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.

Towards global consensus on core outcomes for hidradenitis suppurativa research: an update from the HISTORIC consensus meetings I and II.

BACKGROUND: A core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed-upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e-Delphi surveys. In this manuscript, we describe two in-person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items. OBJECTIVES: To consider which items from a long list of candidate items to exclude and which to cluster into outcome domains. METHODS: The study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey. RESULTS: Forty-one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS-specific quality of life, satisfaction, symptoms, pain and global assessments. CONCLUSIONS: The HISTORIC consensus meetings I and II will be followed by further e-Delphi rounds to finalize the core domain set, building on the work of the in-person consensus meetings.

PKR regulates LPS-induced osteoclast formation and bone destruction in vitro and in vivo.

OBJECTIVE: In this study, we aimed to clarify the precise mechanism underlying lipopolysaccharide (LPS)-induced osteoclastogenesis in periodontal disease with a special reference to double-stranded RNA-dependent protein kinase (PKR). MATERIAL AND METHODS: We dissected the role of PKR in LPS-induced osteoclast differentiation and function using primary mouse bone marrow cells and RAW264.7 pre-osteoclastic cell line. We used a rat experimental periodontitis (PD) model induced by ligature placement with a Porphyromonas gingivalis LPS injection (PD rat) and analyzed the therapeutic effects of C16, a PKR inhibitor, on bone loss in PD rats. RESULTS: Protein kinase is strongly upregulated and phosphorylated by LPS in the osteoclasts. The inhibition of PKR suppressed LPS-stimulated osteoclast formation and activation. PKR inhibition also suppressed the LPS-mediated activation of NF-κB and MAPK, which are critical pathways for osteoclastogenesis. High expressions of PKR were detected in osteoclasts of PD rats, and the treatment with C16 effectively prevented alveolar bone destruction in PD rats. CONCLUSIONS: PKR plays a pivotal role in LPS-induced bone loss in PD and, thus, has potential as a therapeutic target for PD.

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.

Determination of melanin types and relative concentrations: an observational study using a non-invasive inverse skin reflectance analysis.

OBJECTIVE: Melanin is a major skin colour pigment that is made up of eumelanin (the dark brown-black colour) and pheomelanin (the light red-yellow colour) pigments. Skin-whitening products typically contain depigmentation agents that reduce the level of pigmentation by changing the pheomelanin-eumelanin production. Similarly, in skin pigment treatment of skin disorders, the melanin production is managed accordingly. To assess and improve treatment efficacy, it is important to have a measurement tool that is capable of determining the melanin types objectively. So far, the efficacy assessment is subjective. In this study, an inverse skin reflectance pigmentation analysis system that determines eumelanin and pheomelanin content is developed and evaluated in an observational study involving 36 participants with skin photo type IV. METHODS: The reflectance spectra of the left forearms of participants were analysed by the pigmentation analysis system to determine their skin parameters--pheomelanin and eumelanin concentrations, melanosome volume fraction, and epidermal thickness. The determined skin parameters are then inputted into the realistic skin model (RSM) of the Advanced Systems Analyses Program (asap®) to generate the ground truth reflectance spectra for the given skin parameters to validate the system. RESULTS: The developed pigmentation analysis system is found to be accurate with a spectral error of 0.0163 ± 0.009 between measured reflectance and the reflectance output of the analysis system and RSM. The regression analysis shows a strong linear relationship (R(2) = 0.994) indicating good precision. The relative concentrations of pheomelanin (38.23 ± 15.04) and eumelanin (1.68 ± 0.91) analysed by the system gives a ratio of pheomelanin to eumelanin of 0.048 ± 0.029; this value is consistent with previously reported figure of 0.049. CONCLUSION: The proposed pigmentation analysis system is able to determine melanin types and their relative concentrations. It has the potential to assess the efficacy of the skin-whitening and pigmentation treatments objectively in a non-invasive manner.

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.

Comorbidities associated with psoriasis - data from the malaysian psoriasis registry.

All around the world, there is growing evidence of the association between psoriasis and comorbidities which increase the risk of cardiovascular disease. This study aims to determine the prevalence of various comorbidities among adult psoriasis patients in Malaysia. A cross-sectional study was conducted among patients in the Malaysian Psoriasis Registry from January 2007 to December 2008. A total of 2,267 adult patients with psoriasis from 13 dermatology centers were included. Prevalence of various comorbidities were: hypertension 25.9%, diabetes mellitus 17.7 %, dyslipidaemia 17.8%, overweight 33.2%, obesity 20.7%, ischaemic heart disease 5.8% and cerebrovascular disease 1.4%. These comorbidities were more prevalent in patients with psoriasis of late-onset and longer duration. Active screening of these comorbidities in all adult psoriasis patients is recommended.

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.

Characterization of the Chromophore Orientation of Rhodamine B Amphiphiles in Langmuir-Blodgett Monolayers.

SHG (second harmonic generation) interferometry and linear dichroism measurements were applied to the characterization of Langmuir-Blodgett monolayers composed of rhodamine B derivatives on hydrophilic fused silica substrates. When excited with a Nd-YAG laser, the contribution of dimeric species composed of rhodamine B chromophores to the nonlinear optical behavior was large, even though the relative concentration of the dimers was small. This implies the formation of noncentrosymmetrically oriented dimers with a relatively higher nonlinear molecular susceptibility, beta. Therefore, a unique phenomenon was observed; that is, the relative phase of the SH light shifted depending on the incident light polarization (p and s). In addition, it was found that the relatively standing up orientation was favored for the dimer, while a strongly tilted orientation was favored for the monomer. Copyright 2001 Academic Press.

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.

The oxygen uptake efficiency slope and its value in the assessment of cardiorespiratory functional reserve.

Oxygen uptake efficiency slope is a new index of cardiorespiratory functional reserve derived from the logarithmic relation between oxygen uptake (VO(2)) and minute ventilation during incremental exercise. The oxygen uptake efficiency slope represents how effectively oxygen is extracted and taken into the body from the air, and then ventilated. The physiologic backgrounds of the index are based on: 1) the development of metabolic acidosis that is controlled by the distribution of blood to the skeletal muscles; 2) the physiologic dead space that is affected by the perfusion to the lungs; and 3) arterial carbon dioxide partial pressure. One of the greatest advantages of the oxygen uptake efficiency slope is that it can be calculated by exercise data of submaximal levels. Another advantage is that it is mathematically determined from a set of gas analysis data and, therefore, is completely an objective measurement. Moreover, the oxygen uptake efficiency slope is shown to be highly reproducible. Clinical applications of the oxygen uptake efficiency slope have been reported initially from a population of pediatric patients with heart disease, then from adult patients with chronic heart failure, and finally from elite endurance athletes. Further applications are expected with the use of this sophisticated index. (c)2000 by CHF, Inc.