Pathogenetic implication of fusion genes in acute promyelocytic leukemia and their diagnostic utility.

Acute promyelocytic leukemia (APL) has been recognized as a discrete subset of hematopoietic malignancies constituting approximately 10% of acute myeloid leukemia cases. The hallmark reciprocal chromosomal translocation t(15;17) involving fusion between the retinoic acid receptor (RARα) gene and promyelocytic leukemia (PML) gene is a characteristic feature in APL which consequently results in the emergence of PML-RARα chimeric gene. This gene has been substantiated to be responsible for cellular transformation and is a prime target of all-trans-retinoic acid (ATRA) as well as arsenic-trioxide (ATO) therapy. Since this initial discovery, about 10 diverse translocation partner genes of RARα have been reported that result in variant APL forms strongly suggesting that disruption of RARα underlies its pathogenesis. The nature of the fusion partner has a significant bearing upon disease characteristics including sensitivity to retinoids and ATO and thereby underpins the need for rapid and accurate diagnosis and also demands a highly specific treatment approach. In this article we laid emphasis on the rearrangement of the RARα gene and its different fusion partners resulting in variant forms of APL, their implication in underlying molecular pathogenesis of APL and also the different diagnostic modalities that should be employed for their rapid and accurate diagnosis.

Causes of mortality in patients with psoriasis in Malaysia - Evidence from the Malaysian Psoriasis Registry.

BACKGROUND: Patients with severe psoriasis, namely those requiring phototherapy or systemic treatment, have an increased risk of death. The aim of this study was to determine the prevalence, aetiology and risk factors for mortality among adult patients aged 18 years and above with psoriasis in Malaysia. METHODS: This was a retrospective study involving adult patients notified by dermatologists to the Malaysian Psoriasis Registry between July 2007 and December 2013. Data were cross-checked against the National Death Registry. Patients certified dead were identified and the cause of death was analysed. Multivariate analysis using multiple logistic regression were conducted on potential factors associated with higher risk of mortality. RESULTS: A total of 419 deaths were identified among the 9775 patients notified. There were four significant risk factors for higher mortality: age>40 years (age 41-60 years old, Odds Ratio (OR) 2.70, 95%CI 1.75, 4.18; age>60 years OR 7.46, 95%CI 4.62, 12.02), male gender (OR 1.72, 95%CI 1.33,2.22), severe psoriasis with body surface area (BSA) >10% (OR 1.52, 95%CI 1.19, 1.96) and presence of at least one cardiovascular co-morbidity (OR 1.67, 95% CI 1.30, 2.14). Among the 301 patients with verifiable causes of death, the leading causes were infection (33.9%), cardiovascular disease (33.6%) and malignancy (15.9%). CONCLUSION: Infection was the leading cause of death among psoriasis patients in Malaysia. Although cardiovascular diseases are well-known to cause significant morbidity and mortality among psoriasis patients, the role of infections and malignancy should not be overlooked.

Role of SNTA1 in Rac1 activation, modulation of ROS generation, and migratory potential of human breast cancer cells.

BACKGROUND: Alpha-1-syntrophin (SNTA1) has been implicated in the activation of Rac1. However, the underlying mechanism has not yet been explored. Here, we show that a novel complex, involving SNTA1, P66shc, and Grb2 proteins, is involved in Rac1 activation. METHODS: Co-immunoprecipitation assays were used to show the complex formation, while siRNAs and shRNAs were used to downregulate expression of these proteins. Various Rac1 activation assays and functional assays, such as migration assays, in vitro wound healing assays, cell proliferation assays, and ROS generation assays, were also performed. RESULTS: The results showed a significant increase in activation of Rac1 when SNTA1 and P66shc were overexpressed, whereas depletion of SNTA1 and P66shc expression effectively reduced the levels of active Rac1. The results indicated a significant displacement of Sos1 protein from Grb2 when SNTA1 and P66shc are overexpressed in breast cancer cell lines, resulting in Sos1 predominantly forming a complex with Eps8 and E3b1. In addition, the SNTA1/P66shc-mediated Rac1 activation resulted in an increase in reactive oxygen species (ROS) production and migratory potential in human breast cancer cells. CONCLUSION: Together, our results present a possible mechanism of Rac1 activation involving SNTA1 and emphasise its role in ROS generation, cell migration, and acquisition of malignancy.

SU-E-T-497: Study of Restricted Mass Stopping Power Ratio in Small Electron Tube Fields.

PURPOSE: Electron tubes with small radii are useful to treat narrow regions which cannot accommodate normal electron applicators. In small electron fields, it is not trivial to estimate restricted mass stopping power ratio (MSR), which is needed to evaluate dose from ion chamber measurement. We studied MSRs in small electron tube fields using the Monte Carlo simulation. METHODS: Electron tubes with radii, 3 and 2.5 cm, were used in this study. Nominal electron energies were 6 and 9 MeV. There were two types of tubes. One has a normal cut but the other has a 45-degree cut. For the normal cut tube, percent depth dose (PDD) in water was evaluated along the center of axis (CAX) of a beam. For the 45-degree cut tube, PDD was evaluated along the vertical line from the intersection of the CAX and the phantom surface with 45-degree gantry angle. The MSRs and mean electron energies were calculated using the Monte Carlo simulation. RESULTS: We found good agreement between the measured and calculated PDDs. The changes of mean energies from those in the 10×10 cm2 field at the depth of maximum dose (dmax) were very small for the normal cut electron tubes. For the 45-degree cut tubes, the changes of mean energies at dmax were less than 1 MeV. The MSRs in the normal cut tube fields were almost the same as those in the 10×10 cm2 field at the corresponding depths. The MSRs for the 45-degree cut tubes deviated from those in the 10×10 cm2 by about 1% (1.5 % at most). CONCLUSIONS: We evaluated the mean energies and MSRs in small electron tube fields. The deviations of them from the values in the 10×10 cm2 were small. The maximum difference of MSR was 1.5% in 45-degree cut tube fields. This work was supported by KAKENHI (23791449), Japan Society for the Promotion of Science, and Cancer Professional Training Plan, The Ministry of Education, Culture, Sports, Science and Technology, Japan.

Inter-rater reliability of proxy simple symptom assessment scale between physician and nurse: a hospital-based palliative care team setting.

Symptom management in palliative care requires reliable symptom assessment. We assessed the inter-rater reliability of a simple proxy symptom-assessment scale using the Japanese version of the Support Team Assessment Schedule (STAS-J) in a hospital-based palliative care team (HPCT) setting. By doing this, we assessed symptoms in a series of consecutive patients at two university hospitals with certified HPCTs within 2 days of referral and 7 days after. A physician and nurse assessed 20 symptoms. In total, 120 patients were assessed within 2 days of referral and 92 patients at 7 days after referral. As a result, we find that the intra-class correlation coefficients were 0.02-0.89 at referral and 0.20-0.92 at 7 days after. The perfect concordance rates were 37-89% at referral and 53-96% at 7 days after. The perfect or +/-1 concordance rates were 71-97% at referral and 73-100% at 7 days after. In conclusion, the symptom item of the STAS-J had high inter-rater reliability.

Spinal anaesthesia and non-invasive positive pressure ventilation for hip surgery in an obese patient with advanced chronic obstructive pulmonary disease.

We describe the use of non-invasive positive pressure ventilation combined with spinal anaesthesia to allow the insertion of a dynamic hip screw in an obese patient with advanced chronic obstructive pulmonary disease. The technique avoided the hazards of intubation and general anaesthesia in this high-risk patient.

Using a flat-panel detector in high resolution cone beam CT for dental imaging.

OBJECTIVES: Cone beam CT (CBCT) requires a two-dimensional X-ray detector. In the several CBCT systems developed for dental imaging, detection has been by the combination of an X-ray image intensifier and charge-coupled device (CCD) camera. In this paper, we propose a new CBCT system in which the detector is of the flat-panel type and evaluate its performance in dental imaging. METHODS: We developed a prototype CBCT that has a flat-panel-type detector. The detector consists of a CsI scintillator screen and a photosensor array. First, the flat panel detector and image intensifier detector were compared in terms of the signal-to-noise ratio (SNR) of projected images. We then used these data and a theoretical formula to evaluate noise in reconstructed images. Second, reconstructed images of a bar pattern phantom were obtained as a way of evaluating the spatial resolution. Then, reconstructed images of a skull phantom were obtained. RESULTS: The SNR of the developed system was 1.6 times as high as that of a system with an image intensifier detector of equal detector pitch. The system was capable of resolving a 0.35 mm pattern and its field of view almost completely encompassed that of an image intensifier detector which is used in dentomaxillofacial imaging. The fine spatial resolution of the detector led to images in which the structural details of a skull phantom were clearly visible. CONCLUSIONS: The system's isotropically fine resolution will lead to improved precision in dental diagnosis and surgery. The next stage of our research will be the development of a flat panel detector system with a high frame acquisition rate.

Hypoplastic basement membrane of the lens anlage in the inheritable lens aplastic mouse (lap mouse).

Adult homozygous lap mice show various eye abnormalities such as aphakia, retinal disorganization, and dysplasia of the cornea and anterior chamber. In the fetal eye of a homozygous lap mouse, the lens placode appears to develop normally. However, the lens vesicle develops abnormally to form a mass of cells without a cavity, and the mass vanishes soon afterward. Apoptotic cell death is associated with the disappearance of the lens anlage. We examined the basement membranes of the lens anlage of this mutant by immunohistochemical methods under light microscopy using antibodies against basement membrane components of the lens anlage, type IV collagen, fibronectin, laminin, heparan sulfate proteoglycan, and entactin and by transmission electron microscopy. Immunohistochemistry showed the distribution and intensity of antibody binding to the lens anlage to be almost the same for each these antibodies regardless of the stage of gestation or whether the anlagen were from normal BALB/c or lap mice. Thus, positive continuous reactions were observed around the exterior region of the lens anlage from day 10 of gestation for type IV collagen, fibronectin, laminin, heparan sulfate proteoglycan antibodies, and at least from day 11of gestation for entactin antibody. The basement membrane lamina densa of both normal and lap mice was shown by electron microscopy to be discontinuous at days 10 and 10.5 of gestation. However, by day 11 the lamina densa was continuous in the lens anlagen of normal mice but still discontinuous in the lap mice. By day 12 of gestation, the lamina densa had thickened markedly in normal mice, whereas in lap mice it remained discontinuous and its thinness indicated hypoplasia. These results indicate that, while all basement components examined are produced and deposited in the normal region of the lens anlage in the lap mouse, the basement membrane is, for some reason, imperfectly formed. The time at which hypoplasia of the basement membrane was observed in this mutant coincided with the stage during which apoptosis in the lens anlage occurred. This result may indicate a possibility of the relationship between the basement membrane and apoptosis in this mutant.

[An electron microscopic study of the relation between epithelial cell damage and eosinophilia in the nasal mucosa of patients with nasal allergy].

To determine the relationship between epithelial damage and eosinophilia in the nasal mucosa of patients with nasal allergy, we examined the nasal mucosa (obtained by surgery) from 74 patients with allergic rhinitis, using light and electron microscopy. The extent of eosinophilia correlated significantly to grades of epithelial damage and torn tight junctions of the epithelial cells. No significant relationships were found between the severity of nasal symptoms and the extents of eosinophilia or grades of torn tight junctions of the epithelial cells. More than 50% specific granules in eosinophils in the allergic nasal mucosa showed normal findings. There were no significant relationships between the extent of eosinophil degranulation and grades of epithelial damage. Based on our results, the release of tubular vesicular structures from the eosinophil granule may be one form of eosinophil degranulation in the nasal mucosa of patients with nasal allergy.

Apoptosis in the lens anlage of the heritable lens aplastic mouse (lap mouse).

Adult homozygous lap mice show various eye abnormalities, such as aphakia, retinal disorganization, and dysplasia of the cornea and anterior chamber. In the fetal eye of a homozygous lap mouse, the lens placode seems to develop normally. However, the lens vesicle progresses abnormally to form a mass of cells without a cavity, and the mass vanishes soon afterward. We examined cell death in the lens anlage of this mutant. The lens anlagen of homozygous lap and normal mice from days 10 to 12 of gestation were observed by light microscopy after DNA end-labeling by immunohistochemistry and by transmission electron microscopy. By light microscopy, a slight frequency of cell death was detected in the lens anlage encircling the surface ectoderm and in the anlage or in the anlage of both homozygous lap mice and normal mice at day 10 of gestation. Cell death was seen in the lens anlage encircling the surface ectoderm in the normal mouse and sporadically in the anlage of the homozygous lap mouse at day 10.5 of gestation. Cell death was visible at the area of the lens vesicle attached to the surface ectoderm and encircling the surrounding surface ectoderm in the normal mouse, and in the lens anlage encircling the surface ectoderm and the apex areas of the lens anlage in the homozygous lap mouse at day 11 of gestation. At day 12 of gestation, almost no cell death was observed in the lens anlage of the normal mouse. However, extensive areas of cell death were still seen in the lens anlage at its apex, at the inner region, and encircling the surface ectoderm in the homozygous lap mouse. Electron microscopic observation showed that the dead cells observed in the lens anlagen by light microscopy in normal and lap mice are the result of apoptosis. In lap mice, cells with cytoplasmic condensation were observed mainly at days 10 and 10.5 of gestation. Many apoptotic bodies which had been phagocytosed by adjacent cells were seen predominantly at day 11 of gestation. At day 12 of gestation, apoptotic bodies phagocytosed by adjacent cells, which were seen at day 11, were still predominant, but there were more apoptotic bodies per cell and more digested apoptotic bodies than at day 11. These results indicate that cell death, resulting from apoptosis is involved in the disappearance of the lens anlage of lap mice.

Significance of serum sialic acid in patients with Crohn's disease.

Serum sialic acid was measured to evaluate the activity of Crohn's disease. The sialic acid levels of patients with Crohn's disease in remission (CRP 0.0 mg/dl) were significantly higher than those of healthy subjects and postoperative patients with Crohn's disease. In patients in remission, serum sialic acid was significantly correlated with hemoglobin, hematocrit, platelet, and rapid turnover protein. Correlations with platelet, retinol-binding protein, and prealbumin were especially strong. From these findings, it was concluded that serum sialic acid level provides a useful index of the activity of Crohn's disease.