Association of sepsis with risk for osteoporosis: a population-based cohort study.

We conducted a large, retrospective cohort study using data from Taiwan's National Health Insurance Research Database to evaluate whether the risk of developing osteoporosis is associated with sepsis. Our study found that adults younger than 65 years with sepsis had a significantly increased risk of developing osteoporosis. INTRODUCTION: There have been limited studies regarding the osteoporosis risk associated with sepsis. Our purpose is to evaluate whether the risk of developing osteoporosis is associated with sepsis. METHODS: We conducted a large, retrospective cohort study using data from Taiwan's National Health Insurance Research Database. From the insurance claims data, a total of 13,178 patients diagnosed with sepsis from 2000 to 2012 were included in the sepsis cohort, and a propensity score-matched cohort included 13,178 individuals without sepsis. To calculate the incidence of osteoporosis, both groups were followed until 2013. Cox regression analysis was performed to obtain the hazard ratios (HRs) to assess the risk of developing osteoporosis. The Kaplan-Meier method was used to estimate the cumulative incidence of osteoporosis. RESULTS: The overall incidences of osteoporosis (per 1,000 person-years) in the sepsis and non-sepsis groups were 10.2 and 10.7, respectively. The risk of osteoporosis significantly increased in the presence of sepsis (adjusted HR = 1.17, 95% confidence interval (CI) = 1.04-1.31). The risk of osteoporosis in the sepsis group was significantly higher than that in the non-sepsis group for young patients aged 20-49 years and patients aged 50-64 years (adjusted HR = 1.93, 95% CI = 1.08-3.44; adjusted HR = 2.01, 95% CI = 1.52-2.65, respectively). The Kaplan-Meier curves of cumulative probability also showed a significantly increased risk of osteoporosis in patients aged 20-49 years and aged 50-64 years with sepsis compared with non-sepsis (P = 0.025; P < 0.001, respectively). CONCLUSION: Adults younger than 65 years with sepsis had a significantly increased risk of developing osteoporosis.

False-positive Aspergillus galactomannan immunoassays associated with intravenous human immunoglobulin administration.

OBJECTIVES: Evidence of false-positive galactomannan enzyme immunoassay (GM-EIA) results associated with intravenous immunoglobulin (IVIG) administration is scarce. Here, we aimed to determine the false-positive rate of GM-EIA after IVIG administration and to identify the related factors. METHODS: Standard GM-EIA was performed using diluted and pure human IVIG samples with and without heat treatment. We also included adult patients who had at least one GM-EIA result within 1 week of IVIG administration for analysis. Those who had prior invasive aspergillosis within 1 year before IVIG therapy were excluded. The clinical characteristics and galactomannan index (GMI) kinetics between patients with false-positive and true-positive GMI were compared. RESULTS: All diluted and pure IVIG samples tested positive for GM. Heat treatment resulted in the considerable elevation of GMI. Of 48 patients with positive GM-EIA results within 1 week of IVIG administration, 22 (45.8%) were considered to have false-positive antigenaemia (false-positive group, FPG). After the completion of IVIG administration, a decline in GMI was observed in all FPG patients but in only 18 out of 26 patients (69.2%) with true-positive results (true-positive group, TPG). By 7, 14, and 18 days of IVIG administration, GMI reverted to negative values in 7/15 (46.7%), 18/20 (90%) and 22/22 (100%) FPG patients, respectively, and 6/24 (25%), 14/24 (58.3%), and 16/26 (61.5%) of TPG patients, respectively. The TPG was more likely to have two or more consecutively positive GMIs after IVIG administration than the FPG (adjusted odds ratio, 9.01; 95% confidence interval, 1.99-40.9). CONCLUSIONS: IVIG treatment may produce false-positive GM-EIA results. A positive GMI among patients receiving human IVIG should be interpreted with caution.

A Case Rarity: Papillary Thyroid Carcinoma with Squamous Metaplasia Complicated with Chronic Discharging Ulcers.

We report a unique case of differentiated thyroid carcinoma (DTC) with squamous metaplasia complicated with chronic discharging ulcer. A 76-year-old gentleman was referred to us after defaulted treatment 1 year post-total thyroidectomy. He presented to us with long-standing chronic, non-healing, ulcerative and discharging wound at the anterior neck at previous total thyroidectomy scar. The primary tumour was histologically diagnosed as papillary malignant cells with extensive squamous metaplasia. Squamous metaplasia is a rare finding in thyroid carcinoma that carried a poorer prognostic factor.

Resilient healthcare in patient safety.

No abstract available.

Skill validation study on sentinel lymph node biopsy in breast cancer and the challenges of false-negative, in-transit and micrometastatic nodes.

No abstract available.

Nerve conduction block in diabetic rats using high-intensity focused ultrasound for analgesic applications.

BACKGROUND: Nerve conduction block using high-intensity focused ultrasound (HIFU) has been conducted with nerves of mixed fibres in normal animal models. This study tested the feasibility and safety of HIFU for sensory nerve conduction block in diabetic neuropathic nerves to determine its potential for pain relief. METHODS: Diabetes was induced in Sprague-Dawley rats using streptozotocin, and HIFU at 2.68 MHz was used for the block. This study consisted of two sections, in vitro and in vivo. For the in vitro experiments, the entire contiguous sciatic-sural nerves were obtained. Compound action potentials and sensory action potentials were recorded in the sciatic and sural nerves, respectively. For the in vivo experiments, compound muscle action potentials (CMAPs) were recorded from the gastrocnemius muscles. All data were expressed as median (range). RESULTS: The in vitro results showed that HIFU temporarily inhibited sensory action potentials of the control and diabetic rat nerves to 33.9 (8.2) and 14.0 (10.7)% of the baseline values, respectively, whereas the compound action potentials were suppressed to 53.6 (8.4) and 76.2 (7.5)% of baseline, respectively. The in vivo results showed that HIFU acutely blocked CMAPs to 32.9 (12.6) and 19.9 (10.9)% of baseline in control and diabetic rat nerves, respectively. Measurements of CMAPs and histological exanmination were used for indirect assessment of the safety of the HIFU technique. CONCLUSIONS: High-intensity focused ultrasound safely and reversibly suppressed nerve conduction in diabetic rat nerves when the stimulation parameters were appropriate. The results suggest that HIFU may have potential to block sensory nerves reversibly and provide peripheral pain relief.

An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530).

The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different degrees of epithelial-mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial-mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.

Human fucosyltransferase 6 enables prostate cancer metastasis to bone.

BACKGROUND: The interaction between human prostate cancer (PCa) cells and bone marrow (BM) endothelium follows a rolling-and-adhesion cascade mediated by E-selectin ligand (ESL): E-selectin. This adhesion is enabled by elevated expression of α-1,3-fucosyltransferases (FTs), enzymes responsible for ESL-mediated bone metastasis in humans. In contrast, the incidence of bone metastasis in mice is rare. METHODS: FT 3, 6 and 7 were overexpressed in mouse PCa cells. The rolling cell number, cell-rolling velocity and transendothelial migration were characterised in vitro. Fucosyltransferases-transduced mouse PCa cells expressing luciferase were inoculated into mice via left ventricle to compare the capability of bone metastasis. Mass spectrometry and immunoprecipitation were utilised for identification of ESLs. RESULTS: Overexpression of FT3, FT6 or FT7 restored ESLs and enabled mouse PCa cells to roll and adhere in E-selectin-functionalised microtubes, similar to trafficking of circulating PCa cells in BM vessels. Following intracardiac inoculation, FT6-transduced cells induced robust bone metastasis in mice. Inhibition of FT6 by a fucose mimetic significantly reduced bone metastasis. Importantly, comparison of FT3, FT6 and FT7 gene expression in existing clinical samples showed significant upregulation of FT6 in PCa-distant metastases. CONCLUSION: FT6 is a key mediator of PCa cells trafficking to the BM. It may serve as a viable drug target in preclinical tests of therapeutics for reduction of PCa bone metastasis.

Mycophenolate mofetil alleviates lupus nephritis through urokinase receptor signaling in a mice model.

Lupus nephritis (LN) is usually associated with widespread effacement of the podocytes' foot processes leading to proteinuria. Induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via promoting podocytes' motility and kidney permeability in the glomerulus. Very little is known about uPAR signaling in LN. Mycophenolate mofetil (MMF), an immunosuppressive agent, efficiently modulates the development of LN in humans and mice, but there are no data concerning the direct uPAR involvement on podocytes in LN. The MMF efficiency and uPAR involvement signaling in NZB×NZW F1 lupus-prone mice were examined by proteinuria, renal function and pathology, immune complex deposits, and uPAR expression of podocytes by immunofluorescence staining and quantitative RT-PCR. After MMF treatment, the proteinuria (p < 0.01), BUN level (p < 0.05) and immunodeposition in glomeruli (p < 0.001) were significantly improved. Most important, the renal uPAR mRNA levels (p < 0.001) and uPAR protein level of podocytes (p < 0.001) were significantly reduced. The beneficial effect of MMF on LN could be attributed, at least in part, to the inhibition of uPAR expression in podocytes. These findings demonstrated uPAR could have potential as a predictive index for response to LN therapeutics.

Targeting ß-tubulin:CCT-ß complexes incurs Hsp90- and VCP-related protein degradation and induces ER stress-associated apoptosis by triggering capacitative Ca2+ entry, mitochondrial perturbation and caspase overactivation.

We have previously demonstrated that interrupting the protein-protein interaction (PPI) of ß-tubulin:chaperonin-containing TCP-1ß (CCT-ß) induces the selective killing of multidrug-resistant cancer cells due to CCT-ß overexpression. However, the molecular mechanism has not yet been identified. In this study, we found that CCT-ß interacts with a myriad of intracellular proteins involved in the cellular functions of the endoplasmic reticulum (ER), mitochondria, cytoskeleton, proteasome and apoptosome. Our data show that the targeted cells activate both the heat-shock protein 90 (Hsp90)-associated protein ubiquitination/degradation pathway to eliminate misfolded proteins in the cytoplasm and the valosin-containing protein (VCP)-centered ER-associated protein degradation pathway to reduce the excessive levels of unfolded polypeptides from the ER, thereby mitigating ER stress, at the onset of ß-tubulin:CCT-ß complex disruption. Once ER stress is expanded, ER stress-associated apoptotic signaling is enforced, as exhibited by cellular vacuolization and intracellular Ca2+ release. Furthermore, the elevated intracellular Ca2+ levels resulting from capacitative Ca2+ entry augments apoptotic signaling by provoking mitochondrial perturbation and caspase overactivation in the targeted cells. These findings not only provide a detailed picture of the apoptotic signaling cascades evoked by targeting the ß-tubulin:CCT-ß complex but also demonstrate a strategy to combat malignancies with chemoresistance to Hsp90- and VCP-related anticancer agents.

Defect mediated photocatalytic decomposition of 4-chlorophenol on epitaxial rutile thin films under visible and UV illumination.

We show that pure rutile TiO(2) can be photo-responsive even under low energy visible light after annealing in vacuum where we envisage that the point defects, i.e. oxygen vacancies and titanium interstitials, serve an important role. In this study, single crystal rutile films were grown by the pulsed laser deposition technique and then vacuum annealed under different oxygen pressures to introduce defects into their lattices. 4-chlorophenol was selected as a model material and decomposed by the annealed TiO(2) films where the maximum photocatalytic reaction rate constants were determined as 0.0107 and 0.0072 min(-1) under UV and visible illumination. Epitaxial growth along the [200] direction was confirmed by φ-scan and 2θ-scan XRD and the epitaxial relationship between the rutile film and the c-sapphire substrate was explained as (100)[010](R) [parallel] (0001)[12[combining overline]10](S). The formation of atomically sharp interfaces and the epitaxial growth were ascertained by annular dark-field STEM imaging. Based on the XPS, UV-vis and PL spectroscopy results, it was found that the defect concentration increased after annealing under lower pressures, e.g. 5 × 10(-6) Torr. In contrast, more perfect crystals were obtained when the films were annealed under high oxygen pressures, namely 5 × 10(1) Torr. The morphology of the films was also investigated by employing an AFM technique. It was observed that increase of the annealing pressure results in the formation of larger grains. It was also found that the electrical resistivity of the rutile films strongly increased by about three orders of magnitude when the annealing pressure increased from 5 × 10(-4) to 5 × 10(1) Torr.

Regression of early diabetic macular oedema is associated with prevention of dark adaptation.

HYPOTHESIS: Dark-adapted rods consume oxygen at high rates and light adaptation decreases this oxygen burden and can have therapeutic effects on diabetic macular oedema (DMO). METHODS: Patients with mild non-proliferative diabetic retinopathy (DR) and early, untreated non-sight-threatening DMO slept for 6 months wearing masks that illuminated the eyelid of one closed eye by 505 nm light. Exclusion criteria were any concomitant eye disease, DR >ETDRS grade 35, and other systemic diseases. PRIMARY OUTCOME: change of OCT retinal thickness in the local region where oedema was present. RESULTS: A total of 34 out of 40 patients completed the study. Mean baseline OCT macular cube thickness was equivalent for study and fellow eyes. But study eyes had a greater mean thickness in the central subfield zone 1 (282±53 µm) vs (256±19 µm) the fellow eyes. Twenty-eight study eyes showed intraretinal cysts compared with nine in the fellow eyes. At 6 months, only 19 study eyes had cysts while cysts were seen in 20 fellow eyes. After 6 months, the worst affected ETDRS zone and the central subfield zone 1 reduced in thickness in study eyes only by 12 µm (95% CI 20 to -7, P=0.01). The secondary outcomes of change in visual acuity, achromatic contrast sensitivity, and microperimetric thresholds improved significantly in study eyes and deteriorated in fellow eyes. CONCLUSIONS: Sleeping in dim light that can keep rods light adapted may reverse the changes of DMO.

Replication study of SNP associations for colorectal cancer in Hong Kong Chinese.

BACKGROUND: Recent genome-wide association studies of colorectal cancer (CRC) have identified common single-nucleotide polymorphisms (SNPs) mapping to 10 independent loci that confer modest increased risk. These studies have been conducted in European populations and it is unclear whether these observations generalise to populations with different ethnicities and rates of CRC. METHODS: An association study was performed on 892 CRC cases and 890 controls recruited from the Hong Kong Chinese population, genotyping 32 SNPs, which were either associated with CRC in previous studies or are in close proximity to previously reported risk SNPs. RESULTS: Twelve of the SNPs showed evidence of an association. The strongest associations were provided by rs10795668 on 10p14, rs4779584 on 15q14 and rs12953717 on 18q21.2. There was significant linear association between CRC risk and the number of independent risk variants possessed by an individual (P=2.29 × 10(-5)). CONCLUSION: These results indicate that some previously reported SNP associations also impact on CRC risk in the Chinese population. Possible reasons for failure of replication for some loci include inadequate study power, differences in allele frequency, linkage disequilibrium structure or effect size between populations. Our results suggest that many associations for CRC are likely to generalise across populations.

Mercury recovery from cold cathode fluorescent lamps using thermal desorption technology.

Cold cathode fluorescent lamps (CCFLs) are globally used components of high technology products. A large amount of mercury in waste CCFLs is being recovered by thermal desorption technology in Taiwan. However, the complexity of the samples affects the thermal desorption efficiency and increases costs. This study identifies the mercury release behaviour of amalgam, phosphor and mercury-containing components as well as waste CCFLs by bench scale thermal desorption test. The results show that the mercury was released from amalgam and mercury/fluorescent powder from a real treatment plant at temperatures between 550 degrees C to 850 degrees C, which is much higher than from cinnabar at 300 degrees C to 380 degrees C and that of pure mercury, high pressure mercury lamps, and fluorescent tubes containing mercury/fluorescent-powder at 50 degrees C to 250 degrees C. In addition, the experiment also showed the mercury release peak of the mercury/fluorescent powders from a real treatment plant occurs at much higher temperatures than that of commercial phosphor at 50 degrees C to 200 degrees C. Thus, complete separation of the cracked CCFLs is necessary to effectively recover phosphor and mercury at low financial and energy cost.

Evaluation of C-2-substituted 19-nor-1alpha,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer.

1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) is known to inhibit the proliferation and invasiveness of prostate cancer cells. However, 1alpha,25(OH)(2)D(3) can cause hypercalcemia and is not suitable as a therapeutic agent. 19-Nor-vitamin D derivatives are known to be less calcemic when administered systemically. In order to develop more potent anti-cancer agents with less calcemic side effect, we therefore utilized (3)H-thymidine incorporation as an index for cell proliferation and examined the antiproliferative activities of nine C-2-substituted 19-nor-1alpha,25(OH)(2)D(3) analogs in the immortalized PZ-HPV-7 normal prostate cell line. Among the nine analogs we observed that the substitution with 2alpha- or 2beta-hydroxypropyl group produced two analogs having antiproliferative potency that is approximately 500- to 1000-fold higher than 1alpha,25(OH)(2)D(3). The (3)H-thymidine incorporation data were supported by the cell counting data after cells were treated with 1alpha,25(OH)(2)D(3), 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) or 19-nor-2beta-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) for 7 days. 19-Nor-2alpha-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) and 19-nor-2beta-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) were also shown to be about 10-fold more active than 1alpha,25(OH)(2)D(3) in cell invasion studies using prostate cancer cells. In conclusion, a substitution at the C-2 position of 19-nor-1alpha,25(OH)(2)D(3) molecule with a hydroxypropyl group greatly increased the antiproliferative and anti-invasion potencies. Thus, these two analogs could be developed to be effective therapeutic agents for treating early and late stages of prostate cancer.

Unusual pox lesions found in Chinese jungle mynahs (Acridotheres cristatellus).

Pox lesions involving feathered and unfeathered skin, the oral cavity and the uropygial gland were found in Chinese jungle mynahs. Characteristic intracytoplasmic inclusions were detected in the proliferative cells of all lesions. Ultrastructurally, the virus particles consisted of a convoluted outer membrane enclosing lateral bodies and a biconcave central core, typical for poxvirus. The nucleotide sequences of the amplicon obtained with a set of primers for the 4b core protein of fowl poxvirus revealed that the mynah poxvirus was phylogenetically related to wood pigeon poxvirus. This is the first report of poxvirus infection affecting the uropygial gland.

Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling.

In this study, we have used genome-wide expression profiling to categorise synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas (MFHs). Following hierarchical clustering analysis of the expression data, the best match between tumour clusters and conventional diagnosis was observed for synovial sarcomas. Eight of nine synovial sarcomas examined formed a cluster that was characterised by higher expression of a set of 48 genes. In contrast, sarcomas conventionally classified as leiomyosarcomas and MFHs did not match the clusters defined by hierarchical clustering analysis. One major cluster contained a mixture of both leiomyosarcomas and MFHs and was defined by the lower expression of a set of 202 genes. A cluster containing a subgroup of MFHs was also detected. These results may have implications for the classification of soft tissue sarcomas, and are consistent with the view that sarcomas conventionally defined as MFHs do not represent a separate diagnostic category.

TR4 orphan receptor represses the human steroid 21-hydroxylase gene expression through the monomeric AGGTCA motif.

The human TR4 orphan receptor (TR4) is a member of the nuclear receptor superfamily. It functions as a transcriptional factor which regulates and controls many important physiological functions. It has been documented that TR4 may bind as a homodimer to a DNA response element containing two direct repeats of the AGGTCA consensus motif. Surprisingly, our data reveal that the expression of the human steroid 21-hydroxylase (21-OHase) gene could be repressed by TR4 via the monomeric AGGTCA motif (-228TR4RE) at its 5' flanking region (nucleotide numbers 1431-1444, 5'-GGAAAAAGGTCAGG-3'). Electrophoretic mobility shift assay showed specific binding with a dissociation constant of 0.4 nM between TR4 and the monomeric -288TR4RE motif. However, TR4 does not form heterodimers with either retinoid X receptor alpha or SHP (short heterodimer partner) orphan receptor. Additionally, both dual-luciferase and chloramphenicol acetyltransferase assays demonstrated that TR4 can function as a repressor via the -228TR4RE of the 21-OHase gene. In conclusion, our data suggest that TR4 may bind to a monomeric DNA response element and play an important role in the suppression of the 21-OHase gene expression.

Diffuse toxoplasmic retinochoroiditis as the initial manifestation of acquired immunodeficiency syndrome.

Toxoplasmic retinochoroiditis is an important opportunistic retinal infection in human immunodeficiency virus (HIV)-infected patients. It may present as diffuse necrotizing retinochoroiditis instead of a focal lesion and may be the initial manifestation of HIV infection. A 50-year-old heterosexual man presented with blurred vision in his left eye of 3 months' duration. Fundus examination revealed diffuse necrotizing retinochoroiditis, mainly at the posterior pole, with marked vitritis in the left eye. Serologic studies and aqueous fluid antibody titers indicated recent toxoplasmic infection. Positive enzyme immunoassays (EIA) and Western blot tests proved HIV infection. The retinochoroiditis and vitritis improved after an antitoxoplasmic regimen with trimethoprim-sulfamethoxazole (TMP-SMX). Nonetheless, toxoplasmic encephalitis developed 6 months after the onset of ocular toxoplasmosis and responded well to TMP-SMX. This is the first case of toxoplasmic retinochoroiditis as the initial manifestation of AIDS reported in Taiwan. We suggest that Toxoplasma infection should be included in the differential diagnosis of diffuse necrotizing retinochoroiditis and vitritis. We also recommend that adults with newly diagnosed ocular toxoplasmosis be screened for HIV infection.

Convergence of two repressors through heterodimer formation of androgen receptor and testicular orphan receptor-4: a unique signaling pathway in the steroid receptor superfamily.

The androgen receptor (AR) binds to androgen response elements and regulates target genes via a mechanism involving coregulators. Here we demonstrate that the AR can interact with the testicular orphan receptor-4 (TR4) and function as a repressor to down-regulate the TR4 target genes by preventing the TR4 binding to its target DNA. Interestingly, the heterodimerization of AR and TR4 also allows TR4 to repress AR target gene expression. Simultaneous exposure to both receptors therefore could result in bidirectional suppression of their target genes. Together, these data demonstrate that the coupling of two different receptors, through the heterodimerization of AR and TR4, is a unique signaling pathway in the steroid receptor superfamily, which may facilitate further understanding of the complicated androgen action in prostate cancer or libido.