Individual response of humans to ionising radiation: governing factors and importance for radiological protection.

Tissue reactions and stochastic effects after exposure to ionising radiation are variable between individuals but the factors and mechanisms governing individual responses are not well understood. Individual responses can be measured at different levels of biological organization and using different endpoints following varying doses of radiation, including: cancers, non-cancer diseases and mortality in the whole organism; normal tissue reactions after exposures; and, cellular endpoints such as chromosomal damage and molecular alterations. There is no doubt that many factors influence the responses of people to radiation to different degrees. In addition to the obvious general factors of radiation quality, dose, dose rate and the tissue (sub)volume irradiated, recognized and potential determining factors include age, sex, life style (e.g., smoking, diet, possibly body mass index), environmental factors, genetics and epigenetics, stochastic distribution of cellular events, and systemic comorbidities such as diabetes or viral infections. Genetic factors are commonly thought to be a substantial contributor to individual response to radiation. Apart from a small number of rare monogenic diseases such as ataxia telangiectasia, the inheritance of an abnormally responsive phenotype among a population of healthy individuals does not follow a classical Mendelian inheritance pattern. Rather it is considered to be a multi-factorial, complex trait.

Telomere length determined by the fluorescence in situ hybridisation distinguishes malignant and benign cells in cytological specimens.

BACKGROUND: Telomeres are tandem repeats of TTAGGG at the end of eukaryotic chromosomes that play a key role in preventing chromosomal instability. The aim of the present study is to determine telomere length using fluorescence in situ hybridisation (FISH) on cytological specimens. METHODS: Aspiration samples (n = 41) were smeared on glass slides and used for FISH. RESULTS: Telomere signal intensity was significantly lower in positive cases (cases with malignancy, n = 25) as compared to negative cases (cases without malignancy, n = 16), and the same was observed for centromere intensity. The difference in DAPI intensity was not statistically significant. The ratio of telomere to centromere intensity did not show a significant difference between positive and negative cases. There was no statistical difference in the signal intensities of aspiration samples from ascites or pleural effusion (n = 23) and endoscopic ultrasound-guided FNA samples from the pancreas (n = 18). CONCLUSIONS: The present study revealed that telomere length can be used as an indicator to distinguish malignant and benign cells in cytological specimens. This novel approach may help improve diagnosis for cancer patients.

Multiple drug combination of anti-diabetic agents as a predictor for poor clinical response to liraglutide.

AIM: Aim of the study was to retrospectively analyze the clinical parameters that contribute to the therapeutic outcome of GLP-1 analogues. METHODS: We enrolled 106 patients with type 2 diabetes mellitus (T2DM), treated with liraglutide (N.=69) or exenatide (N.=37) for longer than three months. The patients were divided into two groups: good responders and poor responders to GLP-1 analogues, based on pretreatment and post-treatment HbA1c levels. Good responders were those whose HbA1c level had decreased by 1% or more, or maintained at less than 7%. All other patients were categorized as poor responders. We used univariate and multivariate analyses to assess pretreatment parameters between the two groups. RESULTS: Approximately 35% of the patients were poor responders. Our analysis of the pretreatment clinical parameters revealed that number of anti-diabetic agents and use of sulfonylurea were significantly associated with poor response to liraglutide (P=0.02 and P=0.03, respectively) in a multivariate analysis. We were not able to find any candidate related to clinical response to exenatide. CONCLUSION: Our study showed that the therapeutic effects of GLP-1 analogues on T2DM patients were heterogeneous. T2DM patients who require multiple anti-diabetic agents, especially sulfonylurea, do not benefit from liraglutide treatment.

MR imaging-based correction for partial volume effect improves detectability of intractable epileptogenic foci on iodine 123 iomazenil brain SPECT images: an extended study with a larger sample size.

BACKGROUND AND PURPOSE: It has been suggested, on the basis of a previous pilot study conducted in a small number of patients, that MR imaging-based PVE correction in I-123 iomazenil brain SPECT improves the detectability of cortical epileptogenic foci. In the present study, we performed an investigation by using a larger sample size to establish the effectiveness of the PVE correction and to conduct a detailed evaluation based on the histologic classification of lesions. MATERIALS AND METHODS: Seventy-five patients (male/female, 37/38; age, 28 ± 12 years) with intractable epilepsy who had undergone surgical treatment were enrolled in this study. I-123 iomazenil SPECT and MR imaging examinations were performed before the operation in all patients. I-123 iomazenil SPECT images with and without MR imaging-based PVE correction were assessed visually and by semiquantitative analysis based on the AI(%) of the SPECT count in the resected lesions. RESULTS: The sensitivity, specificity, and accuracy of foci detection by visual assessment were significantly higher after PVE correction compared with the values obtained before the correction. The results of the semiquantitative analysis revealed that the asymmetry of the SPECT counts was significantly increased after the PVE correction in the surgically resected lesions in cases of mesial temporal sclerosis, tumor, and malformations of cortical development. CONCLUSIONS: The effectiveness of MR imaging-based PVE correction in I-123 iomazenil brain SPECT in improving the detection of cortical epileptogenic foci with abnormal histologic findings was established by our investigation conducted on a large sample size.

Lipid infiltration in the parotid glands: a clinical manifestation of metabolic syndrome.

BACKGROUND: The clinical features of lipid infiltration in the parotid glands (LIPG) have not been studied. Monitoring of atomic-bomb survivors for late effects of radiation exposure has provided the opportunity to review the clinical findings of LIPG. METHODS: A total of 992 atomic-bomb survivors in Nagasaki, Japan underwent lachrymal and salivary secretion tests and anthropometric, biochemical, and abdominal ultrasonographic examinations between 2002 and 2004. Among 465 subjects who had reduced tear and/or salivary excretion, 176 subjects took a salivary magnetic resonance imaging (MRI) examination. RESULTS: LIPG was detected in 53 of the 176 subjects who had salivary MRI. LIPG cases showed a preponderance of females and fatty liver compared with the subjects without LIPG. Age-and-sex-adjusted regression analysis revealed that body mass index (BMI), low-density lipoprotein cholesterol, triglycerides, hemoglobin A1c, and C-reactive protein were higher, whereas high-density lipoprotein cholesterol and adiponectin were lower, in the subjects with LIPG. Multivariate logistic regression analysis showed that BMI and fatty liver were mutually associated with LIPG independently from radiation dose. CONCLUSIONS: LIPG associated with BMI, fatty liver, and coronary risk factors was a clinical manifestation of metabolic syndrome.

[Outcome of treatment for chest trauma at a single institution].

Between March 2005 and September 2009, 41,827 patients visited our emergency outpatient clinic, and 50 patients (0.12%) were admitted to our institution for chest trauma. Seventy percent of the chest traumas were caused by traffic accidents. Eighty-five percent of the traffic accidents were associated with car driving or motorcycle driving. Rib fracture, pneumothorax, hemothorax, and lung injury were seen in 56%, 40%, 22%, and 28% of the patients, respectively. Chest tube drainage was performed in 36% of the patients. Sixty-two percent of the patients with chest trauma underwent conservative follow-up. Only 1 patient underwent the ligation of the intercostal artery. One patient with chest trauma and fracture of the cervical vertebra and the pelvis died, who was in the state of cardio-pulmonary arrest on arrival. Forty-nine patients were discharged in 15.2 +/- 17.0 days. Twenty-two percent of the patients were hospitalized only 1 night.

[Reconstruction of the left common carotid artery for dissective occlusion detected by intra-operative ultrasonography].

We describe a case of Stanford type A acute aortic dissection. Replacement of the ascending aorta and aortic arch was performed using an "arch 1st technique". Following the completion of replacement, hypotension of the left superficial temporal artery pressure was detected. Ultrasonography revealed dissection of the left common carotid artery (LCCA) and compressive occlusion of the true lumen. Reconstruction of the LCCA was performed in the neck. The patient did well after the operation without any neurological abnormalities.

Prevalence of adult-onset multifactorial disease among offspring of atomic bomb survivors.

The first study to examine whether parental radiation exposure leads to increased heritable risk of common adult-onset multifactorial diseases (i.e., hypertension, diabetes mellitus, hypercholesterolemia, ischemic heart disease, and stroke) was conducted among 11,951 participants in the clinical examination program out of a potential of 24,673 mail survey subjects who were offspring of survivors born from May 1946 through December 1984. Logistic regression analyses demonstrated no evidence of an association between the prevalence of multifactorial diseases in the offspring and parental radiation exposure, after adjusting for age, city, gender and various risk factors. The odds ratio (OR) for a paternal dose of 1 Gy was 0.91 [95% confidence interval (CI) 0.81-1.01, P = 0.08], and that for a maternal dose of 1 Gy was 0.98 (95% CI 0.86-1.10, P = 0.71). There was no apparent effect of parental age at exposure or of elapsed time between parental exposure and birth, but male offspring had a low odds ratio (OR = 0.76 at 1 Gy) for paternal exposure, but cautious interpretation is needed for this finding. The clinical assessment of nearly 12,000 offspring of A-bomb survivors who have reached a median age of about 50 years provided no evidence for an increased prevalence of adult-onset multifactorial diseases in relation to parental radiation exposure.

Adiponectin induces insulin secretion in vitro and in vivo at a low glucose concentration.

AIMS/HYPOTHESIS: A decrease in plasma adiponectin levels has been shown to contribute to the development of diabetes. However, it remains uncertain whether adiponectin plays a role in the regulation of insulin secretion. In this study, we investigated whether adiponectin may be involved in the regulation of insulin secretion in vivo and in vitro. METHODS: The effect of adiponectin on insulin secretion was measured in vitro and in vivo, along with the effects of adiponectin on ATP generation, membrane potentials, Ca2+ currents, cytosolic calcium concentration and state of 5'-AMP-activated protein kinase (AMPK). In addition, insulin granule transport was measured by membrane capacitance and total internal reflection fluorescence (TIRF) analysis. RESULTS: Adiponectin significantly stimulated insulin secretion from pancreatic islets to approximately 2.3-fold the baseline value in the presence of a glucose concentration of 5.6 mmol/l. Although adiponectin had no effect on ATP generation, membrane potentials, Ca2+ currents, cytosolic calcium concentrations or activation status of AMPK, it caused a significant increase of membrane capacitance to approximately 2.3-fold the baseline value. TIRF analysis revealed that adiponectin induced a significant increase in the number of fusion events in mouse pancreatic beta cells under 5.6 mmol/l glucose loading, without affecting the status of previously docked granules. Moreover, intravenous injection of adiponectin significantly increased insulin secretion to approximately 1.6-fold of baseline in C57BL/6 mice. CONCLUSIONS/INTERPRETATION: The above results indicate that adiponectin induces insulin secretion in vitro and in vivo.

Prevalence of Sjogren syndrome among Nagasaki atomic bomb survivors.

OBJECTIVES: Through a comprehensive epidemiological study, we determined Sjögren syndrome (SS) prevalence and examined the association between SS and ionising radiation dose. METHODS: A total of 1008 atomic bomb survivors in Nagasaki agreed to undergo the tests comprising a questionnaire for xerophthalmia and xerostomia, Schirmer-I test, Saxon test, and tests of anti-SS-A/Ro and anti-SS-B/La antibodies, and, if necessary, Rose Bengal stain test, salivary ultrasonographic and MRI examination from November 2002 through October 2004. Diagnosis of SS was based on the American-European Consensus Group criteria, or a modified version thereof. RESULTS: Among the 1008 participants (male 398, female 610, average age 71.6 years), 154 participants (15.3%) complained of xerophthalmia, and 264 (26.2%) of xerostomia. Reduced tear flow as assessed by the Schirmer-I test was detected in 371 of 992 participants (37.4%) and reduced saliva flow as assessed by the Saxon test in 203 of 993 participants (20.4%). Among all participants, 38 (3.8%) and 10 (1.0%) participants tested positive for anti-SS-A/Ro and anti-SS-B/La antibodies, respectively. Taking into consideration all the results, 23 participants were diagnosed with SS (primary 20, secondary 3), yielding a prevalence of 2.3%. Although the association between SS and radiation dose was not significant, radiation dose was significantly associated with hyposalivation. CONCLUSIONS: The present comprehensive epidemiological study reveals that the prevalence of SS was 2.3% among Nagasaki atomic bomb survivors and was not associated with radiation dose. The association between radiation dose and hyposalivation supported the possibility that radiation exposure damaged salivary gland function.

[Anaphylactic shock related to aprotinin induced by anti-aprotinin immunoglobulin G antibody alone; report of a case].

Anaphylactic shock related to aprotinin has been reported to be induced exclusively in the presence of IgE antibody. And the possibility of anaphylactic shock induced by anti-aprotinin IgG antibody alone was controversial. In this paper, we describe the first case of anaphylactic shock induced by aprotinin-specific IgG antibody alone. A 55-year-old man underwent surgical repair of the descending aorta with the use of aprotinin at 2 months after first aprotinin usage. Immediately after initiation of cardiopulmonary bypass with the continuous infusion of aprotinin, clinical symptoms of anaphylactic reaction were found. Postoperative drug lymphocyte stimulation test for aprotinin and aprotinin-specific IgE antibody were negative, but aprotinin-specific IgG antibody was 163 mg/l and positive.

Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19.

Hypercalcemia is relatively rare but clinically important complication in childhood leukemic patients. To clarify the clinical characteristics, mechanisms of hypercalcemia, response to management for hypercalcemia, incidence of t(17;19) and final outcome of childhood acute lymphoblastic leukemia (ALL) accompanied by hypercalcemia, clinical data of 22 cases of childhood ALL accompanied by hypercalcemia (>12 mg/dl) reported in Japan from 1990 to 2005 were retrospectively analyzed. Eleven patients were 10 years and older. Twenty patients had low white blood cell count (<20 x 10(9)/l), 15 showed hemoglobin> or =8 g/dl and 14 showed platelet count > or =100 x 10(9)/l. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcemia was confirmed in 11 of the 16 patients in whom elevated-serum level or positive immunohistochemistry of PTHrP was observed. Hypercalcemia and accompanying renal insufficiency resolved quickly, particularly in patients treated with bisphosphonate. t(17;19) or add(19)(p13) was detected in five patients among 17 patients in whom karyotypic data were available, and the presence of E2A-HLF was confirmed in these five patients. All five patients with t(17;19)-ALL relapsed very early. Excluding the t(17;19)-ALL patients, the final outcome of ALL accompanied by hypercalcemia was similar to that of all childhood ALL patients, indicating that the development of hypercalcemia itself is not a poor prognostic factor.

Auditory and tactile processing in a postmeningitic deaf-blind patient with a cochlear implant.

The authors examined the neural function of a postmeningitic deaf-blind patient who regained his hearing with a multichannel cochlear implant. Auditory stimuli activated the temporal cortices of both sides in a manner similar to that of controls, reflecting the successful recruitment of the auditory cortex after implantation. The patient's occipital lobes were deactivated during the tactile language task, the results of which were completely different from those before cochlear implantation.

Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma.

Retinoic acid (RA) has been shown to induce neuronal differentiation and/or apoptosis, and is widely used as a chemotherapeutic agent for treating the patients with neuroblastoma. However, the therapeutic effect of RA is still limited. To unveil the molecular mechanism(s) inducing differentiation and apoptosis in neuroblastoma cells, we compared CHP134 and NB-39-nu cell lines, in which all-trans-RA (ATRA) induces apoptosis, with LA-N-5 and RTBM1 cell lines, in which it induces neuronal differentiation. Here, we found that Bcl-2 was strongly downregulated in CHP134 and NB-39-nu cells, whereas it was abundantly expressed in LA-N-5 and RTBM1 cells. ATRA-mediated apoptosis in CHP134 and NB-39-nu cells was associated with a significant activation of caspase-9 and caspase-3 as well as cytoplasmic release of cytochrome c from mitochondria in a p53-independent manner. Enforced expression of Bcl-2 significantly inhibited ATRA-mediated apoptosis in CHP134 cells. In addition, treatment of RTBM1 cells with a Bcl-2 inhibitor, HA14-1, enhanced apoptotic response induced by ATRA. Of note, two out of 10 sporadic neuroblastomas expressed bcl-2 at undetectable levels and underwent cell death in response to ATRA in primary cultures. Thus, our present results suggest that overexpression of Bcl-2 is one of the key mechanisms to give neuroblastoma cells the resistance against ATRA-mediated apoptosis. This may provide a new therapeutic strategy against the ATRA-resistant and aggressive neuroblastomas by combining treatment with ATRA and a Bcl-2 inhibitor.

[Arch first technique using handmade branched graft].

We created a method using handmade branched graft to do the aortic arch surgery easier and safer. We made the branched graft using 12 and 8 mm vascular graft. A 77-year-old man with Stanford type A aortic dissection was operated with this method under deep hypothermia. After aortic root manipulation, perfusion of the aortic arch was stopped and selective cerebral perfusion was established. Left subclavian artery (LSCA) was anastomosed to one of the branches. The perfusion of the LSCA was re-started via one of its branches. Respectively, left common carotid artery and brachiocephalic artery reconstruction and reperfusion were performed in a same fashion. After distal anastomosis, anastomosis between the branched graft and main graft was performed consecutively. Postoperative course was uneventful and there was no complication. The treatment of our branched graft was easier than that of ready-made 4-branched graft. We could perform the operation under clear view for its movability with minimal cerebral ischemic time.

Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t(1;19)(q23;p13.3) in acute lymphoblastic leukemia.

We analyzed the TS-2 acute lymphoblastic leukemia (ALL) cell line that contains a t(1;19)(q23;p13.3) but lacks E2A-PBX1 fusion typically present in leukemias with this translocation. We found that the t(1;19) in TS-2 fuses the 19p13 gene DAZAP1 (Deleted in Azoospermia-Associated Protein 1) to the 1q23 gene MEF2D (Myocyte Enhancer Factor 2D), leading to expression of reciprocal in-frame DAZAP1/MEF2D and MEF2D/DAZAP1 transcripts. MEF2D is a member of the MEF2 family of DNA binding proteins that activate transcription of genes involved in control of muscle cell differentiation, and signaling pathways that mediate response to mitogenic signals and survival of neurons and T-lymphocytes. DAZAP1 is a novel RNA binding protein expressed most abundantly in the testis. We demonstrate that MEF2D/DAZAP1 binds avidly and specifically to DNA in a manner indistinguishable from that of native MEF2D and is a substantially more potent transcriptional activator than MEF2D. We also show that DAZAP1/MEF2D is a sequence-specific RNA-binding protein. MEF2D has been identified as a candidate oncogene in murine retroviral insertional mutagenesis studies. Our data implicate MEF2D in human cancer and suggest that MEF2D/DAZAP1 and/or DAZAP1/MEF2D contribute to leukemogenesis by altering signaling pathways normally regulated by wild-type MEF2D and DAZAP1.

Optic nerve compression by normal carotid artery in patients with normal tension glaucoma.

AIM: To determine whether compression of the optic nerve by the intracranial carotid artery (ICA) can be a causative factor of normal tension glaucoma (NTG). METHODS: The medical records of 103 eyes of 54 Japanese patients with NTG and 104 eyes of 52 age matched control patients were reviewed. The neuroradiological findings of magnetic resonance images (MRI) were evaluated to determine the relation between the optic nerve and ICA. The clinical characteristics and general medical conditions, such as diabetes and systemic hypertension, were also compared between the two groups. RESULTS: The prevalence of optic nerve compression by the ICA in patients with NTG was 49.5%, which was significantly higher than that in control group with 34.6% (p = 0.035). Bilateral compression of the optic nerve was detected in 22 patients with NTG (40.7%), and this was also significantly higher (p = 0.029) than that in the control group (11 patients, 21.2%). In the NTG group, eyes with cup/disc ratio (C/D ratio) > or =0.7 showed a higher percentage of compression (52.6%) compared with eyes with C/D ratio of <0.7 (12.5%; p = 0. 042). The presence of diabetes and hypertension did not affect the incidence of optic nerve compression by ICA significantly. CONCLUSIONS: The significantly higher percentage of NTG patients who had optic nerve compression by the ICA suggests that compression of the optic nerve by ICA may be a possible causative factor or a risk factor for optic nerve damage in some patients with NTG.

[Mucinous adenocarcinoma of the anterior mediastinum].

The authors report are a rare case of primary mucinous adenocarcinoma of the anterior mediastinum in a 34-year-old Japanese woman. Routine chest radiography revealed an abnormal mass lesion in the left upper mediastinum. Her serum CA 19-9 level was elevated at 299 (normal < 37) U/ml. The large tumor in the anterior mediastinum, 8 cm in diameter, were made of multicystic part with thick wall and thick spetrum and solid part in chest computed tomography (CT). Teratoma was suggested by percutaneous needle biopsy under CT scanning. When the chest was opened through a median sternotomy, adding a left collar incision, we found a hard tumor occupying the superior anterior mediastinum and then resected the tumor together with the left brachiocephalic vein, the left pleura, the pericardium and the left phrenic nerve because of invaded them. Grossly, the tumor was 13 x 10 x 8 cm and weighted 400 g. Pathologic diagnosis was mucinous adenocarcinoma of the anterior mediastinum. No primary cancer lesions were found in pancreas, ovarium, gastrointestinal tract and mammary gland. Microscopic examination showed minimal atypia site in mucinous adenocarcinoma and normal thymic tissues surrounding this tumor. These findings have led this case to conclude the primary tumor of thymus.

Correlation of syntaxin-1 and SNAP-25 clusters with docking and fusion of insulin granules analysed by total internal reflection fluorescence microscopy.

AIMS/HYPOTHESIS: The interaction of syntaxin-1 and SNAP-25 with insulin exocytosis was examined using the diabetic Goto-Kakizaki (GK) rat and a total internal reflection fluorescence (TIRF) imaging system. METHODS: Primary rat pancreatic beta cells were immunostained with anti-syntaxin-1A, anti-SNAP-25 and anti-insulin antibodies, and then observed by TIRF microscopy. The real-time image of GFP-labelled insulin granules motion was monitored by TIRF. RESULTS: The number of syntaxin-1A and SNAP-25 clusters, and the number of docked insulin granules on the plasma membrane were reduced in GK beta cells. When GK rats were treated with daily insulin injection for 2 weeks, the number of syntaxin-1 and SNAP-25 clusters was restored, along with the number of docked insulin granules. The infection of GK beta cells with Adex1CA SNAP-25 increased the number of docked insulin granules. TIRF imaging analysis demonstrated that the decreased number of fusion events from previously docked insulin granules in GK beta cells was restored when the number of docked insulin granules increased by insulin treatment or Adex1CA SNAP-25 infection. CONCLUSIONS/INTERPRETATION: There was a close correlation between the number of syntaxin-1 and SNAP-25 clusters and the number of docked insulin granules, which is associated with the fusion of insulin granules.