Long-term allopurinol use decreases the risk of prostate cancer in patients with gout: a population-based study.

BACKGROUND: Clinical observations indicated an increased risk of developing prostate cancer in gout patients. Chronic inflammation is postulated to be one crucial mechanism for prostate carcinogenesis. Allopurinol, a widely used antigout agent, possesses potent anti-inflammation capacity. We elucidated whether allopurinol decreases the risk of prostate cancer in gout patients. METHODS: We analyzed data retrieved from Taiwan National Health Insurance Database between January 2000 and December 2012. Patients diagnosed with gout during the study period with no history of prostate cancer and who had never used allopurinol were selected. Four allopurinol use cohorts (that is, allopurinol use (>365 days), allopurinol use (181-365 days), allopurinol use (91-180 days) and allopurinol use (31-90 days)) and one cohort without using allopurinol (that is, allopurinol use (No)) were included. The study end point was the diagnosis of new-onset prostate cancer. Multivariable Cox proportional hazards regression and propensity score-adjusted Cox regression models were used to estimate the association between the risk of prostate cancer and allopurinol treatment in gout patients after adjusting for potential confounders. RESULTS: A total of 25 770 gout patients (aged between 40 and 100 years) were included. Multivariable Cox regression analyses revealed that the risk of developing prostate cancer in the allopurinol use (>365 days) cohort was significantly lower than the allopurinol use (No) cohort (adjusted hazard ratio (HR)=0.64, 95% confidence interval (CI)=0.45-0.9, P=0.011). After propensity score adjustment, the trend remained the same (adjusted HR=0.66, 95% CI=0.46-0.93, P=0.019). CONCLUSIONS: Long-term (more than 1 year) allopurinol use may associate with a decreased risk of prostate cancer in gout patients.

Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species.

Lon protease is a multifunction protein and operates in protein quality control and stress response pathways in mitochondria. Human Lon is upregulated under oxidative and hypoxic stresses that represent the stress phenotypes of cancer. However, little literature undertakes comprehensive and detailed investigations on the tumorigenic role of Lon. Overexpression of Lon promotes cell proliferation, apoptotic resistance to stresses, and transformation. Furthermore, Lon overexpression induces the production of mitochondrial reactive oxygen species (ROS) that result from Lon-mediated upregulation of NDUFS8, a mitochondrial Fe-S protein in complex I of electron transport chain. Increased level of mitochondrial ROS promotes cell proliferation, cell survival, cell migration, and epithelial-mesenchymal transition through mitogen-activated protein kinase (MAPK) and Ras-ERK activation. Overall, the present report for the first time demonstrates the role of Lon overexpression in tumorigenesis. Lon overexpression gives an apoptotic resistance to stresses and induces mitochondrial ROS production through Complex I as signaling molecules to activate Ras and MAPK signaling, giving the survival advantages and adaptation to cancer cells. Finally, in silico and immunohistochemistry analysis showed that Lon is overexpressed specifically in various types of cancer tissue including oral cancer.

Antizyme, a natural ornithine decarboxylase inhibitor, induces apoptosis of haematopoietic cells through mitochondrial membrane depolarization and caspases' cascade.

Antizymes delicately regulate ornithine decarboxylase (ODC) enzyme activity and polyamine transportation. One member of the family, antizyme-1, plays vital roles in molecular and cellular functions, including developmental regulation, cell cycle, proliferation, cell death, differentiation and tumorigenesis. However, the question of how does it participate in the cell apoptotic mechanism is still unsolved. To elucidate the contribution of human antizyme-1 in haematopoietic cell death, we examine whether inducible overexpression of antizyme enhances apoptotic cell death. Antizyme reduced the viability in a dose- and time-dependent manner of human leukemia HL-60 cells, acute T leukemia Jurkat cells and mouse macrophage RAW 264.7 cells. The apoptosis-inducing activities were determined by nuclear condensation, DNA fragmentation, sub-G(1) appearance, loss of mitochondrial membrane potential (Deltapsi( m )), release of mitochondrial cytochrome c into cytoplasm and proteolytic activation of caspase 9 and 3. Following conditional antizyme overexpression, all protein levels of cyclin-dependent kinases (Cdks) and cyclins are not significantly reduced, except cyclin D, before their entrance into apoptotic cell death. However, introduced cyclin D1 into Jurkat T tetracycline (Tet)-On cell system still couldn't rescue cells from apoptosis. Antizyme doesn't influence the expression of tumor suppressor p53 and its downstream p21, but it interferes in the expressions of Bcl-2 family. Inducible antizyme largely enters mitochondria resulting in cytochrome c release from mitochondria to cytosol following Bcl-xL decrease and Bax increase. According to these data, we suggest that antizyme induces apoptosis mainly through mitochondria-mediated and cell cycle-independent pathway. Furthermore, antizyme induces apoptosis not only by Bax accumulation reducing the function of the Bcl-2 family, destroying the Deltapsi( m ), and releasing cytochrome c to cytoplasm but also by the activation of apoptosomal caspase cascade.

Increasing ornithine decarboxylase activity is another way of prolactin preventing methotrexate-induced apoptosis: crosstalk between ODC and BCL-2.

Prolactin has more than 300 separate functions including affecting mammary growth, differentiation, secretion and anti-apoptosis. In the previous studies, prolactin induced Bcl-2 expression to prevent apoptosis and also provoked the activity of ornithine decarboxylase (ODC). Our previous data showed that ODC overexpression upregulates Bcl-2 and prevents tumor necrosis factor alpha (TNF-alpha)- and methotrexate (MTX)-induced apoptosis. Here, we further investigate whether prolactin prevents MTX-induced apoptosis through inducing ODC activity and the relationship between ODC and Bcl-2 upon prolactin stimulation. Prolactin prevented MTX-induced apoptosis in a dose-dependent manner in HL-60 cells. Following prolactin stimulation, ODC enzyme activity also shows an increase in a dose-dependent manner, expressing its maximum level at 3 h, and rapidly declining thereafter. Prolactin-induced ODC activity is completely blocked by a protein kinase C delta (PKCdelta) inhibitor, rottlerin. However, there are no changes in the expressions of ODC mRNA and protein level after prolactin stimulus. It indicates that prolactin may induce ODC activity through the PCKdelta pathway. Besides, Bcl-2 expresses within 1 h of prolactin treatment and this initiating effect of prolactin is not inhibited by alpha-difluoromethylornithine (DFMO). However, Bcl-2 is further enhanced following prolactin stimulation for 4 h and this enhancement is blocked by DFMO. Bcl-2 has no effect on ODC activity and protein levels, but ODC upregulates Bcl-2, which is inhibited by DFMO. Overall, there are two different forms of prolactin effect, it induces Bcl-2 primarily, and following this it stimulates ODC activity. Consequently induced ODC activity further enhances the expression of Bcl-2. The anti-apoptotic effect of prolactin is diminished by DFMO and recovered by putrescine. Obviously, ODC activity is one basis for the anti-apoptotic mechanisms of prolactin. A Bcl-2 inhibitor, HA14-1, together with DFMO, completely blocks the anti-apoptotic effects of prolactin. These results suggest that increasing ODC activity is another way of prolactin preventing MTX-induced apoptosis and that this induction of ODC activity enhances the expression of Bcl-2 strongly enough to bring about the anti-apoptotic function.

Ornithine decarboxylase prevents methotrexate-induced apoptosis by reducing intracellular reactive oxygen species production.

Methotrexate (MTX), a folate antagonist, was developed for the treatment of malignancies, and is currently used in rheumatoid arthritis (RA) and other chronic inflammatory disorders. It has been proven in short-term and long-term prospective studies that low doses of MTX (0.75 mg/Kg/week) are effective in controlling the inflammatory manifestations of RA. Low-concentrations of MTX achieve apoptosis and clonal deletion of activated peripheral T cells. One of the mechanisms of the anti-inflammatory and immunosuppressive effects may be the production of reactive oxygen species (ROS). However, the drug resistance of MTX in malignancies remains poorly understood. Ornithine decarboxylase (ODC) plays an important role in diverse biological functions, including cell development, differentiation, transformation, growth and apoptosis. In our previous studies, ODC overexpression was shown to prevent TNFalpha-induced apoptosis via reducing ROS. Here, we also investigated one mechanism of MTX-induced apoptosis and of drug resistance as to the anti-apoptotic effects of ODC during MTX treatment. We found MTX could induce caspase-dependent apoptosis and promote ROS generation together with disrupting the mitochondrial membrane potential (DeltaPsim) of HL-60 and Jurkat T cells. Putrescine and ROS scavengers could reduce MTX-induced apoptosis, which leads to the loss of DeltaPsim, through reducing intracellular ROS. Overexpression of ODC in parental cells had the same effects as putrescine and the ROS scavengers. Moreover, ODC overexpression prevented the decline of Bcl-2 that maintains DeltaPsim, the cytochrome c release and activations of caspase 9 and 3 following MTX treatment. The results demonstrate that MTX-induced apoptosis is ROS-dependent and occurs along a mitochondria-mediated pathway. Overexpressed ODC cells are resistant to MTX-induced apoptosis by reducing intracellular ROS production.

Prediction of the distance from skin to epidural space for low-thoracic epidural catheter insertion by computed tomography.

BACKGROUND: It may be clinically useful to predict the depth of the epidural space. METHODS: To investigate the accuracy of preoperative abdominal computed tomography (CT) in prediction of the distance for low-thoracic epidural insertion, a single group observational study was conducted in 30 male patients undergoing elective major abdominal surgery requiring epidural analgesia for postoperative pain relief. Using the paramedian approach, low-thoracic epidural insertion at T10-11 interspace was performed with a standardized procedure to obtain an actual insertion length (AIL). According to the principles of trigonometry, an estimated insertion length (EIL) was calculated as 1.26 times the distance from skin to epidural space measured from the preoperative abdominal CT. RESULTS: The mean (SD) EIL and AIL were 5.5 (0.7) and 5.1 (0.6) cm, respectively, with a significant correlation (r=0.899, P<0.01). The EIL tended to have a higher value than the AIL (0.4 (0.3) cm). There were significant correlations of both EIL and AIL with weight (P<0.01), BMI (P<0.01), and body fat percentage (P<0.01), but not with height (P>0.05). CONCLUSIONS: We conclude that the preoperative abdominal CT is helpful in prediction of the distance for low-thoracic epidural insertion using the paramedian approach.

Modulation of NO and cytokines in microglial cells by Cu/Zn-superoxide dismutase.

The activation of microglial cells in response to neuropathological stimuli is one of the prominent features of human neurodegenerative diseases. Cytokines such as IL-1 beta and TNF-alpha and inflammation-related enzymes such as inducible nitric oxide synthase are usually induced during the activation of microglial cells. We investigated the modulation of the activation of microglial cell by transfecting a Cu/Zn-SOD cDNA into BV-2 cells. Parental and transfected BV-2 cells were then subjected to LPS stimulation. The results showed that in Cu/Zn-SOD-transfected BV-2 cells, the expression and activity of Cu/Zn-SOD increased. On the other hand, upon activation by LPS, these cells produced less NO, IL-1 beta, and TNF-alpha than the parental microglial cells. This finding suggests that superoxide may be an early signal triggering the induction of cytokines and that the transfected Cu/Zn-SOD may provide a neuroprotective function via suppression of microglial activation. In addition, this approach may provide a rationale for the development of treatments for neurodegenerative diseases.

Immunoglobulin D multiple myeloma.

BACKGROUND: Immunoglobulin D (IgD) multiple myeloma (MM) is rare, accounting for less than 2% of all patients with MM in Western countries. In Taiwan, the frequency and clinicopathologic features of IgD MM have not yet been reported. METHODS: The clinicopathologic features and treatment outcome of patients with IgD MM diagnosed between January 1, 1982, and December 31, 1998, in Chang Gung Memorial Hospital were retrospectively reviewed. Nineteen patients with IgD MM were diagnosed. Of those patients, the medical records of 16 were available for review. RESULTS: Most of the patients were male (11/16) with a median age of 59 years. The most common presenting features included bone pain (56%), gastrointestinal discomfort (38%), general malaise (38%), and body weight loss (25%). The majority of patients had cytopenia (88%), renal function impairment (75%), hypercalcemia (63%), hyperuricemia (69%), elevated beta 2-microglobulin levels (86%), and Bence Jones proteinuria (92%). Serum protein electrophoresis showed an M-peak in 9 cases (9/12), whereas immunoelectrophoresis or immunofixation identified an IgD monoclonal gammopathy in all 16 patients. All of the M-proteins were of a lambda-light chain type. The IgD level ranged between 584 and 129,000 IU/ml (normal, < 100 IU/ml). All the patients had stage III disease except one (stage I). Four patients were still alive at the time of this analysis. The median survival time was 12 months. Infection was the leading cause of death (50%). CONCLUSION: The present series showed that IgD MM had aggressive clinical features, male predominance, a high frequency of renal function impairment, high incidence of M-protein undetected by serum protein electrophoresis, a predilection for lambda-light chains, and a short period of survival.

Thoracic cord compression due to gout: a case report and literature review.

An 82-year-old man developed progressive weakness of both legs 1 month prior to admission. He reported no previous history of trauma. Spine radiography revealed marked thoracic and lumbar spondylosis. Magnetic resonance imaging of the spine disclosed segmental stenosis with cord compression at T10-11 due to an extradural soft tissue lesion. Based on a diagnosis of thoracic spondylosis with cord compression, decompression laminectomy was performed. During the operation, fragile chalky-white material was noted over the epidural space, compressing the thoracic cord. The granular lesion was meticulously removed until the dura was identified and the cord was decompressed. Histologic examination of the surgical specimen revealed deposits of needle-like crystals that were consistent with monosodium urate, demonstrating that a gouty lesion of the thoracic spine had caused the cord compression. The patient had previously experienced several attacks of gouty arthritis of his feet. The postoperative serum uric acid concentration was 8.5 mg/dL. After surgery, he was treated with benzbromarone 100 mg per day. He was able to walk 3 months after the operation. A high index of suspicion of gouty involvement of the spine is necessary in patients with gout. Surgical decompression followed by regular administration of antigout drugs can provide satisfactory results.