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Introduction To investigate effects of Sitagliptin on the enhancement of beta-cell function, reducing insulin resistance, serum glucagon like peptide-1 (GLP-1) concentrations and blood glucose in patients with type 2 diabetes mellitus (T2D) and suggest one of the underlying mechanisms on beta-cell function and insulin resistance. Patients and methods This was a cross-sectional and observational study in comparison to the control group. A study population of 44 newly diagnosed patients with T2D treated with Sitagliptin with a dose of 100 mg/day for 3 months was analyzed to compare 52 healthy participants. Indices for beta-cell function, peripheral insulin sensitivity, and insulin resistance were calculated with homeostasis model assessment 2 (HOMA2) calculator and compared. Serum GLP-1 concentrations were analyzed, and regression analysis was conducted to find the correlations between GLP-1 and beta-cell function and insulin resistance. Results Newly diagnosed patients with T2D witnessed a significant reduction in beta-cell function, serum GLP-1 concentrations at the time of diagnosis. After treatment with Sitagliptin 100 mg/day, they achieved significant improvements in beta-cell function, peripheral insulin sensitivity and insulin resistance. Serum GLP-1 concentrations were increased significantly to those levels in the control group and correlated with peripheral insulin sensitivity and insulin resistance in patients whose beta-cell functions improved. Conclusion Sitagliptin improved beta-cell function, insulin resistance and blood glucose in newly diagnosed patients with T2D. Meanwhile, Sitagliptin ameliorated serum GLP-1 concentrations, which contributed to the enhancement of beta-cell.

Background The Victorian Audit of Surgical Mortality (VASM) investigates all surgically related deaths in Victoria, Australia, as a surgical educational activity aimed to make surgery safer. Whilst data collected within the audit are regularly reviewed for accuracy, there has never been a review of the data provided from health services. Methods Two-year death data provided by one Victorian health service were reviewed. Hospital notes for 4 months of each year were analysed to assess patients dying under surgical care. These data were compared to referrals to the VASM over the same period. Results Of the 3907 patient deaths recorded, 35.1% were reviewed. During their final admission, 178 (13%) patients underwent a procedure (93 medical and 85 surgical). Only 29.2% of these were recorded in the health service data set. Eighteen patients died under the care of a surgeon without a procedure, meaning that 103 deaths should have been reported to the VASM of which only 55.3% (57/103) were reported. Conclusion There were major errors in the health service database resulting in under-reporting of deaths to the VASM which could have education and policy repercussions. For improvements to the safety and quality of health services, it is critical that all deaths are accurately recorded by health services and reported to the relevant bodies with internal verification processes.

Neuroendocrine cervical cancer is a rare subtype of cervical cancer with a highly aggressive malignancy. This study was conducted to analyse the human papillomavirus (HPV) infection and molecular abnormalities in Vietnamese neuroendocrine carcinomas of the uterine cervix. HPV genotyping and p53 mutations were examined using polymerase chain reaction (PCR)-based direct sequencing. Mutations of epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS) and v-Raf murine sarcoma viral oncogene homolog B (BRAF) were identified using commercial kits. Four high-risk HPV genotypes were identified in 26 (86.7%) out of a total of 30 tumours. The prevalence of HPV 16, 18, 31 and 45 was 20.0%, 50.0%, 20.0% and 36.7%, respectively. Overexpression of p16INK4a was observed in 93.3% of cases and was significantly correlated with high-risk HPV infections. Furthermore, p53 and NRAS mutations were detected in five (16.7%) and one (3.3%) cases, respectively, whereas no EGFR, KRAS or BRAF mutations were observed. These results demonstrate that high-risk HPV infection may be an important oncogenic factor for the development and progression of cervical neuroendocrine carcinoma.

Background. During ECMO, anticoagulants, in particular, unfractionated heparin (UFH), are commonly used and monitored by laboratory tests, including ACT, APTT, and anti-Xa level. Method. A single-center retrospective observational study was conducted on adult patients undergoing ECMO between January 2019 and January 2020 at a tertiary hospital. The correlations between ACT, APTT, anti-Xa, antithrombin, and UFH dose were assessed. Results. 129 sets of measurements from 37 patients were obtained including ACT, APTT, anti-Xa, antithrombin, and UFH dose measured simultaneously. 102 out of 129 sets of values were interpreted as antithrombin deficiencies. The correlation coefficient between APTT and anti-Xa; ACT and anti-Xa are 0.72 and 0.33, respectively, p < 0.001 . The patients with normal antithrombin levels exhibited a significant correlation between APTT and anti-Xa (r = 0.80, p < 0.001 ). ACT, on the other hand, was poorly correlated with UFH dose, whether there is AT deficiency or not. Anti-Xa and APTT are only moderately correlated with UFH dose in the group without antithrombin deficiency, with correlation coefficients of 0.62 and 0.57, respectively, p < 0.05 . Conclusion. APTT value is strongly correlated with anti-Xa value, particularly in patients with normal antithrombin levels. However, the ACT value was poorly correlated with anti-Xa and not with the UFH dose. In groups without antithrombin deficiency, APTT and anti-Xa values only moderately correlated with UFH dose.

Osteoporosis, which is a common disorder associated with low bone mineral density (BMD), is one of the primary reasons for hip fracture. It not only limits mobility, but also makes the patient suffer from pain. Unlike traditional methods, which require both expensive equipment and long scanning times, this study aims to develop a novel technique employing a convolutional neural network (CNN) directly on radiographs of the hips to evaluate BMD. To construct the dataset, X-ray photographs of lower limbs and dual-energy X-ray absorptiometry (DXA) results of the hips of patients were collected. The core of this research is a deep learning-based model that was trained using the pre-processed X-rays images of 510 hips as the input data and the BMD values obtained from DXA as the standard reference. To improve performance quality, the radiographs of the hips were processed with a Sobel algorithm to extract the gradient magnitude maps, and an ensemble artificial neural network which analyses the outputs of CNN models corresponding to three Singh sites and biological parameters was utilized. The superior performance of the proposed method was confirmed by the high correlation coefficient of 0.8075 ( p 0.0001 ) of the BMD measured by DXA in a total of 150 testing cases, with only 0.12 s required for applying the computing configuration to a single X-ray image.

One of the first tasks in osteotomy and arthroplasty is to identify the lower limb varus and valgus deformity status. The measurement of a set of angles to determine this status is generally performed manually with the measurement accuracy depending heavily on the experience of the person performing the measurements. This study proposes a method for calculating the required angles in lower limb radiographic (X-ray) images supported by the convolutional neural network. To achieved high accuracy in the measuring process, not only is a decentralized deep learning algorithm, including two orders for the radiographic, utilized, but also a training dataset is built based on the geometric knowledge related to the deformity correction principles. The developed algorithm performance is compared with standard references consisting of manually measured values provided by doctors in 80 radiographic images exhibiting an impressively low deviation of less than 1.5° in 82.3% of the cases.

Low back pain which is caused by the abnormal spinal alignment is one of the most common musculoskeletal symptom and, consequently, is the reason for not only reduction of productivity but also personal suffering. In clinical diagnosis for this disease, estimating adult spinal deformity is required as an indispensable procedure in highlighting abnormal values to output timely warnings and providing precise geometry dimensions for therapeutic therapies. This paper presents an automated method for precisely measuring spinopelvic parameters using a decentralized convolutional neural network as an efficient replacement for current manual process which not only requires experienced surgeons but also shows limitation in ability to process large numbers of images to accommodate the explosion of big data technologies. The proposed method is based on gradually narrowing the regions of interest (ROIs) for feature extraction and leads the model to mainly focus on the necessary geometry characteristics represented as keypoints. According to keypoints obtained, parameters representing the spinal deformity are calculated, which consistency with manual measurement was validated by 40 test cases and, potentially, provided 1.45o mean absolute values of deviation for PTA as the minimum and 3.51o in case of LSA as maximum.

We previously reported human papillomavirus type 52 (HPV52) as the most prevalent high-risk genotype in non-cancer individuals in Vietnam. This study aimed to evaluate HPV genotypes and HPV16 E6 and E7 (E6/E7) gene variations in Vietnamese patients with genital cancers. Biopsy samples were collected from 124 Vietnamese patients with genital cancers (20 with vaginal, 50 with vulvar, and 54 with penile cancer). The HPV-DNA was amplified and genotyped, and HPV16 E6/E7 genes were compared with those previously reported for women with normal cervical cytology (N = 23). HPV-DNA was detected in 80.6% (100/124) of the cancer patients (80.0% of vaginal, 82.0% of vulvar, and 79.6% of penile), with HPV16/18 in 86.0% (86/100) and HPV52 in 7.0% (7/100) of the HPV-positive samples. The HPV-DNA prevalence and HPV genotype distribution did not significantly differ among the genital cancer patients (both P = 0.95). Significantly fewer instances of the HPV16 A4 sublineage (34.8% vs. 82.6%, P < 0.0001) and HPV16 E7 29S (36.4% vs. 87.0%, P = 0.0002) occurred in the cancer patients than in the women with normal cytology. Our results indicate that HPV16/18 accounts for more than 85% of genital cancers in Vietnam, and the HPV16 sublineage A4 containing E7 29S may be less oncogenic.

Purpose To identify patterns of analgesic prescription and to explore patient-reported pain intensity, sleep disturbance, and quality of life among cancer patients with pain in Southeast Asia (SEA). Methods This cross-sectional observational study included 465 adult outpatients prescribed analgesics for cancer pain for 1 month or longer at 22 sites in Indonesia, Malaysia, Philippines, Singapore, Thailand, and Vietnam. Data on analgesic prescription and cancer characteristics were extracted from medical records. Pain intensity, sleep disturbance, and quality of life measures were recorded via questionnaires. Results Most patients (84.4%) had stage III or IV cancer. A total of 419 patients (90.7%) were prescribed opioids; of these, 42.2% received only weak opioids, whereas 57.8% received at least one strong opioid. The mean worst pain intensity during the past 24 hours was 4.76 (standard deviation [SD], 2.47) on a scale of 0 (no pain) to 10 (worst possible pain); the mean current pain intensity was 4.10 (SD, 2.61). More than half of patients (54.8%) reported sleep disturbance caused by pain in the past 7 days. The majority of patients reported problems with pain/discomfort (82.3%), usual activities (65.8%), mobility (58.2%), and anxiety/depression (56.3%). The median daily dose prescribed in oral morphine equivalents was 30 mg for both morphine and tramadol. Conclusion Despite unrelieved pain, sleep disturbance, and issues with quality of life, a notable proportion of patients were prescribed only weak opioids, and opioid doses prescribed were generally low. Efforts focused on encouragement of prescriptions with analgesic strength and/or doses proportional to the pain management needs of patients are vital to improve the status of cancer pain management in the region.

Fecal samples submitted to our clinical microbiology laboratory from patients in the Philadelphia region were prospectively analyzed for Campylobacter species other than C. jejuni and C. coli using a filtration method and microaerobic conditions with increased H 2 concentrations. Of 225 samples tested, 13 (5.8%) yielded Campylobacter species, with frequent isolation of C. concisus . The majority of Campylobacter species were not clinically significant. Additional studies in U.S. populations are warranted.

Objective Misuse of prescription opioids is a significant public health issue in Australia. There has been a rapid rise in prescription opioid use, with an associated increase in overdose and death. The over-prescribing of oral opioids, especially oxycodone, in the ED has been identified as a contributor to this problem overseas. It is unclear if similar practice occurs in the Australian ED. The primary aim of our study was to identify the incidence of oral oxycodone administration to patients within the ED. The secondary outcome was to identify the incidence of oxycodone prescribed to patients on discharge from the ED into the community. Methods Our study was designed as an observational, retrospective data analysis of the incidence of oxycodone prescribed within the three EDs of a large Australian public health service. All immediate-release (IR) and slow-release (SR) oral oxycodone prescribed over a 4-year period (2015-2018) was included. Results There were 890 557 presentations to the three EDs during the period, which resulted in 288 242 episodes of oxycodone administration within department, equivalent to 324 administrations per 1000 presentations. There were 39 381 prescriptions for oxycodone provided on discharge, resulting in an incidence of 44 prescriptions per 1000 discharged. The most frequently prescribed opioid medication in the ED was oxycodone IR 5 mg, 78.6% of discharge prescriptions generated provided a maximum quantity (20 for IR formulation or 28 for SR) of tablets allowable under the pharmaceutical benefits scheme. Conclusions There is a higher incidence of oxycodone prescribing in the Australian ED than previously recognised. An overuse of oxycodone may be contributing to adverse patient outcomes and a public health crisis. Hospitals should consider appropriate steps to reduce the incidence of opioid prescribing and the supply of these medications into the community.

Lumbar spondylolisthesis, which is a common disorders caused by the extent of slipping of the spondylolysis vertebra and making the spinal posture unstable, mostly provides no painful symptoms and, consequently, can only be diagnosed by using X-rays. Manual methods currently used for measuring the slipping of the vertebra and segmental motions in X-rays, is not only considered as a high-levelled pre-anatomy process requiring high experienced surgeons to ensure the measurement accuracy but also practically ineffective for in handling a large number of X-ray images. Therefore, this paper mainly concerns the development of a deep learning system with supported by the convolutional neural network (CNN), in which the supplementary CNN model is trained to re-correct the keypoints located on corners of vertebra based on the first CNN regression model, to precisely measure required characteristics. In order to determine the instability of the lumbar spondylolisthesis, the measurement ability of the proposed method is also required to adapt to multiple lateral bending views including flexion and extension postures. Finally, the performance obtained has been validated with comparison between standard references measured from an experienced surgeon and automatic measured values which appreciably performed precise results with the mean deviation of 1.76° within 0.12 s for treating a single X-ray image on the computing configuration utilized.

Background: Extracorporeal shockwave lithotripsy (SWL) is still an important option in the treatment of renal tract stones. SWL is not without its limitations and alternatives should be considered. This study investigates the referral data to a new SWL planning meeting to identify reasons why SWL was not offered.Methods: A review of 12 months of data prospectively collected at a weekly stone meeting was supplemented with a retrospective chart analysis to identify the source of all referrals for SWL. The principal reason for diverting a patient to other stone management was noted.Results: 142 patients (median age 52 years) were referred for SWL over the 12-month period. SWL was not recommended in 40 (28.2%) patients. SWL was most commonly contraindicated due to excessive stone size±position (32.5%), anatomical complexity (25.0%) and radiolucency on x-ray (10.0%). The majority of patients who were diverted away from SWL were referred from an emergency department (32.5%) and the general urology clinics (20.0%).Conclusions: A significant portion of patients referred for SWL prove unsuitable for this method of stone clearance. This highlights an educational gap amongst clinicians regarding the indications and more importantly contraindications for SWL. Only 6.3% of total referrals originated from general practice suggesting a lack of awareness of the process of direct referral for SWL. Improving this with guidelines will relieve demand in outpatient clinics and help streamline patient care.

Recent evidence shows that the disruption of constitutive insulated neighbourhoods might lead to oncogene dysregulation. We present here a systematic pan-cancer characterisation of the associations between constitutive boundaries and genome alterations in cancer. Specifically, we investigate the enrichment of somatic mutation, abnormal methylation, and copy number alteration events in the proximity of CTCF bindings overlapping with topological boundaries (junctions) in 26 cancer types. Focusing on CTCF motifs that are both in-boundary (overlapping with junctions) and active (overlapping with peaks of CTCF expression), we find a significant enrichment of somatic mutations in several cancer types. Furthermore, mutated junctions are significantly conserved across cancer types, and we also observe a positive selection of transversions rather than transitions in many cancer types. We also analyzed the mutational signature found on the different classes of CTCF motifs, finding some signatures (such as SBS26) to have a higher weight within in-boundary than off-bounday motifs. Regarding methylation, we find a significant number of over-methylated active in-boundary CTCF motifs in several cancer types; similarly to somatic-mutated junctions, they also have a significant conservation across cancer types. Finally, in several cancer types we observe that copy number alterations tend to overlap with active junctions more often than in matched normal samples. While several articles have recently reported a mutational enrichment at CTCF binding sites for specific cancer types, our analysis is pan-cancer and investigates abnormal methylation and copy number alterations in addition to somatic mutations. Our method is fully replicable and suggests several follow-up tumour-specific analyses.

Genetic and epigenetic alterations importantly contribute to the pathogenesis of lung cancer. In the study, we measured the frequency and distribution of molecular abnormalities of EGFR as well as the aberrant promoter methylations of BRCA1, MGMT, MLH1, and RASSF1A in Vietnamese lung adenocarcinomas. We investigated the association between genetic and epigenetic alteration, and between each abnormality with clinicopathologic parameters. Somatic EGFR mutation that was found in 49/139 (35.3%) lung adenocarcinomas showed a significant association with young age, female gender, and non-smokers. EGFR overexpression was identified in 82 tumors (59.0%) and statistical relationships with EGFR or BRCA1 methylation but not EGFR mutation. In addition, EGFR, BRCA1, MGMT, MLH1, and RASSF1A methylations were found in 33 (23.7%), 41 (29.5%), 46 (33.1%), 28 (20.1%), and 41 (29.5%) cases of a total of 139 lung adenocarcinomas, respectively. The RASSF1A methylation was found to be linked to the smoking habit. Methylations in MGMT and RASSF1A were also found to correlate with metastasis status. Furthermore, the distribution of EGFR mutation and that of BRCA1, MGMT or RASSF1A methylation were significantly exclusive in lung adenocarcinomas. The main finding of our study demonstrate that epigenetic abnormalities might play a critical role for the lung tumorigenesis in patients with smoking history and metastasis, and partly affect the predictive value of EGFR mutations through blocking expression due to promoter EGFR hypermethylation. Mutually exclusive distribution of genetic and epigenetic alterations reflects differently biological characteristics in the etiology of lung adenocarcinomas.

Objective: To investigate the association between ABO blood group and upper limb venous thrombosis (VT) risk in patients with peripherally inserted central catheters (PICC). Methods: Single centre retrospective cohort study. A cohort of patients who underwent PICC insertion from September 2010 to August 2014 were followed up for symptomatic VT presentations diagnosed by ultrasound. Blood group status was identifed from hospital information systems. Results: 2270 participants had 3020 PICCs inserted. There were 124 cases of symptomatic VT, an incident rate of 4% [95% confdence interval, CI (3-5%)]. Univariate analysis adjusting for the clustered sample showed that having chemotherapy, two or more previous PICCs, a larger catheter size, a diagnosis of cancer and having a blood group B were all associated with an increased risk of a VT. In the multivariate analysis, PICC diameter, cancer diagnosis and blood group B were all independently associated with increased risk of VT. Conclusion: Patients undergoing PICC insertion with a blood group B appear to have a higher risk of VT, independent of risks attached to the PICC procedure and cancer diagnosis. Without any existing guidelines for PICC-related VT, this investigation creates a platform for further research to be conducted in order to establish guidelines. Advances in knowledge: Previous studies investigating VT risk associated with blood group status related to large heterogeneous populations. In this article, we look at patients specifcally with PICC, which reduces the heterogeneity in the cohort. In addition, due to the substantial number of patients enrolled, we had a chance to perform multivariate analyses with statistical signifcance. Refereed/Peer-reviewed

Aim. The aim of this study was to examine patients’ and physicians’ satisfaction, and concordance of patient-physician satisfaction with patients’ pain control status. Methods. This cross-sectional observational study involved 465 adults prescribed analgesics for cancer-related pain from 22 sites across Indonesia, Malaysia, Philippines, Singapore, Thailand, and Vietnam. Pain intensity, pain control satisfaction, and adequacy of analgesics for pain control were documented using questionnaires. Results. Most patients (84.4%) had stage III or IV cancer. On a scale of 0 (no pain) to 10 (worse pain), patients’ mean worst pain intensity over 24 hours was 4.76 (SD 2.47). More physicians (19.0%) than patients (8.0%) reported dissatisfaction with patient’s pain control. Concordance of patient-physician satisfaction was low (weighted kappa 0.36; 95% CI 0.03–0.24). Most physicians (71.2%) found analgesics to be adequate for pain control. Patients’ and physicians’ satisfaction with pain control and physician-assessed analgesic adequacy were significantly different across countries (P<0.001 for all). Conclusions. Despite pain-related problems with sleep and quality of life, patients were generally satisfied with their pain control status. Interestingly, physicians were more likely to be dissatisfied with patients’ pain control. Enhanced patient-physician communication, physicians’ proactivity in managing opioid-induced adverse effects, and accessibility of analgesics have been identified to be crucial for successful cancer pain management. This study was registered at ClinicalTrials.gov (identifier NCT02664987).

Background Although palliative care is an important public healthcare issue worldwide, the current situation in the Asia-Pacific region has not been systematically evaluated. Objectives This survey aimed to clarify the current status of palliative care in the Asia-Pacific region. Methods Questionnaires were sent to a representative physician of each member country/region of the Asia Pacific Hospice Palliative Care Network (APHN). The questionnaire examined palliative care service provision, information regarding physician certification in palliative care, the availability of essential drugs for palliative care listed by the International Association for Hospice and Palliative Care (IAHPC) and the regulation of opioid-prescribing practice. Results Of the 14 member countries/regions of the APHN, 12 (86%) responded. Some form of specialist palliative care services had developed in all the responding countries/regions. Eight member countries/regions had physician certifications for palliative care. Most essential drugs for palliative care listed by the IAHPC were available, whereas hydromorphone, oxycodone and transmucosal fentanyl were unavailable in most countries/regions. Six member countries/regions required permission to prescribe and receive opioids. Conclusions The development of palliative care is in different stages across the surveyed countries/regions in the Asia-Pacific region. Data from this survey can be used as baseline data for monitoring the development of palliative care in this region.

Background Cervical spondylotic myelopathy (CSM) is typically encountered in the elderly population. Significant inconsistencies currently exist regarding the definition of the disorder, the true incidence of CSM in younger populations, and the established diagnostic criteria. Objective To highlight the lack of standardization in the definition and diagnosis of CSM. Methods A PubMed literature search was conducted spanning the years 2001–2011. The search was limited by the following terms: (1) English language, (2) adults (19–44 years old), and (3) “cervical spondylotic myelopathy.” Each article was reviewed to determine if the presence of the definition of CSM existed in the article. The clinical characteristics used to make the diagnosis of CSM were recorded for each article. Cochran's Q statistic was used to determine whether some clinical characteristics were more frequently used than others. Results Ninety-three papers were reviewed in detail and 16 case reports, reviews, and articles concerning less than 3 patients were excluded, resulting in 77 articles in the final analysis. The most common clinical definitions were gait disturbance (22/77 articles (28.6%)), upper limb paresthesias or sensory disturbance (21/77 (27.3%)), and clumsy hands (15/77 (19.5%)). Hyperreflexia, spasticity, and pathologically increased reflexes were identified as diagnostic criteria in a minority of patients. Conclusion The literature employs a wide range of neurologic signs and symptoms to make the diagnosis of CSM, with a majority of studies failing to rely on strict diagnostic criteria. The clinician should not discount CSM as an explanation for the aforementioned findings, as it is well-reported in the literature among the ages 18–44.

Extracts from Drosera species have been published as therapeutics, especially as antioxidants. In this research, quercetin was screened and isolated for antioxidant properties from D. indica L. in vitro plantlets. Its structure has been elucidated on the basic of its spectral data mainly, 1H-, 13C-NMR, DEPT and COSY, HSQC, HMBC. HPLC also has been applied for quantitative analysis of quercetin.

e21698 Background: Adequate dosing of analgesics is important for optimum cancer pain control & quality of life (QoL). To understand current attitudes toward analgesic treatment for cancer pain in SEA, the ACE study explored patient & physician satisfaction with pain control in 6 SEA countries. Methods: This cross-sectional observational study included 465 adult outpatients prescribed analgesics for cancer pain for ≥1 month in Indonesia, Malaysia, Philippines, Singapore, Thailand, & Vietnam. Pain intensity, sleep disturbance, QoL, satisfaction with pain control, & physicians’ assessment of adequacy of analgesics were recorded via questionnaires. Current analgesic doses prescribed were extracted from medical records. Results: Most patients (84%) had stage 3 or 4 cancer. While 91% were prescribed opioids, mean reported pain intensity was 4.1 (0/no pain, 10/worst possible pain) & most had problems with sleep (55%) & QoL (problems with pain/discomfort [82%], usual activities [66%] & anxiety/depression [56%]). 60% of patients were satisfied with their pain control status & 30% found it acceptable. Physicians more often reported dissatisfaction with patients’ pain control status compared with patients (21% vs 10%). Patient-physician concordance in satisfaction with pain control was low (weighted Kappa 0.36; 95% CI 0.30-0.43). More than 1 in 4 physicians (29%) assessed prescribed analgesics to be “inadequate” for pain control. Median daily dose prescribed in oral morphine equivalents was 30 mg for both morphine & tramadol. Of the SEA countries included, prescribed doses of opioids were generally lower in Indonesia & higher in Vietnam. Conclusions: The results highlight the complexity of managing cancer pain in SEA. Despite unrelieved pain, sleep disturbance & QoL issues, many patients still reported satisfaction with pain control. Notably, physicians expressed dissatisfaction more frequently than patients. These findings suggest a need for all-round pain status assessment (including pain intensity, sleep disturbance, QoL) & improved patient-physician communication about analgesic treatment expectations, pain control & adverse effects.

Fas (APO1/CD95) is a type 1 transmembrane protein critically involved in receptor-mediated apoptosis. Previous studies have shown that Fas exists in monomeric form in resting cells and aggregates upon cross-linking to form a complex that serves to recruit additional signaling molecules to the cell membrane. To study the molecular fate of the Fas antigen following receptor activation, a monoclonal antibody specific for the cell death domain of Fas has been generated. This monoclonal antibody (3D5) could be used in Western blot analysis using total cell lysates to identify different forms of Fas antigens without immunoprecipitation. High molecular mass (>200 kDa), SDS- and beta-mercaptoethanol-resistant Fas aggregates were formed immediately following receptor cross-linking, and a 97-kDa band (p97) was detected about 2 h later. p97 could be detected by antibodies against either the death domain or the C terminus. However, p97 could not be precipitated by antiextracellular domain antibodies. Thus, p97 most likely represents a processed form of the high molecular weight Fas aggregates. Although p97 generation followed a similar time course as CPP32 activation and poly(ADP-ribose) polymerase cleavage, it could not be inhibited by cysteine protease, calpain, or proteasome inhibitors.

Dehydroxychlorofusarielin B (1), a new antibacterial polyoxygenated decalin derivative, and the previously described fusarielins A (2) and B (3) have been isolated from the broth of a marine isolate of the fungus Aspergillus. The structure and absolute stereochemistry of the new compound was determined on the basis of the physicochemical data and X-ray diffraction. Compounds 1-3 exhibited a mild antibacterial activity against Staphylococcus aureus, methicillin-resistant S. aureus, and multidrug-resistant S. aureus. The MIC values for each strain were as follows: compounds 1 and 3, 62.5 microg/mL for all strains; compound 2, 32.5 microg/mL for S. aureus and methicillin-resistant S. aureus and 62.5 microg/mL for multidrug-resistant S. aureus.

Acute promyelocytic leukemia arises following a reciprocal chromosome translocation t(15;17), which generates PML-retinoic acid receptor alpha fusion proteins (PML-RARalpha). We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins (Kamitani, T., Nguyen, H. P., Kito, K., Fukuda-Kamitani, T., and Yeh, E. T. H. (1998) J. Biol. Chem. 273, 3117-3120). To understand the mechanisms underlying the differential sentrinization of PML versus PML-RARalpha, extensive mutational analysis was carried out to determine which Lys residues are sentrinized. We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized. Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation. Furthermore, we showed that sentrinization of PML-RARalpha could be restored by overexpression of sentrin, but not by retinoic acid treatment. These studies provide novel insight into the pathobiochemistry of acute promyelocytic leukemia and the sentrinization pathway.

Sentrin is a novel ubiquitin-like protein that can be conjugated to other proteins in a manner analogous to ubiquitination. Two additional cDNA sequences that encode proteins highly homologous to sentrin have been reported to GenBankTM. It is not known whether these sentrin-like proteins could also function as protein modifiers. In this report, a second member of the sentrin family was characterized in detail. Sentrin-2 is a 95-amino acid polypeptide that is 46% identical and 66% homologous to sentrin-1. Northern blot analysis showed that the sentrin-2 message was expressed in all tissues, but was barely detectable in the liver and placenta. The ability of sentrin-2 to conjugate to other proteins was tested by expressing hemagglutinin epitope-tagged sentrin-2 in COS cells. Western blot analysis showed that sentrin-2 could be transferred to other proteins in a pattern similar to that of sentrin-1 conjugation and had similar C-terminal processing. We further showed that both sentrin-1 and sentrin-2 could covalently modify RanGAP1, a Ran GTPase-activating protein critically involved in nuclear transport. Immunocytochemical analysis showed that sentrin-2 derivatives were highly enriched in the nucleus. Taken together, our results demonstrate that sentrin-2 is another protein modifier for the sentrinization pathway.

PML, a RING finger protein with tumor suppressor activity, has been implicated in the pathogenesis of acute promyelocytic leukemia that arises following a reciprocal chromosomal translocation that fuses the PML gene with the retinoic acid receptor alpha (RARalpha) gene. Immunocytochemical analysis has demonstrated that PML is co-localized with a novel ubiquitin-like protein in the nuclear bodies, which could be disrupted by the PML-RARalpha fusion protein. The physical nature of this co-localization is unknown. Using a COS cell expression system, we show that PML is covalently modified by all three members of the sentrin family of ubiquitin-like proteins. Covalent modification of PML requires the conserved Gly residue near the C termini of sentrin proteins. Sentrinization of PML is highly specific because neither NEDD8 nor ubiquitin could modify PML. Similar specificity is also observed for the covalent modification of RanGAP1 by the sentrin member of ubiquitin-like proteins. These observations highlight the fine substrate specificity of the sentrinization pathway. In acute promyelocytic leukemia, two forms of PML-RARalpha fusion proteins have been reported. Remarkably, both forms of PML-RARalpha fusion proteins could not be sentrinized. Thus differential sentrinization of PML and PML-RARalpha could play an important role in regulating the biological function of PML and in the pathogenesis of acute promyelocytic leukemia.