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.

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.

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.

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.

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.

Oxygen uptake efficiency slope: a new index of cardiorespiratory functional reserve derived from the relation between oxygen uptake and minute ventilation during incremental exercise.

OBJECTIVES: We investigated the usefulness of a new variable, oxygen uptake efficiency slope (OUES), as a submaximal measure of cardiorespiratory functional reserve. The OUES is derived from the relation between oxygen uptake (Vo2 [ml/min]) and minute ventilation (VE [liters/min]) during incremental exercise and is determined by VO2 = a log VE + b, where a = OUES, which shows the effectiveness of Vo2. BACKGROUND: Maximal oxygen uptake (VO2max) is effort dependent. There is no standard submaximal measurement of cardiorespiratory reserve that provides generally acceptable results. METHODS: Exercise tests, following a standard Bruce protocol, were performed on a treadmill by 108 patients with heart disease and 36 normal volunteers. Expired gas was continuously analyzed. The OUES was calculated from data of the first 75%, 90% and 100% of exercise duration. We also determined the following submaximal variables: the ventilatory anaerobic threshold (VAT), the slope of the regression line of the minute ventilation-carbon dioxide production relation (VE-VCO2 slope) and the extrapolated maximal oxygen consumption (EMOC). We analyzed the relation of OUES and other submaximal variables against VO2max and examined the effects of submaximal exercise on OUES. RESULTS: The correlation coefficient of the logarithmic curve-fitting model was 0.978 +/- 0.016 (mean +/- SD). The OUES and VO2max had a significant correlation (r = 0.941, p < 0.0001). The correlation between VO2max and OUES was stronger than that between VO2max and VAT, the VE-VCO2 slope or EMOC. The OUES values for 100% and 90% of exercise were not different from each other (at an alpha value of 0.05 and treatment effect of 170, the power of the test [1-beta] was 0.90); OUES for 75% of exercise was slightly lower (3.5%). CONCLUSIONS: Our results suggest that OUES may provide an objective, effort-independent estimation of cardiorespiratory functional reserve that is related both to pulmonary dead space and to metabolic acidosis.

Developmental changes of esteroprotease and androgen receptors in the mouse submandibular gland.

The activities of p-tosyl-L-arginine methyl ester (TAMEase) and cytosolic and nuclear androgen receptors in the submandibular glands of male and female mice were determined at various developmental stages. In males, the activity of TAMEase was detectable at four weeks after birth, and thereafter it increased rapidly. Cytosolic androgen receptor increased gradually with age, whereas nuclear androgen receptor, which was minimal one week after birth, increased remarkably four weeks after birth. In females, the minimal activity of TAMEase was detectable at five weeks after birth and increased very slowly with age. Cytosolic receptor increased with age, but nuclear receptor level was unchanged. These findings suggest that the appearance of TAMEase was in accordance with an elevation of nuclear androgen receptor in mice submandibular glands.

Oxygen intake efficiency slope: a new index of cardiorespiratory functional reserve derived from the relationship between oxygen consumption and minute ventilation during incremental exercise.

We investigated the usefulness of the oxygen intake efficiency slope (OIES) as a submaximal measure of cardiorespiratory functional reserve. OIES was derived from the relationship between oxygen consumption (VO2; ml/min) and minute ventilation (VE; l/min) during incremental exercise, which was determined by the following equation: VO2 = a logVE + b, where "a" represents OIES, which shows the effectiveness of ventilation. Maximal oxygen consumption (VO2max) is effort-dependent. There is no standard submaximal measurement of cardiorespiratory reserve that provides generally acceptable results. Exercise tests were performed by 17 normal volunteers on an ergometer using a symptom-limited Ramp protocol. Expired gas was continuously analyzed. OIES was calculated using the first 75%, 90%, and 100% of exercise data. We also determined the following submaximal parameters: the ventilatory anaerobic threshold (VAT), the slope of the minute ventilation-carbon dioxide production relationship (VE-VCO2 slope), and the extrapolated maximal oxygen consumption (EMOC). We analyzed the relationship between OIES, other submaximal parameters and VO2max, and examined the effects of submaximal exercise on OIES. The correlation coefficient of the logarithmic curve-fitting model was 0.991 +/- 0.006. OIES and VO2max were significantly correlated (r = 0.966, p < 0.0001). The correlation between OIES and VO2max was stronger than the correlation between VO2max and VAT, the VE-VCO2 slope and EMOC. OIES values for 100% and 90% of exercise were identical; OIES for 75% of exercise was slightly lower (3%). Our results suggested that OIES may provide an objective, effort-independent estimation of cardiorespiratory functional reserve.

The alteration of nasal resistance before and after local exposure to heated aerosol in perennial allergic rhinitis.

To determine the patho-physiological effects of heated vapour to the normal or allergic nasal mucosa, we measured the nasal resistance before and after a 10 min. exposure of hyperthermal (43.0 degrees C) aerosol to the nasal mucosa in normal subjects and perennial allergic rhinitis patients. In the allergic patients the mean nasal resistances after hyperthermal stimulation were significantly higher than those resistances without stimulation, both in expiration or inspiration. No significant differences of nasal resistances in normal individuals during the whole schedule with and without heated aerosol stimulation were found on expiration or inspiration. The local heated aerosol exposure increases the nasal resistance in nasal allergic patients while in normal subjects no changes were found, and the reaction may have arisen from a non-specific hypersensitivity of the susceptible allergic nasal mucosa.

Reproducibility of the oxygen uptake efficiency slope in normal healthy subjects.

BACKGROUND: To elucidate the intertest agreement of the oxygen uptake efficiency slope (OUES) in comparison with those of the maximal oxygen uptake (VO2max) and the ventilatory anaerobic threshold (VAT). EXPERIMENTAL DESIGN: A comparative study. SETTING: Institutional practice. A total of 19 healthy volunteers underwent two sessions of maximal exercise testing with an interval of no more than 7 days. The testing was conducted on a cycle ergometer with the work rate increased by either 20, 30, or 40 Watts (W)/min so that the subject would reach exhaustion within 9 to 12 min of exercise. VAT was defined as the level of oxygen uptake (VO2) at which either an increase in the ventilatory equivalent for oxygen without a concomitant increase in the ventilatory equivalent for carbon dioxide or a change in the slope of the linear relationship between carbon-dioxide production (VCO2) and VO2 occurred. OUES was determined by the following equation: VO2 = a log VE + b, where VE was minute ventilation and "a" was the OUES. Intertest reproducibility was assessed by coefficient of repeatability (COR). RESULTS: The intertest reproducibility of VO2max and OUES were excellent (COR = 570 ml/min [16%] and 740 [20%], respectively). VAT showed poor agreement between the two tests (COR = 650 ml/min [31%]). CONCLUSIONS: Results show that OUES is reproducible and reliable, supporting the clinical usefulness of this index.

Cardiorespiratory response to exercise in patients with exercise-induced bronchial obstruction.

OBJECTIVE: To document the characteristics of the ventilatory response to exercise in patients with exercise-induced bronchial obstruction (EIB). EXPERIMENTAL DESIGN: Comparative study during the period between December 1993 and March 1994. SETTING: Ambulatory care in Ohgaki Municipal Hospital. SUBJECTS AND METHOD: We evaluated 11 children with EIB. Each subject under went symptom-limited cardiopulmonary treadmill exercise testing (Bruce protocol). RESULTS: Patients with EIB showed a significantly lower peak oxygen consumption (peak VO2) than the control subjects. Three patients with EIB developed relative hypoventilation during incremental exercise: an increase in end-tidal carbon dioxide partial pressure (PETCO2) and a decrease in VE/VCO2 were observed at the end-stage of exercise testing. CONCLUSIONS: These findings demonstrate that some patients with EIB develop bronchoconstriction during exercise.

Small-scale field trials of Bacillus sphaericus (strain 2362) formulations against Mansonia mosquitoes in Malaysia.

Five formulations of Bacillus sphaericus (strain 2362) including aqueous suspension BSP 1, BSP 2, technical powder ABG 6184, corncob granules ABG 6185 (potencies 2 x 10(10), 2 x 10(7), 9.5 x 10(10), 5 x 10(10), 5 x 10(10) spore/g, respectively) and wettable powder ABG 6232 (1,000 BS ITU/mg) were tested against laboratory-cultured late third/early fourth instar larvae of Mansonia uniformis in floating screened cages in small plots at swampy ditches on Penang Island, Malaysia. Mean dosage/response values at 90% mortality levels were 6.93, 95.32, 1.45, 11.92 and 2.86 liters or kg per ha, respectively, for the formulations tested. There were practically no residual effects for the formulations tested with larvae introduced at 48, 96, and 168 h post-treatment. In trials of BSP 1, ABG 6184 and ABG 6185 (1 liter or 1 kg per ha) against immature Mansonia spp. in impounded paddy field ditches, improved efficacy and residual effects were obtained with mean reductions of 93.1, 91.9 and 80.4% at days 3, 7 and 14 posttreatment, respectively.

Field efficacy of mosquito coil formulations containing d-allethrin and d-transallethrin against indoor mosquitos especially Culex quinquefasciatus Say.

Comparative field efficacy studies of four mosquito coil formulations containing active ingredient of d-allethrin (0.19 or 0.28 w/w) and d-transallethrin (0.12 or 0.16% w/w) and blank coils without active ingredient were carried out in living rooms (mean size 54.1 m3) of residential houses in a squatter area in Butterworth, Malaysia. The major indoor biting mosquitos collected in the test site were that of Culex quinquefasciatus Say (84.7%). Mean percentage reduction of blank coils, coils with 0.19 and 0.28% d-allethrin and coils with 0.12 and 0.16% d-transallethrin were 29.0, 71.7, 70.9, 75.0 and 72.6%, respectively. The use of coils as a mean of personal protection against mosquitos is discussed.

Apical endocytosis of lectins by the absorptive cells of the suckling rat jejunum in vivo.

Apical endocytosis in the absorptive cells of the suckling rat jejunum was examined in vivo using the intraluminal injection of a range of different lectin-horseradish peroxidase (HRP) conjugates. Con A-HRP, PNA-HRP, LCA-HRP and RCA120-HRP bound strongly to components of the glycocalyx on the plasma membrane of the microvilli, apical coated pits and the small tubular pits at the base of the microvilli of the absorptive cells. The lectin-conjugates on the plasma membranes were endocytosed from the coated pits and small tubular pits, and then transported into coated vesicles, vesicles and small tubules. Lectin-HRP conjugates were later found within the intercellular space. In contrast, SBA-HRP and DBA-HRP bound weakly to the plasma membranes. The absorptive cells demonstrated little uptake or transepithelial transport. When WGA-HRP was injected into the intestinal lumen in vivo, the jejunum absorptive cells formed a deep and wide apical invagination at the base of the microvilli. WGA-HRP bound strongly to the components of the glycocalyx on the plasma membranes of the microvilli, the deep and wide apical invaginations, the apical coated pits and the small tubular pits. The WGA-HRP conjugate was also found in the coated vesicles, tubules, early endosomes, late endosomes, multivesicular bodies and lysosomes, and within the intercellular space. The lectin-HRP conjugate on the plasma membranes however was almost entirely transported into the early endosomes, late endosomes, multivesicular bodies and lysosomes. Therefore, lectin-HRP conjugates may bind to the glycocalyx component on the apical membrane domains, thus resulting in different membrane formations of apical endocytosis by adsorption to the apical plasma membrane specific glycoconjugates in the absorptive cells of the suckling rat jejunum. In addition, WGA induces deep and wide invaginations in the dynamic (not static) membrane domain of the apical plasma membrane in the suckling rat jejunum in vivo.

Contributing factors in non-union of the humeral shaft fracture and the results of treatments.

Out of 218 fractures of humeral shaft treated in the department, 23 (10.5%) of them developed non-union. 14/23 (60.9%) fracture were located in middle third. Transverse (52.2%), short oblique (17.4%) and comminuted fracture (13.0%) constituted about 82% of all initial fracture pattern. Twelve cases (52.5%) were initially treated with hanging cast. Radial nerve palsy occurred in 4/23 (17.4%) of patient and all of them located at lower third of humerus and only one recovered after eight weeks of injury. Factors such as middle third comminuted opened fractures, soft tissue interposition, improper immobilization and poor patient compliance were found to be directly associated with the non-union. All non-unions healed following plating and bone grafting. Overall 17/23 patient (74%) had good results, 4/23 (17%) fair and 2/23 (9%) with poor functional results.

[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.

[Local eosinophilia of the nose, the larynx and the trachea in rats sensitized with Japanese cedar pollen].

Eight Brown Norway rats were immunized twice at days 0 and 13 by intraperitneal injections of 10 micrograms Cry j I, one of major allergen to Japanese cedar pollinosis, mixed with 4.5 mg aluminium hydroxide gel. Serum level of Anti-Cry j I IgE antibody was detected by the method of ELISA. Mean value of serum levels of specific IgE to Cry j I in the sensitized rats was significantly higher than that in the non-sensitized five rats (p < 0.01). The grades of eosinophil and lymphocyte accumulation in the nasal mucosa of the sensitized rats were higher than those in the non-sensitized rats respectively (p < 0.05, p < 0.01). In the laryngeal mucosa, the grade of eosinophilia in the sensitized rats was higher than that in the control (p < 0.01), but no significant differences of lymphocyte accumulation in the larynx between the two groups were found. Only a small number of eosinophil and lymphocyte accumulations in the trachea of the both groups were observed and no significant differences of the grade of inflammatory cells accumulation between the two groups were found. According to the results of this fundamental study, allergic laryngitis in Japanese cedar pollinosis might be originated from Japanese cedar pollen.