points corresponding to the blind spot are excluded; and among the remaining 51 points, the 85th percentile value of pupil perimetry was calculated. The abnormal and normal test points were recorded, and the amount of positive or negative deviation of each test point from the normal median value for the corresponding test points was determined. We also used this technique to identify the value for distinguishing glaucomatous pupil field loss from the normal pupil field.
This study could be improved by calculating the sensitivity and specificity of a certain cut-off value between the normative data and the glaucoma patients. The value for identifying both abnormal and normal test points was a negative deviation of −4. Based on these results, pupil perimetry gray scales were determined: white (< −3), 25% gray (from −4 to −8), 50% gray (from −9 to −13), 75% gray (from −14 to −18) and black (> −19). Glaucomatous pupil field losses were generally distinguished from the normal pupil field by use of a gray scale.
Our studies demonstrated that, when a deviation of > −4 was regarded as an abnormal value, the detection of pupil perimetry exhibited improvement in glaucoma patients.
pupil perimetry; percentage pupil constriction; glaucoma; pattern deviation; gray scale
A case of bilateral pedicle stress fracture of L4 in a patient with osteoporotic compression fracture of L5 and without a history of major trauma or surgery is reported, and the literature is reviewed. Bilateral pedicle fracture is a rare entity and few cases have been reported in the literature. All reported cases had some underlying causative factors like previous spine surgery or stress related activities. To the best of the authors’ knowledge, only one case of bilateral pedicle stress fracture without a history of trauma, previous spine surgery, or stress-related activities has been reported. A 77-year-old woman presented with severe low back pain and radiating pain in the right leg that was exacerbated after standing and walking. Plain radiograph showed pathological fracture at L5 level. Magnetic resonance imaging (MRI) revealed the compression of dural sac at L5 level. CT scan taken 3 months after admission revealed bilateral pedicle fractures through L4. The patient was treated with decompressive laminectomies of L4, followed by posterior spinal fusion with rigid pedicle screw fixation and autogenous bone graft mixed with hydroxyapatite. The patient achieved pain relief and returned to normal activity. Stress fracture of the pedicle within the proximal vertebra of an osteoporotic compression fracture of lumbar spine is an uncommon entity. It may, however, be an additional source of symptoms in patients with osteoporosis who present with further back pain. Surgeons caring for this group of patients should be aware of this condition.
Pedicle fracture; Stress fracture; Osteoporosis; Low back pain; Lumbar spine
We have developed anodized-aluminum pressure-sensitive paint (AA-PSP) as a global oxygen sensor in water. Platinum (II) meso-tetra(pentafluorophenyl)porphine is selected as a luminophore based on a dipping deposition study. The developed AA-PSP is characterized using water calibration setup by controlling dissolved oxygen concentration. It is shown that AA-PSP yields 4.0% change in luminescence per 1 mg/L of oxygen concentration at 23°C. Other characteristics, such as temperature dependency, photo-degradation, and physical stability, are discussed in this paper. This AA-PSP is used to demonstrate its capability of global oxygen detection in water using the impingement of oxygen rich water (20 mg/L). Even though the difference in water is only the concentration of oxygen, we can obtain global oxygen information of the jet impingement using a fast frame rate camera. Oxygen maps as well as cross-sectional distributions are shown every 0.1 s.
global measurement; optical technique; dissolved oxygen; anodized aluminum; pressure-sensitive paint
Erysipelothrix rhusiopathiae is a causal agent of swine erysipelas, which is of economic importance in the swine industry by virtue of causing acute septicemia, chronic arthritis, and endocarditis. However, little is known about the genetic properties of its protective antigens. Recently, a surface protective antigen (SpaA) gene was identified from serotype 2 in a mouse model. We cloned spaA from virulent strain Fujisawa (serotype 1a) and determined that the N-terminal 342 amino acids without C-terminal repeats of 20 amino acids have the ability to elicit protection in mice. Fusions of 342 amino acids of Fujisawa SpaA and histidine hexamer (HisSpa1.0) protected pigs against challenge with both serotype 1 and serotype 2, the most important serotypes in the swine industry. Pigs immunized with HisSpa1.0 reacted well with both HisSpa1.0 and intact SpaA by enzyme-linked immunosorbent assay and immunoblotting. Serum collected at the time of challenge from a pig immunized with HisSpa1.0 markedly enhanced the in vitro phagocytic and killing activity of pig neutrophils against the bacteria. DNA sequences of protective regions of spaA genes from five strains of serotypes 1 and 2 were almost identical. The full DNA sequences also seemed to be conserved among strains of all 12 serotype reference strains harboring the spaA gene by restriction fragment length polymorphism analysis of PCR products. These results indicates that SpaA is a common protective antigen of serotypes 1 and 2 of E. rhusiopathiae in swine and will be a useful tool for development of new types of vaccines and diagnostic tools for effective control of the disease.