18 F-Fluorodeoxyglucose positron-emission tomography for the investigation of malignancy in patients with suspected paraneoplastic neurologic syndromes and negative or indeterminate conventional imaging: a retrospective analysis of the Ontario PET Access Program, with systematic review and meta-analysis.

Objective: Paraneoplastic neurologic syndrome (pns) is a rare condition indirectly caused by an underlying malignancy. In many cases, the malignancy is occult at the time of the pns diagnosis, and the optimal diagnostic modality to detect the underlying tumour is unclear. In the present study, we aimed to assess the utility of 18F-fluorodeoxyglucose positron-emission tomography (fdg-pet) or pet integrated with computed tomography (pet/ct) in the investigation of these patients. Methods: We retrospectively analyzed data from the PET Access Program (pap) database in the province of Ontario to identify patients who underwent fdg-pet/ct imaging as part of a workup for pns. In all patients, prior conventional imaging was negative or indeterminate. To determine the diagnostic accuracy of fdg-pet/ct, data about demographics, presenting symptoms, and biochemical and radiologic workup, including fdg-pet/ct imaging results, were compared with data collected by the Ontario Cancer Registry (ocr). A systematic review of the literature and meta-analysis using our study inclusion criteria were performed for studies of fdg-pet accuracy. Results: Of 29 patients identified in the pap database, 9 had fdg-pet/ct results suspicious for malignancy. When correlated with data from the ocr, 5 fdg-pet/ct results were informative, resulting in a detection rate of 17%. Local sensitivity and specificity were 0.83 and 0.83 respectively. Two studies meeting our criteria were identified in the literature. The pooled sensitivity and specificity from the literature and local data were 0.88 and 0.90 respectively. Conclusions: When investigating for underlying malignancy in patients with suspected pns and negative conventional imaging, pet has high sensitivity and specificity.

Saliva as a diagnostic specimen for testing respiratory virus by a point-of-care molecular assay: a diagnostic validity study.

OBJECTIVES: Automated point-of-care molecular assays have greatly shortened the turnaround time of respiratory virus testing. One of the major bottlenecks now lies at the specimen collection step, especially in a busy clinical setting. Saliva is a convenient specimen type that can be provided easily by adult patients. This study assessed the diagnostic validity, specimen collection time and cost associated with the use of saliva. METHODS: This was a prospective diagnostic validity study comparing the detection rate of respiratory viruses between saliva and nasopharyngeal aspirate (NPA) among adult hospitalized patients using Xpert® Xpress Flu/RSV. The cost and time associated with the collection of saliva and nasopharyngeal specimens were also estimated. RESULTS: Between July and October 2017, 214 patients were recruited. The overall agreement between saliva and NPA was 93.3% (196/210, κ 0.851, 95% CI 0.776-0.926). There was no significant difference in the detection rate of respiratory viruses between saliva and NPA (32.9% (69/210) versus 35.7% (75/210); p 0.146). The overall sensitivity and specificity were 90.8% (81.9%-96.2%) and 100% (97.3%-100%), respectively, for saliva, and were 96.1% (88.9%-99.2%) and 98.5% (94.7%-99.8%), respectively, for NPA. The time and cost associated with the collection of saliva were 2.26-fold and 2.59-fold lower, respectively, than those of NPA. CONCLUSIONS: Saliva specimens have high sensitivity and specificity in the detection of respiratory viruses by an automated multiplex Clinical Laboratory Improvement Amendments-waived point-of-care molecular assay when compared with those of NPA. The use of saliva also reduces the time and cost associated with specimen collection.

New developments in liquid-liquid extraction, surface modification and agglomerate-free processing of inorganic particles.

This review describes new methods for the particle extraction through liquid-liquid interface (PELLI). The discovery of new surface modification techniques, advanced extractors and new adsorption mechanisms enabled novel applications of PELLI in nanotechnology of metals, quantum dots, oxides and hydroxides. Colloidal and interface chemistry of PELLI is emerging as a new area of technological and scientific interest. The progress achieved in the understanding of particle behavior and interactions at the liquid-liquid interface, phase transfer and interface reactions allowed for the development of new extraction mechanisms. An important breakthrough was the development of surface modification techniques for extraction of functional oxides. Especially important is the possibility of particle transfer from the synthesis medium to the device processing medium, which facilitates agglomerate-free processing of functional nanoparticles. Multifunctional extractor molecules were discovered and used as capping and reducing agents for particle synthesis or dispersing and charging agents for colloidal processing. The progress achieved in the development of extractors and extraction mechanisms has driven the advances in the surface modification and functionalization of materials. New PELLI techniques were used for the development of advanced materials and devices for optical, photovoltaic, energy storage, electronic, biomedical, sensor and other applications.

Randomized clinical trial of hepatic resection versus radiofrequency ablation for early-stage hepatocellular carcinoma.

BACKGROUND: Hepatic resection and radiofrequency ablation (RFA) are treatment options for early-stage hepatocellular carcinoma (HCC). Whether tumour recurrence and long-term survival favour either treatment has not been established. This randomized trial aimed to test the hypothesis that RFA is superior to hepatic resection in terms of lower tumour recurrence rate and better long-term survival. METHODS: Patients with early-stage HCC (solitary tumour no larger than 5 cm; or no more than 3 tumours, each 3 cm or smaller) were randomized into hepatic resection and RFA groups. Demographic and clinical characteristics, and short- and long-term outcome measures were compared between groups. Primary and secondary outcome measures were overall tumour recurrence and survival respectively. RESULTS: Clinicopathological data were similar in the two groups, which each contained 109 patients. The RFA group had a shorter treatment duration, less blood loss and shorter hospital stay than the resection group. Mortality and morbidity rates were similar in the two groups. The overall tumour recurrence rate was similar in the resection and RFA groups (71·3 versus 81·7 per cent respectively). The 1-, 3-, 5- and 10-year overall survival rates were 94·5, 80·6, 66·5 and 47·6 per cent respectively in the resection group, compared with 95·4, 82·3, 66·4 and 41·8 per cent in the RFA group (P = 0·531). Corresponding disease-free survival rates were 74·1, 50·9, 41·5 and 31·9 per cent in the resection group, and 70·6, 46·6, 33·6 and 18·6 per cent in the RFA group (P = 0·072). CONCLUSION: RFA for early-stage HCC is not superior to hepatic resection, in terms of tumour recurrence, overall survival and disease-free survival. Registration number: HKUCTR-10 (http://www.hkuctr.com).

Synthesis and liquid-liquid extraction of non-agglomerated Al(OH)3 particles for deposition of cellulose matrix composite films.

A cathodic electrophoretic deposition (EPD) method has been developed for the deposition of quaternized hydroxyethyl cellulose ethoxylate (QHECE) films. A quartz crystal microbalance was used for in-situ investigation of the deposition yield in dilute QHECE solutions. The deposition rate increased with increasing QHECE concentration in the range of 1-10gL-1. Aluminium hydroxide (AH) was prepared by a chemical precipitation method and used as a flame retardant additive for QHECE. AH particle agglomeration was avoided by a new strategy, based on combined synthesis and liquid-liquid extraction method. In the biomimetic surface modification approach, 3,4-dihydroxybenzaldehyde (R'-CHO) and 2,3,4-trihydroxybenzaldehyde (R''-CHO) were used for particle modification during synthesis. The Schiff base reaction at the water-n-butanol interface between R'-CHO or R''-CHO adsorbed on the particle surface in water, and hexadecylamine in the n-butanol phase, allowed for efficient particle modification and phase transfer from water to the n-butanol phase. The extraction mechanism was confirmed by FTIR investigation. The modified particles showed good suspension stability and were utilized for the EPD of smooth and uniform QHECE-AH films. The formation a composite material, which contained flame retardant AH in the QHECE matrix was confirmed by the thermogravimetric and differential thermal analyses. Further development of the particle synthesis and liquid-liquid extraction method can be used for the fabrication of advanced QHECE composites, containing various functional materials.

Examining Determinants of Radiotherapy Access: Do Cost and Radiotherapy Inconvenience Affect Uptake of Breast-conserving Treatment for Early Breast Cancer?

AIMS: Radiotherapy utilisation is likely affected by multiple factors pertaining to radiotherapy access. Radiotherapy is an integral component of breast-conserving treatment (BCT) for early breast cancer. We aimed to determine if stepwise improvements in radiotherapy access in regional Australia affected the uptake of BCT and thus radiotherapy. MATERIALS AND METHODS: Breast cancer operations in the Central Coast of New South Wales between January 2010 and March 2014 for T1-2N0-1M0 invasive or in situ (≤5 cm) disease in female patients eligible for BCT were examined. BCT uptake was calculated for three 1 year periods: period 1 (local radiotherapy available at cost to user or out of area radiotherapy with travel cost and inconvenience); period 2 (as per period 1 + publicly funded transport and radiotherapy at out of area facilities at no cost to user); period 3 (as per period 1 + publicly funded local radiotherapy at no cost to user). RESULTS: In total, 574 cases met eligibility criteria. BCT declined with increasing distance to publicly funded radiotherapy (P = 0.035). BCT rates for periods 1, 2 and 3 were 63% (113/180), 61% (105/173) and 71% (156/221). There were no statistically significant differences in BCT between periods 1 and 2 in the whole cohort or within age, histology or tumour size subgroups. Overall, there was a 9% increase in BCT in the whole cohort in period 3 compared with periods 1 and 2 (P = 0.031). This increase was statistically significant for women over 70 years (19% increase, P = 0.034), for women with ductal carcinoma in situ (25% increase, P = 0.013) and for women with primary tumours that were ≤10 mm (21% increase, P = 0.016). CONCLUSIONS: Improving the affordability of radiotherapy through publicly funded transport and radiotherapy at out of area facilities did not improve BCT uptake in a region where radiotherapy was locally available, albeit at cost to the user. Improving both affordability and convenience through the provision of local publicly funded radiotherapy increased BCT uptake. Service availability and affordability have long been recognised as important determinants of radiotherapy access. Our findings suggest that inconvenience may also influence radiotherapy utilisation.

Containment of Clostridium difficile infection without reduction in antimicrobial use in Hong Kong.

Clostridium difficile ribotype 002 with hypersporulating capacity has been increasingly identified in Hong Kong. Proactive infection control measures are important to prevent the establishment of endemicity of C. difficile ribotype 002. A total of 329 patients with healthcare-associated C. difficile infection (CDI) were recruited in our healthcare network between 1 January 2008 and 30 June 2012 in this study. The incidence rates of healthcare-associated CDI per 10,000 admissions and 10,000 patient-days increased significantly by 15.3 and 17.0%, respectively, per quarter (p < 0.001) from 2008 1Q to 2010 1Q by segmented Poisson regression. With the full implementation of enhanced infection control interventions, there was an immediate significant reduction in both healthcare-associated CDI rates per 10,000 admissions and per 10,000 patient-days by 47% (p < 0.001) in 2010 2Q, followed by a further decline of CDI per 10,000 admissions and CDI per 10,000 patient-days by -19.4 and -19.8% from 2010 2Q to 2012 2Q, respectively (p < 0.001), despite a replacement of hand washing with soap and water by alcohol-based hand rub in the healthcare network. The proportion of C. difficile ribotype 002 was not statistically different (34/177, 19.2% vs. 25/152, 16.4%, p = 0.515), and the consumption of broad-spectrum antibiotics presented as divided daily dose per 1,000 acute bed-day occupancy per quarter remained unchanged (140.9 vs. 152.3) before and after infection control interventions. Our results suggested that the reduction of healthcare-associated CDI was attributable to infection control interventions instead of replacement of ribotypes or reduction in antimicrobial selective pressure.

Control of hospital endemicity of multiple-drug-resistant Acinetobacter baumannii ST457 with directly observed hand hygiene.

An increasing endemicity of multiple-drug-resistant Acinetobacter baumannii (MRAB) ST457 was noted in Hong Kong. The epidemiology, risk factors, and infection control measures to prevent nosocomial transmission of this epidemic clone were analyzed. A total of 5,058 patients cultured positive with A. baumannii between 1 January 2004 and 30 June 2014 were included, of which 297 (5.9 %) had bacteremia. The first case of MRAB bacteremia emerged in 2009, with an incidence that increased from 0.27 (one case) in 2009 to 1.86 (14 cases) per 100,000 patient-days in 2013 (p < 0.001). With the implementation of strict contact precautions and directly observed hand hygiene in conscious patients immediately before receiving meals and medications in July 2013, the incidence of MRAB bacteremia reduced from its peak to 0.77 (one case) per 100,000 patient-days in the first 6 months of 2014 (p < 0.001). Patients from long-term care facilities for the elderly [odds ratio (OR) 18.6, confidence interval (CI) 2.1-162.4, p = 0.008] and history of carbapenem (OR 7.0, CI 1.7-28.0, p = 0.006) and beta-lactam/beta-lactamase use (OR 5.6, CI 1.1-28.7, p = 0.038) 90 days prior to admission were independent risk factors for MRAB bacteremia by logistic regression when compared with carbapenem-susceptible A. baumannii bacteremia.

Reduction in unstimulated salivary flow rate in burning mouth syndrome.

BACKGROUND: Burning mouth syndrome (BMS) is a chronic condition of burning of the tongue and oral mucosa. It is often accompanied with complaints of xerostomia, although it is unknown whether the dryness is a sensory change similar to the burning sensation or due to hyposalivation. To determine whether there is change in salivary flow rate, whole salivary flows were measured in BMS patients. METHODS: A clinical ambispective study was conducted. Patients' clinical files were reviewed for stimulated and unstimulated whole salivary flow. Patients were divided into four groups based on diagnosis into Sjögren's syndrome (SS), BMS, BMS taking oral drying medications (BMS-med), and control (C). Whole stimulated (SF) and unstimulated flow (USF) measurements were collected and compared among groups. Data were analysed with ANOVA, Levene's test, Tukey's test and Games-Howell test. RESULTS: Twenty SS, 22 BMS, 24 BMS-med and 15 C were included in the study. SF was significantly lower in SS (0.59 ml ± 0.36) compared with BMS (1.56 ml ± 0.65, p <0.001), BMS-med (1.44 ml ± 0.64, p <0.001) and C (2.32 ml ± 1.06, p = 0.001). USF was significantly lower in SS (0.12 ml ± 0.10) compared with BMS (0.30 ml ± 0.18, p = 0.002), BMS-med (0.27 ml ± 0.21, p = 0.022) and C (0.52 ml ± 0.26, p <0.001). SF was not significantly different between BMS and C (p = 0.172) and BMS-med and C (p = 0.096). Both BMS and BMS-med had significantly lower USF compared with C (p = 0.040 and p = 0.018 respectively). SF in BMS was not significantly affected by number of oral drying medications (p = 0.254); however, USF was significantly lower with two or more oral drying medications (0.13 ml ± 0.07) compared with one oral drying medication (0.32 ml ± 0.22) (p = 0.034). CONCLUSION: BMS patients have statistically significant decreased unstimulated salivary flow rate with non-statistically significant decreased stimulated flow rate. Salivary flow rates in BMS patients are decreased further by medication usage whose side effects include dry mouth. This suggests that hyposalivation may play a role in causing dry mouth in BMS, which may respond to treatment with a sialogogue.

Salt-inducible kinase 3 is a novel mitotic regulator and a target for enhancing antimitotic therapeutic-mediated cell death.

Many mitotic kinases are both critical for maintaining genome stability and are important targets for anticancer therapies. We provide evidence that SIK3 (salt-inducible kinase 3), an AMP-activated protein kinase-related kinase, is important for mitosis to occur properly in mammalian cells. Downregulation of SIK3 resulted in an extension of mitosis in both mouse and human cells but did not affect the DNA damage checkpoint. Time-lapse microscopy and other approaches indicated that mitotic exit but not mitotic entry was delayed. Although repression of SIK3 alone simply delayed mitotic exit, it was able to sensitize cells to various antimitotic chemicals. Both mitotic arrest and cell death caused by spindle poisons were enhanced after SIK3 depletion. Likewise, the antimitotic effects due to pharmacological inhibition of mitotic kinases including Aurora A, Aurora B, and polo-like kinase 1 were enhanced in the absence of SIK3. Finally, in addition to promoting the sensitivity of a small-molecule inhibitor of the mitotic kinesin Eg5, SIK3 depletion was able to overcome cells that developed drug resistance. These results establish the importance of SIK3 as a mitotic regulator and underscore the potential of SIK3 as a druggable antimitotic target.

p53 deficiency enhances mitotic arrest and slippage induced by pharmacological inhibition of Aurora kinases.

A number of small-molecule inhibitors of Aurora kinases have been developed and are undergoing clinical trials for anti-cancer therapies. Different Aurora kinases, however, behave as very different targets: while inhibition of Aurora A (AURKA) induces a delay in mitotic exit, inhibition of Aurora B (AURKB) triggers mitotic slippage. Furthermore, while it is evident that p53 is regulated by Aurora kinase-dependent phosphorylation, how p53 may in turn regulate Aurora kinases remains mysterious. To address these issues, isogenic p53-containing and -negative cells were exposed to classic inhibitors that target both AURKA and AURKB (Alisertib and ZM447439), as well as to new generation of inhibitors that target AURKA (MK-5108), AURKB (Barasertib) individually. The fate of individual cells was then tracked with time-lapse microscopy. Remarkably, loss of p53, either by gene disruption or small interfering RNA-mediated depletion, sensitized cells to inhibition of both AURKA and AURKB, promoting mitotic arrest and slippage respectively. As the p53-dependent post-mitotic checkpoint is also important for preventing genome reduplication after mitotic slippage, these studies indicate that the loss of p53 in cancer cells represents a major opportunity for anti-cancer drugs targeting the Aurora kinases.

Epsilon toxin is essential for the virulence of Clostridium perfringens type D infection in sheep, goats, and mice.

Clostridium perfringens type D causes disease in sheep, goats, and other ruminants. Type D isolates produce, at minimum, alpha and epsilon (ETX) toxins, but some express up to five different toxins, raising questions about which toxins are necessary for the virulence of these bacteria. We evaluated the contribution of ETX to C. perfringens type D pathogenicity in an intraduodenal challenge model in sheep, goats, and mice using a virulent C. perfringens type D wild-type strain (WT), an isogenic ETX null mutant (etx mutant), and a strain where the etx mutation has been reversed (etx complemented). All sheep and goats, and most mice, challenged with the WT isolate developed acute clinical disease followed by death in most cases. Sheep developed various gross and/or histological changes that included edema of brain, lungs, and heart as well as hydropericardium. Goats developed various effects, including necrotizing colitis, pulmonary edema, and hydropericardium. No significant gross or histological abnormalities were observed in any mice infected with the WT strain. All sheep, goats, and mice challenged with the isogenic etx mutant remained clinically healthy for ≥24 h, and no gross or histological abnormalities were observed in those animals. Complementation of etx knockout restored virulence; most goats, sheep, and mice receiving this complemented mutant developed clinical and pathological changes similar to those observed in WT-infected animals. These results indicate that ETX is necessary for type D isolates to induce disease, supporting a key role for this toxin in type D disease pathogenesis.

Outbreak of microsporidial keratoconjunctivitis with rugby sport due to soil exposure.

AIMS: To investigate a cluster of microsporidial keratoconjunctivitis in 33 eyes of 25 previously healthy paediatric and teenage individuals after a rugby match. METHODS: An observational case series was reported. Analysis of medical record of patients with microsporidial keratoconjunctivitis, who presented within May 2012, was performed. All patients were treated by a single ophthalmologist with a standardized topical regime, including a fluoroquinolone (moxifloxacin) and an antiseptic (Brolene or Desomedine). Five eyes received corneal scrapings. RESULTS: The mean age was 13.36 years (range 5-16). All patients have participated in a rugby match on 21-22 April 2012. The onset of symptoms ranged from 10 to 30 days post exposure. All eyes had multiple superficial coarse punctate keratitis. Four (12%) eyes presented with keratic precipitates. One (3%) eye had intraocular pressure of 27 mm Hg. Microscopic examination of corneal scrapings with modified trichrome or calcofluor white (CFW) fluorescent staining was unremarkable but subsequent PCR test was positive for the small subunit rRNA gene of Vittaforma corneae in three out of five eyes. Sequencing of the PCR product of 1150 bp showed 96-100% identity with the Indian or Singaporean strains of V. corneae. After treatment, all eyes healed without sequel. CONCLUSIONS: The first outbreak of microsporidial keratoconjunctivitis in paediatric and teenage individuals with a rugby match is reported. A standardized topical regime, including a fluoroquinolone (moxifloxacin) and an antiseptic (Brolene or Desomedine), seems to be safe and effective, and requires validation in future treatment trials.

The CDK1 inhibitory kinase MYT1 in DNA damage checkpoint recovery.

Inhibition of cyclin-dependent kinase 1 (CDK1) by phosphorylation is a key regulatory mechanism for both the unperturbed cell cycle and the DNA damage checkpoint. Although both WEE1 and MYT1 can phosphorylate CDK1, little is known about the contribution of MYT1. We found that in contrast to WEE1, MYT1 was not important for the normal cell cycle or checkpoint activation. Time-lapse microscopy indicated that MYT1 did, however, have a rate-determining role during checkpoint recovery. Depletion of MYT1 induced precocious mitotic entry when the checkpoint was abrogated with inhibitors of either CHK1 or WEE1, indicating that MYT1 contributes to checkpoint recovery independently of WEE1. The acceleration of checkpoint recovery in MYT1-depleted cells was due to a lowering of threshold for CDK1 activation. The kinase activity of MYT1 was high during checkpoint activation and reduced during checkpoint recovery. Importantly, although depletion of MYT1 alone did not affect long-term cell growth, it potentiated with DNA damage to inhibit cell growth in clonogenic survival and tumor xenograft models. These results reveal the functions of MYT1 in checkpoint recovery and highlight the potential of MYT1 as a target for anti-cancer therapies.

Dickkopf 4 (DKK4) acts on Wnt/ß-catenin pathway by influencing ß-catenin in hepatocellular carcinoma.

Deregulation of Wnt/ß-catenin pathway is a hallmark of major gastrointestinal cancers including hepatocellular carcinoma (HCC). The oncogenic role of ß-catenin is well defined but reasons for its accumulation in HCC remain unclear. Dickkopf 4 (DKK4) acts as a negative regulator of Wnt/ß-catenin pathway but its functional role in liver carcinogenesis has not been studied. We investigated the role of DKK4 in ß-catenin regulation in HCC. Reduced expression of DKK4 was found in 47% (38/81) of HCC, as measured by quantitative real time PCR. Ectopic expression of DKK4 in two HCC cell lines, PLC/PRF/5 (PLC) and MHCC97L (97L), attenuated ß-catenin responsive luciferase activity, and decreased both ß-catenin and cyclin D1 protein levels. To study the effect of DKK4 on cell growth and tumourigenicity, two stable HCC cell lines were established from PLC and 97L cells. Functional assays demonstrated that overexpression of DKK4 hampered cell proliferation, reduced colony formation and retarded cell migration. When DKK4-expressing 97L stable cells were used to induce tumour xenografts in nude mice (n=8), reduction in tumour sizes was observed (P=0.027). Furthermore, immunohistochemical studies showed that decreased expression of DKK4 was associated with ß-catenin accumulation in HCC tissues. Additionally, inhibition of the proteasome using specific inhibitor in DKK4-expressing 97L stable cells masked the effect of ß-catenin. Our findings suggest a potential tumour suppressive role of DKK4 as well as that of an important regulator of HCC.

Outcome after partial hepatectomy for hepatocellular cancer within the Milan criteria.

BACKGROUND: There is a trend to offer liver transplantation to patients with hepatocellular carcinoma (HCC) with tumour status within the Milan criteria but with preserved liver function. This study aimed to evaluate the outcome of such patients following partial hepatectomy as primary treatment. METHODS: A retrospective analysis was performed on all adult patients with HCC and tumour status within the Milan criteria undergoing partial hepatectomy at a single centre from 1995 to 2008. Their outcomes were compared with those of similar patients having right-lobe living donor liver transplantation (LDLT) as primary treatment. RESULTS: A total of 408 patients with HCC were enrolled. Some 384 patients with a solitary tumour 5 cm or less in diameter had a better 5-year survival rate than 24 patients with oligonodular tumours (2-3 nodules, each 3 cm or less in size) (70·7 versus 46 per cent; P = 0·025). Multivariable analysis identified younger age (65 years or less), lack of postoperative complications, negative resection margin, absent microvascular invasion and non-cirrhotic liver as predictors of favourable overall survival. The 5-year survival rate of 287 younger patients with chronic liver disease and R0 hepatectomy was 72·8 per cent, comparable to that of 81 per cent in 50 similar patients treated by LDLT (P = 0·093). CONCLUSION: Partial hepatectomy for patients with HCC and tumour status within the Milan criteria achieved a satisfactory 5-year survival rate, particularly in younger patients with solitary tumours and R0 hepatectomy. Patients with oligonodular tumours have a worse survival and might benefit from liver transplantation.

Testosterone regulates cell proliferation in aggressive fibromatosis (desmoid tumour).

BACKGROUND: Aggressive fibromatosis (desmoid tumour) is a locally invasive tumour caused by mutations resulting in ß-catenin protein stabilisation. Apc1638N mice are predisposed to developing aggressive fibromatosis tumours, and male mice develop greater numbers of tumours than female mice, suggesting a role for androgens in this tumour type. METHODS: Human aggressive fibromatosis tumours were examined for the expression of the androgen receptor, and primary human tumour cell cultures were treated with testosterone. Orchidectomised Apc1638N mice were investigated for the development of tumours, and were treated with testosterone to study the effect of tumour formation and the level of ß-catenin. RESULTS: Androgen receptors are universally expressed in human aggressive fibromatosis tumours. Testosterone increased the proliferation rate and ß-catenin protein level in a dose-dependent manner in human aggressive fibromatosis tumours. Orchiectomy reduced the number and size of tumours that formed in male Apc1638N mice to a similar level as observed in female mice. Testosterone treatment increased the number of tumours that formed in orchidectomised male mice, and resulted in a marked increase in ß-catenin protein levels. CONCLUSION: Testosterone regulates ß-catenin protein level and proliferation rate in this mesenchymal tumour. This work identifies the therapeutic use of testosterone blockade in aggressive fibromatosis as an area for further investigation.

Effects of 5-chloro-2-methyl-4-isothiazolin-3-one and other candidate biodiesel biocides on rat alveolar macrophages and NR8383 cells.

Biocides are added to biodiesels to inhibit and remove microbial growth. The effects of 5-chloro-2-methyl-4-isothiazolin-3-one (CMIT), a candidate biodiesel biocide, were studied using freshly isolated rat alveolar macrophages (AM) and NR8383 cell line. CMIT markedly inhibited phagocytic oxidative burst as measured by zymosan-induced chemiluminescence, and cellular cytokine secretion as measured by zymosan-induced TNF-α secretion. The 50% inhibition concentration (LC(50)) for CMIT was 0.002-0.004 mM for both cellular functions. AM exposed to CMIT for as little as 2 min showed markedly inhibited functions that persisted for at least 5 h. Sodium metabisulfite was able to partially neutralize the inhibitory activity of CMIT. Cysteine and glutathione, when present at a molar ratio of 2-1 or higher against CMIT, were effective neutralizers, while serine, histidine, alanine, and albumin were without effect. When the AM testing system was used to compare the toxicity of CMIT against three other candidate biodiesel biocides, methylene dithiocyanate (MDC) was found to be of comparable toxicity to CMIT, 2-methyl-4-isothiazolin-3-one (MIT) was much less toxic, and dimethyl acetylenedicarboxylate (DMAD) was non-toxic. Because AM is among the first cell-type exposed to inhaled biodiesel aerosols, the result suggested that CMIT present in biodiesel may produce respiratory effects, and further investigations including animal studies are warranted.