Improved risk stratification of nasopharyngeal cancer by targeted sequencing of Epstein-Barr virus DNA in post-treatment plasma.

BACKGROUND: Quantitative measurement of plasma Epstein-Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients. PATIENTS AND METHODS: Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA. RESULTS: The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS. CONCLUSION: NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.

Psychological and work-related factors predicting work engagement in Malaysian employees.

BACKGROUND: Past research on work engagement has focused almost exclusively on either psychological or work-related factors in almost wholly separate literature. There is therefore a need to examine how these factors collectively influence work engagement. AIMS: To determine levels of work engagement and to identify psychological and work-related characteristics predicting work engagement in employees in Malaysia. METHODS: We recruited 5235 employees from 47 public and private organizations in Malaysia who responded to an online health survey. We assessed work engagement with the 9-item Utrecht Work Engagement Scale (UWES-9) and psychological distress using the 6-item Kessler scale. We performed multiple linear regression to determine predictors of work engagement. RESULTS: Employee mean age was 33.8 years (standard deviation [SD] ± 8.8). The mean work engagement score on the UWES-9 was 3.53 (SD ± 0.94). Eleven of 18 variables on multiple regression predicted work engagement, F(18, 4925) = 69.02, P < 0.001, R2 = 0.201. Factors that predicted higher work engagement were age, marital status, education level, job type, job permanency, longer sleep duration, lower psychological distress and no history of workplace bullying. CONCLUSIONS: Key factors associated with poorer work engagement in Malaysian employees include inadequate sleep, psychological distress and a history of workplace bullying. These are modifiable factors that individuals and employers can target to improve work engagement, ideally tailored according to occupational type.

Identifying an early indicator of drug efficacy in patients with metastatic colorectal cancer-a prospective evaluation of circulating tumor cells, 18F-fluorodeoxyglucose positron-emission tomography and the RECIST criteria.

BACKGROUND: This study investigated the predictive and prognostic significance of assessing early drug response with both positron-emission computerized tomography (PET-CT) and circulating tumor cells (CTCs) in patients receiving first-line chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: Eligible patients had PET-CT and CTC analysis at baseline and 4-6 weeks after starting chemotherapy, and then a CT scan at 10-12 weeks to assess the Response Evaluation Criteria In Solid Tumors (RECIST) response. Early response was defined as achieving a dual-endpoint consisting of PET-CT (30% drop in the sum of maximum standard uptake values-SUVmax-of target lesions) and CTC response (CTC < 3 cells/7.5 ml blood) at 4-6 weeks after starting chemotherapy. RESULTS: About 84 patients were enrolled with a median follow-up of 32.9 months (95% confidence interval, CI, 24.5 months-not reached, NR), and 70 patients (84.3%) completed all assessments. Achieving an early response based on the dual-endpoint was independently associated with progression-free survival (hazard ratio, HR = 0.452, 95% CI 0.267-0.765). The median progression-free survival of early responders was 7.41 months (95% CI, 6.05-9.11) compared with 5.37 months (95% CI, 4.68-6.24) in non-responders (log-rank, P = 0.0167). RECIST response at 10 weeks was independently associated with overall survival (OS) (HR = 0.484, 95% CI, 0.275-0.852). Early response based on the dual-endpoint could predict the subsequent RECIST response with a sensitivity, specificity and positive predictive value of 64%, 70% and 74%, respectively. CONCLUSIONS: Early response based on both PET-CT and CTC analysis has prognostic and probably predictive significance in patients undergoing first-line chemotherapy for metastatic colorectal cancer. Its utility as a new tool for assessing early drug response should be further validated.

Operator variability in scan positioning is a major component of HR-pQCT precision error and is reduced by standardized training.

In this study, we determined that operator positioning precision contributes significant measurement error in high-resolution peripheral quantitative computed tomography (HR-pQCT). Moreover, we developed software to quantify intra- and inter-operator variability and demonstrated that standard positioning training (now available as a web-based application) can significantly reduce inter-operator variability. INTRODUCTION: HR-pQCT is increasingly used to assess bone quality, fracture risk, and anti-fracture interventions. The contribution of the operator has not been adequately accounted in measurement precision. Operators acquire a 2D projection ("scout view image") and define the region to be scanned by positioning a "reference line" on a standard anatomical landmark. In this study, we (i) evaluated the contribution of positioning variability to in vivo measurement precision, (ii) measured intra- and inter-operator positioning variability, and (iii) tested if custom training software led to superior reproducibility in new operators compared to experienced operators. METHODS: To evaluate the operator in vivo measurement precision, we compared precision errors calculated in 64 co-registered and non-co-registered scan-rescan images. To quantify operator variability, we developed software that simulates the positioning process of the scanner's software. Eight experienced operators positioned reference lines on scout view images designed to test intra- and inter-operator reproducibility. Finally, we developed modules for training and evaluation of reference line positioning. We enrolled six new operators to participate in a common training, followed by the same reproducibility experiments performed by the experienced group. RESULTS: In vivo precision errors were up to threefold greater (Tt.BMD and Ct.Th) when variability in scan positioning was included. The inter-operator precision errors were significantly greater than the short-term intra-operator precision (p < 0.001). New trained operators achieved comparable intra-operator reproducibility to experienced operators and lower inter-operator reproducibility (p < 0.001). Precision errors were significantly greater for the radius than for the tibia. CONCLUSION: Operator reference line positioning contributes significantly to in vivo measurement precision and is significantly greater for multi-operator datasets. Inter-operator variability can be significantly reduced using a systematic training platform, now available online ( http://webapps.radiology.ucsf.edu/refline/ ).

Simultaneous pancreas and kidney transplantation as the standard surgical treatment for diabetes mellitus patients with end-stage renal disease.

OBJECTIVES: To review the outcome following simultaneous pancreas and kidney transplantation in patients with type 1 diabetes mellitus and end-stage renal disease, as well as those with type 2 diabetes mellitus, and to discuss the applicability of this treatment in this locality. METHODS: A systematic literature review was performed by searching the PubMed and Elsevier databases. The search terms used were "simultaneous pancreas and kidney transplantation", "diabetes", "pancreas transplant" and "SPK". Original and major review articles related to simultaneous pancreas and kidney transplantation were reviewed. Papers published in English after 1985 were included. Clinical outcomes following transplantation were extracted for comparison between different treatment methods. Outcomes of simultaneous pancreas and kidney transplant and other transplantation methods were identified and categorised into patient survival, graft survival, diabetic complications, and quality of life. Patient survivals and graft survivals were also compared. RESULTS: Currently available clinical evidence shows good outcomes for type 1 diabetes mellitus in terms of patient survival, graft survival, diabetic complications, and quality of life. For type 2 diabetes mellitus, the efficacy and application of the procedure remain controversial but the outcomes are possibly comparable with those in type 1 diabetes mellitus. CONCLUSIONS: Simultaneous pancreas and kidney transplantation is a technically demanding procedure that is associated with significant complications, and it should be regarded as a 'last resort' treatment in patients whose diabetic complications have become life-threatening or severely burdensome despite best efforts in maintaining good diabetic control through lifestyle modifications and medications.

A Review of Smoking Research In Malaysia.

Two hundred and seventy one original published materials related to tobacco use were found in a search through a database dedicated to indexing all original data relevant to Medicine and Health in Malaysia from 1996 - 2015. A total of 147 papers were selected and reviewed on the basis of their relevance and implications for future research. Findings were summarised, categorised and presented according to epidemiology, behaviour, clinical features and management of smoking. Most studies are cross-sectional with small sample sizes. Studies on smoking initiation and prevalence showed mixed findings with many small scale studies within the sub-groups. The majority of the studies were related to factors that contribute to initiation in adolescents. Nonetheless, there are limited studies on intervention strategies to curb smoking among this group. There is a lack of clinical studies to analyse tobacco use and major health problems in Malaysia. In addition, studies on the best treatment modalities on the use of pharmacotherapy and behavioural counselling have also remained unexplored. Reasons why smokers do not seek clinic help to quit smoking need further exploration. A finding on the extent of effort carried out by healthcare providers in assisting smokers to make quit attempts is not known. Studies on economic and government initiatives on policies and tobacco use focus mainly on the effects of cigarette bans, increased cigarettes taxes and the influence of the tobacco industry. Recommendations are given for the government to increase efforts in implementing smoke-free legislation, early and tailored interventions. Clinical studies in this area are lacking, as are opportunities to research on ways to reduce smoking initiation age and the most effective quit smoking strategies.

Prevalence and characteristics associated with default of treatment and follow-up in patients with cancer.

Defaulting is an important issue across all medical specialties, but much more so in cancer as delayed or incomplete treatment has been shown to result in worse clinical outcomes such as treatment resistance, disease progression as well as lower survival. Our objective was to identify psychosocial variables and characteristics associated with default among cancer patients. A total of 467 consecutive adult cancer patients attending the oncology clinic at a single academic medical centre completed the Hospital Anxiety and Depression Scale and reported their preference for psychological support at baseline, 4-6 weeks and 12-18 months follow-up. Default was defined as refusal, delay or discontinuation of treatment or visit, despite the ability to do so. A total of 159 of 467 (34.0%) cancer patients were defaulters. Of these 159 defaulters, 89 (56.0%) desired psychological support, compared to only 13 (4.2%) of 308 non-defaulters. Using a logistic regression, patients who were defaulters had 52 times higher odds (P = 0.001; 95% confidence interval 20.61-134.47) of desiring psychological support than non-defaulters after adjusting for covariates. These findings suggest that defaulters should be offered psychological support which may increase cancer treatment acceptance rates and improve survival.

Endovascular treatment of ruptured internal carotid artery pseudoaneurysms after irradiation for nasopharyngeal carcinoma patients.

OBJECTIVES. To evaluate the efficacy and complications of endovascular treatment for ruptured internal carotid artery pseudoaneurysms following irradiation of nasopharyngeal carcinoma. DESIGN. Retrospective case series. SETTING. Tertiary neurosurgical referral unit of a Hong Kong public hospital. PATIENTS. Patients with ruptured radiation-induced internal carotid artery pseudoaneurysms that were treated endovascularly from October 1999 to October 2011 at Queen Elizabeth Hospital were reviewed. Hospital records, imaging, and angiographic data were studied. RESULTS. During the study period, 15 such nasopharyngeal carcinoma patients were treated by endovascular means at Queen Elizabeth Hospital. Ten presented with epistaxis, three with otorrhagia (bleeding from the ear), and two with both. Therapeutic occlusion of the affected internal carotid artery was performed in four patients, and stenting of the artery (with or without coil obliteration of the pseudoaneurysm) was performed in 11. Immediate haemostasis was achieved in all cases. One (7%) of the 15 patients endured symptomatic recurrence of the pseudoaneurysm, and in another an asymptomatic residual pseudoaneurysm was noted in the follow-up angiogram. Three patients suffered clinically significant procedure-related complications, including cerebral infarction (n=2) and brain abscess (n=1). In the angiograms obtained after a mean post-treatment interval of 13 (range, 0.7-60) months, the stent patency rate was 67%. All three patients with occluded stents were asymptomatic. CONCLUSIONS. Ruptured internal carotid artery pseudoaneurysms following radiotherapy is a rare but life-threatening condition. Endovascular treatment by occlusion or reconstruction of the internal carotid artery with stents provides immediate haemostasis and obliteration of the pseudoaneurysms, with a low recurrence rate. Long-term follow-up is necessary to look out for delayed post-treatment complications.

Pediatric head and neck manifestations associated with multiple endocrine neoplasia syndromes.

INTRODUCTION: Multiple endocrine neoplasia (MEN) syndromes are a group of hereditary cancer syndromes that can predispose children to endocrine neoplasms developing within the head and neck. OBJECTIVE: To examine the neoplastic manifestations of MEN type 1 (MEN1) and MEN type 2 (MEN2) in the pediatric head and neck. METHODS: Single-institution, retrospective review of pediatric MEN between 2005 and 2022. RESULTS: Fifty-three children were genetically confirmed with MEN (15 MEN1, 34 MEN2A, and 4 MEN2B), while three patients received clinical diagnoses of MEN1. The male to female ratio was essentially equal (1.15:1), and a documented family history of cancer was present in 89% (50/56). After multidisciplinary evaluation, a familial MEN diagnosis was confirmed in 91% (51/56). The mean ages of initial presentation and surgical intervention were 8.9 years (SD 5) and 9.8 years (SD 4.8), respectively. Although patients with MEN2 received surgery earlier than patients with MEN1 (8.7 vs 12.7 years), surgical patients with MEN2 in this cohort were older relative to current American Thyroid Association (ATA) guidelines primarily due to late presentation. Thyroid malignancies were identified in 36% (9/25) of thyroidectomy specimens (21 MEN2A, 4 MEN2B), with medullary thyroid carcinoma (MTC) present in five MEN2A patients and three MEN2B patients (89%), and papillary thyroid carcinoma (PTC) present in one MEN2A patient (11%). Nearly 90% (8/9) of thyroid malignancies were occult, with some occurring earlier than predicted by current guidelines (ATA-MOD and ATA-H). Central neck dissections were performed in 24% (2 MEN1, 2 MEN2A, and 4 MEN2B), with two MEN2B (50%) demonstrating cervical lymph node (LN) metastases. Additional histopathologic findings included C-cell hyperplasia in 57% (12/21) of MEN2A thyroidectomy patients. Of the eight MEN1 parathyroidectomy patients, four demonstrated parathyroid hyperplasia and four presented with parathyroid adenoma. CONCLUSION: Nearly 60% required head and neck procedures. While MEN1 guidelines were appropriate for our cohort, we identified patients with MEN2 that developed MTC earlier than expected based on current ATA guidelines, including children in categories considered lower risk. In conjunction with a multidisciplinary approach, pediatric head and neck surgeons should be aware of the potential need for earlier surgical intervention in the pediatric MEN2 population.

Antibacterial activity of ZnO nanoparticles with a modified surface under ambient illumination.

In various practical applications, nanomaterials typically have functionalized surfaces. Yet, the studies of toxicity and antibacterial activity of functionalized nanoparticles are scarce. We investigated the effect of surface modifications on antibacterial activity of ZnO under ambient illumination, and we found that nanoparticles coated with different surface modifying reagents could exhibit higher or lower toxicity compared to bare ZnO, depending on the surface modifying reagent used. Different surface modifying reagent molecules resulted in differences in the release of Zn(2+) ions and the production of reactive oxygen species (ROS). However, the antibacterial activity did not correlate with the ROS levels or the Zn(2+) ion release. One of the surface-modified ZnO samples exhibited significantly lower Zn(2+) ion release while at the same time exhibiting improved antibacterial activity. In all cases, damage of the cell wall membranes and/or changes in the membrane permeability have been observed, together with the changes in ATR-FTIR spectra indicating differences in protein conformation. Mechanisms of antibacterial activity are discussed.

Differences in physician attitudes towards patient-centredness: across four medical specialties.

AIMS: There is limited study on patient-centred attitudes with regards to the patient-physician relationship in physicians. The objective of this study was to examine and compare physician attitudes toward patient-centredness in four different medical settings. METHODS: The present study utilised a cross-sectional survey design and purposive sampling to recruit physicians from a single academic medical centre via face-to-face interviews. Patient-centred attitudes of physicians specialising in surgery, oncology, obstetrics and gynaecology and primary care (N = 78) were compared on the Patient-Practitioner Orientation Scale (PPOS) using an independent one-way analysis of variance (ANOVA). The four medical specialties comprised the four levels, with role orientation (patient-centred orientation vs. doctor-centred orientation) as the dependent measure. RESULTS: A significant level of difference (p < 0.001) was found between the four specialisations: oncologists were found to have the highest level of patient-centeredness, followed by obstetricians & gynaecologists and primary care physicians, with surgeons being the least patient-centred among specialisations sampled. CONCLUSION: These data are the first from the South-East Asian region to demonstrate differences in physician attitudes between medical specialties. Our findings prompt further investigation and confirmation as to whether physicians with particular attitudinal traits are attracted to any particular specialties of medicine, or if physician attitudes are acquired through professional experience and training. In addition, this study offers better insight into the attitudinal differences of physician between medical specialities.

Transarterial embolisation with Guglielmi detachable coils in an infant with a vein of Galen aneurysmal malformation.

Vein of Galen aneurysmal malformation is a rare entity in the paediatric population. However, it is being recognised with increasing frequency due to better diagnostic techniques. Neonates usually present with congestive heart failure, while in older infants and children it tends to manifest with seizures, hydrocephalus, intracerebral or subarachnoid haemorrhages. We present a case of ruptured vein of Galen aneurysmal malformation in a 3-month-old baby boy treated by transarterial embolisation using Guglielmi detachable coils.

Clinical significance of CDX2-positive circulating tumour cells in colorectal cancer patients.

BACKGROUND: Our recent work has shown the feasibility of using a refined immunomagnetic enrichment (IE) assay to detect cytokeratin 20-positive circulating tumour cells (CK20 pCTCs) in colorectal cancer (CRC) patients. We attempted to improve the sensitivity for CRC by detecting another intestinal-type differentiation marker, CDX2 pCTCs, using the same methodology. METHODS: CDX2 pCTCs were detected in patients with CRC, colorectal adenoma (CAD), benign colorectal diseases (BCD), other common cancers (OCC) and normal subjects (NS). Statistical analysis was used to correlate CDX2 pCTCs to the clinicohistopathological factors, recurrence, metastasis and survival after follow-up for 42 months in CRC patients. RESULTS: CDX2 pCTCs were detected in 81% CRC patients (73 out of 90, median number=21.5 CTCs), 7.5% CAD patients (3 out of 40), 0% patients with BCD (0 out of 90), 2.5% patients with OCC (2 out of 80) and 0% NS (0 out of 40). Furthermore, statistical analysis showed that CDX2 pCTC numbers were associated with tumour- node-metastasis stage and lymph node status. Using the median CDX2 pCTC numbers as the cutoff points, stratified groups of CRC patients had significant differences in their recurrence and survival. CONCLUSIONS: This study showed that the refined IE assay can detect CDX2 pCTCs with high sensitivity and that CDX2 pCTCs can generate clinically important information for CRC patients.

Impact of patterns of proteinuria on renal allograft function and survival: a prospective cohort study.

BACKGROUND: Proteinuria is an important complication in renal transplant recipients. The aim of this prospective study was to evaluate the long-term impact of transplant proteinuria patterns on allograft function and survival. METHODS: We analyzed urinary protein of a cohort of 83 renal transplants with proteinuria ≥0.5 g/d by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and radial immunogel diffusion assay. After initial stratification and analysis, the cohort was followed up for 16 yr. The graft outcome and survival were analyzed using Cox regression model to determine their association with different patterns of initial transplant proteinuria. RESULTS: Group with predominantly glomerular (middle- and high-molecular-weight with or without low-molecular-weight) proteinuria (61%) had higher serum creatinine (p < 0.001) than the group with predominantly tubular (low-molecular-weight) proteinuria (39%). The incidences of chronic graft dysfunction and graft loss had increased in the glomerular proteinuria group (p < 0.001, hazard ratio 3.6, 95% confidence interval 1.7-7.5 and p < 0.001, hazard ratio 4.9, 95% confidence interval 1.9-12.1, respectively). Patient death did not differ (p = 0.434, hazard ratio 1.5, 95% confidence interval 0.5-4.5). CONCLUSION: Proteinuria in renal transplants can be differentiated into glomerular and tubular types based on molecular weight. Glomerular proteinuria is associated with significant increase in graft dysfunction and graft loss.

A venographic operational classification for transvenous embolization of dural carotid-cavernous fistula.

INTRODUCTION: It is hypothesized that a venographic-based operational classification of dural carotid-cavernous fistula (DCCF) will facilitate early selection of the optimal venous route and enhance the efficacy of transvenous catheterization and embolization of the cavernous sinus. METHODS: This was a retrospective study on 97 patients who presented with symptomatic DCCF. Definition of classification type 1: both the anterior and posterior compartments of the cavernous sinus were opacified, type 2: only the anterior compartment was opacified, type 3: only the posterior compartment was opacified. Subtype a: the facial vein (FV) draining the superior ophthalmic vein (SOV) was opacified, subtype b: only the inferior petrosal sinus (IPS) was opacified, subtype c: neither the FV nor the IPS were opacified, subtype d: both the FV and the IPS were opacified. The SOV route was recommended for subtype 1a and type 2. The IPS route was recommended for subtype 1b, 1c, 1d, and type 3. Success rates of catheterization by the recommended routes and non-recommended routes were calculated. RESULTS: Number of DCCF lesions were 20 (1a), 28 (1b), 23 (1c), 26 (1d), 16 (2a), 10 (2c), 2 (3b). Of 145 attempted catheterization, 91 and 54 were performed with a recommended route and un-recommended route, respectively. Success rate for catheterization and embolization performed with the recommended route and un-recommended route was 71/91 (78%) and 20/54 (37%), respectively (Chi-Square test P = 0.0024). CONCLUSIONS: Venographic operational classification is useful for guiding the selection of optimal venous route which enhances the efficacy of transvenous embolization of the DCCF.

Intracranial aneurysms in twins: case report and review of the literature.

Intracranial aneurysm in twins is a rare clinical disease entity. Only 15 cases have been described in the literature. We report on a pair of identical twins with intracranial aneurysms. One presented with subarachnoid haemorrhage; digital subtraction angiography showed a left posterior communicating artery aneurysm, which was treated by coiling. The patient's twin sister was called for screening, whereupon digital subtraction angiography revealed a right ophthalmic internal carotid artery aneurysm that was treated conservatively.

Laparoscopic sacrocolpopexy for uterine and post-hysterectomy prolapse: anatomical and functional outcomes.

OBJECTIVE: To evaluate the anatomical and functional outcomes following laparoscopic sacrocolpopexy in a local unit. DESIGN: Retrospective case series. SETTING: A regional hospital in Hong Kong. PATIENTS: All women who underwent laparoscopic sacrocolpopexy for symptomatic uterine or post-hysterectomy prolapse from January 2003 to December 2008. MAIN OUTCOME MEASURES: Anatomical outcomes, functional outcomes including complications. RESULTS: A total of 31 patients were recruited. The success rate in treating apical vaginal wall prolapse was 100%. There were no recurrences of vault prolapse (defined as stage II or higher). Approximately 19% of women had anterior vaginal wall prolapse and 23% had urinary stress incontinence postoperatively; 6% had a second operation because of anterior vaginal wall prolapse. The rates of dyspareunia and constipation were low. The mean hospital stay was 4 (range, 2-11) days. Two patients sustained bladder injuries and one rectal injury resulting in a rectovaginal fistula. For three patients the procedure was converted to a laparotomy. CONCLUSIONS: Laparoscopic sacrocolpopexy is feasible in our population and has a high success rate for treating apical vaginal wall prolapse. The incidence of complications was acceptable.

The changing pattern of primary glomerulonephritis in Singapore and other countries over the past 3 decades.

This review of 2,586 renal biopsies over the past 3 decades in Singapore documents the changing pattern of glomerulonephritis (GN) from that of a third world country to that of a developed nation. In the 1st decade, mesangial proliferative glomerulonephritis was the most common form of primary GN, just as it was in the surrounding Asian countries. In the 2nd decade, the prevalence of mesangial proliferative GN decreased with a rise in membranous, GN which is also seen in China and Thailand. In the 3rd decade, there was a dramatic increase in focal sclerosing glomerulosclerosis. This increase reflects aging and obesity in keeping with more developed countries like Australia, India, Thailand and the United States of America. IgA nephritis remains the most common GN. Apart from the geographical influence, other socioeconomic factors play a significant role in the evolution of the renal biopsy pattern. Mesangial proliferative GN remains prevalent in many Asian countries, but in Singapore the prevalence is decreasing just as it is in Japan, Korea and Malaysia. Worldwide, the prevalence of focal sclerosing glomerulosclerosis continues to increase in many countries.

Phase I dose escalating study of oral cyclophosphamide in tumour-bearing cats.

Cyclophosphamide is an alkylating agent used to treat cats with lymphoma, carcinomas and sarcomas. However, no clear consensus exists regarding the maximum tolerated dose (MTD) of oral cyclophosphamide in cats. Toxicities are rarely reported at published oral dosages of cyclophosphamide (200-300 mg/m2). The primary aim of this prospective study was to determine the MTD of oral cyclophosphamide in tumour-bearing cats via a modified phase I trial. A secondary aim was to define any toxicity. Forty-six client-owned tumour-bearing cats were enrolled. The cyclophosphamide dosage was escalated by approximately 10% (300, 330, 360, 400, 440, 460 and 480 mg/m2) in cohorts of at least six cats. The MTD of oral cyclophosphamide in this study was 460 mg/m2 with an inter-treatment interval of two to three weeks. Haematology is recommended 7 and 14 days after first cyclophosphamide treatment, and immediately before each subsequent dosage of cyclophosphamide or any potentially myelosuppressive chemotherapy agent. The dose-limiting toxicity was neutropenia with nadir at 7-21 days. This higher dosage was considered safe in combination with prednisolone and L-asparaginase. However, the higher dose of oral cyclophosphamide has not been evaluated in combination with other chemotherapy agents and thus should not be administered with these agents.

The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles.

The production of virus-like particles (VLPs) constitutes a relevant and safe model to study molecular determinants of virion egress. The minimal requirement for the assembly of VLPs for the coronavirus responsible for severe acute respiratory syndrome in humans (SARS-CoV) is still controversial. Recent studies have shown that SARS-CoV VLP formation depends on either M and E proteins or M and N proteins. Here we show that both E and N proteins must be coexpressed with M protein for the efficient production and release of VLPs by transfected Vero E6 cells. This suggests that the mechanism of SARS-CoV assembly differs from that of other studied coronaviruses, which only require M and E proteins for VLP formation. When coexpressed, the native envelope trimeric S glycoprotein is incorporated onto VLPs. Interestingly, when a fluorescent protein tag is added to the C-terminal end of N or S protein, but not M protein, the chimeric viral proteins can be assembled within VLPs and allow visualization of VLP production and trafficking in living cells by state-of-the-art imaging technologies. Fluorescent VLPs will be used further to investigate the role of cellular machineries during SARS-CoV egress.