Dietary polyphenols as antioxidants and anticancer agents: More questions than answers
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Miao-Lin Hu
High intake of fruit and vegetables is believed to be beneficial to human health. Fruit, vegetables and some beverages, such as tea and coffee, are particularly rich in dietary polyphenols. Various studies have suggested (but not proven) that dietary polyphenols may protect against cardiovasucalar diseases, neurodegenerative diseases and some forms of cancer. Dietary polyphenols may exert their anticancer effects through several possible mechanisms, such as removal of carcinogenic agents, modulation of cancer cell signaling and antioxidant enzymatic activities, and induction of apoptosis as well as cell cycle arrest. Some of these effects may be related, at least partly, to their antioxidant activities. In recent years, a new concept of the antioxidant effects of dietary polyphenols has emerged, i.e., direct scavenging activity toward reactive species and indirect antioxidant activity; the latter activity is thought to arise primarily via the activation of nuclear factor-erythroid-2-related factor 2 which stimulates the activities of antioxidant enzymes such as glutathione peroxidase (GPx), glutathione S-transferase, catalase, NAD(P)H: quinone oxidoreductase-1 (NQO1), and/or phase II enzymes. The direct antioxidant activity of dietary polyphenols in vivo is probably limited because of their low concentrations in vivo, except in the gastrointestinal tract where they are present in high concentrations. Paradoxically, the pro-oxidant effect of dietary polyphenols may contribute to the activation of antioxidant enzymes and protective proteins in cultured cells and animal models because of the adaptation of cells and tissues to mild/moderate oxidative stress. Despite a plethora of in vitro studies on dietary polyphenols, many questions remain to be answered, such as: (1) How relevant are the direct and indirect antioxidant activities of dietary polyphenols in vivo? (2) How important are these activities in the anticancer effects of dietary polyphenols? (3) Do the pro-oxidant effects of dietary polyphenols observed in vitro have any relevance in vivo, especially in the potential anticancer effect of dietary polyphenols? Apparently, more carefully-designed in vivo studies are needed to answer these questions.
The fluoroquinolones (FQs) are used to treat a wide range of infections because of their excellent gastrointestinal absorption, superior tissue penetration and broad-spectrum activity. Recently, FQ-associated tendinopathy and tendon rupture have been reported, especially in the elderly and patients with diabetes
and renal failure. However, these adverse effects do not appear to be widely known among physicians. Because of the frequent use of FQs in clinical practice, physicians should be aware of their potential for severe disability from tendon rupture. Achilles tendinopathy or rupture is among the most serious side effects associated with FQ use, with reports markedly increasing, especially with the use of ciprofloxacin. The histopathologic findings include degenerative lesions, fissures, interstitial edema without cellular infiltration, necrosis and neovascularization. There are possible molecular mechanisms accounting for FQ-associated tendinopathy. First, ciprofloxacin mediates inhibition of cell proliferation and G2/M cell cycle arrest in tendon cells by down-regulation of cyclin B and cyclin-dependent kinase 1. Second, ciprofloxacin inhibits the spead and migration of tenocytes by down-regulation of focal adhesion kinase phosphorylation. Third, ciprofloxacin
enhances the enzymatic activity of matrix metalloproteinase-2 with degradation of type I collagen. Management of FQ-associated tendinopathy includes immediate discontinuation of FQs, rest, non-steroidal anti-inflammatory drugs, physical modalities and eccentric strengthening exercise. Tendon rupture may require surgical intervention.
Background: Epidermal growth factor (EGF)-like module-containing mucin-like hormone
receptor-like 2 (EMR2) is an adhesion G protein-coupled receptor previously shown to potentiate neutrophil responses to a number of inflammatory stimuli. EMR2 activation promotes neutrophil adhesion and migration, and augments production of reactive oxygen species and degranulation. In this study,we examined the effect of EMR2 ligation by its specific antibody on the cytokine expression profile and cell survival of lipopolysaccharide (LPS)-treated neutrophils.
Methods: Neutrophils were treated with LPS in the absence or presence of the anti-EMR2 mAb, 2A1. Cell apoptosis was determined by flow cytometry analysis using annexin-V and propidium iodide staining. Cell supernatants were collected for the detection of cytokine secretion by enzyme-linked immunosorbent
assay.
Results: We confirmed the specific priming effect of EMR2 on the response of neutrophils
to formyl-Met-Leu-Phe by measuring the production of reactive oxygen species. Furthermore, we showed that EMR2 ligation suppresses LPS-induced neutrophil survival. In addition, we demonstrated that ligation of EMR2 changes the secretion profiles of multiple cytokines, including interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1. Finally, higher levels of EMR2 were detected on neutrophils of liver cirrhosis patients and were correlated to a pro-apoptotic phenotype.
Conclusion: Collectively, the present data indicate a functional role for EMR2 in the modulation of neutrophil activation during inflammation.
Background: The toxicity and efficacy of biochemotherapy with low-dose interleukin-2
for patients with metastatic malignant melanoma (MM) were studied.
Method: Metastatic chemo-naïve MM patients were given biochemotherapy (BCDT regimen) with carmustine (BCNU), cisplatin (CDDP), dacarbazine (DTIC), and tamoxifen and interleukin-2 (IL-2) 18 Million International Units in divided doses by subcutaneous injection three times a week for four weeks. BCDT consisted of BCNU (150 mg/m2, day l every 8 weeks), CDDP (25 mg/m2, days l-3 every 4 weeks), DTIC (220 mg/m2, days 1-3 every 4 weeks) and tamoxifen 10 mg twice a day. Treatment was repeated for a total of 6 cycles, or until disease progression or unbearable toxicity.
Results: From Nov 2001 to July 2005, 40 patients (20 men; 20 women) were enrolled. Their median age was 54 years (range 22-79 years). Subtypes of melanoma included 23 (57.5%) acral lentiginous, 11 (27.5%) nodular, 1 (2.5%) mucosal, and 5 (12.5%) others. Grade 3-4 toxicities included neutropenia
(27.5%), anemia (45%), and thrombocytopenia (40%). Constitutional IL-2 toxicities included indurate injection site (57.5%), fever (60%), chills (55%), itchy skin (42.5%), bone pain (32.5%) and myalgia (45%). Grade 1-2 hypotension was noted in 12.5% of patients. Eosinophilia (range 5% to 71%) was evident in 72.5% of patients. The response rate was 32.5% including 5% with a complete response, 27.5% with a partial response, and 17.5% with stable disease. The median progression-free survival was 6.2 months (95% CI: 2.9~9.6 months). The median overall survival was 11.3 months (95% CI: 7.0~15.6 months). Five patients (12.5%) who presented with oligo-metastasis achieved five-year survivals.
Conclusions: Our data demonstrated that low-dose IL-2 plus BCDT is tolerable. A durable response and long-term survival can be achieved in a small subgroup of patients.
Background: Previous reports have indicated that insulin resistance (IR) is associated with chronic hepatits C virus (HCV) infection. However, the correlations between IR, metabolic syndrome (MS), and serum HCV RNA levels are still controversial. The aim of this study was to determine the relationships between IR, MS, and HCV RNA in patients with chronic genotype 1 or 2 HCV infection.
Methods: One hundred and twenty subjects with chronic genotype 1 or 2 HCV infection with complete clinical data were prospectively enrolled. Baseline and laboratory data were collected and analyzed. IR was defined as a homeostatic model assessment- IR (HOMA-IR) score > 2.5.
Results: Of the 120 patients, 47 (39.2%) had a HOMA-IR > 2.5, and 42 (35%) met the criteria for MS. IR was significantly associated with a high body mass index (p < 0.0001), high waist circumference (p < 0.0001) and high triglyceride level (p = 0.025). IR was an independent predictor of MS. However, in multivariate linear regression analysis, the serum HCV RNA level was not significantly different in chronic hepatitis C patients with or without IR (p = 0.761), and with or without MS (p = 0.292).
Conclusions: IR and MS are not uncommon in patients with chronic hepatitis C. The serum HCV RNA level is not associated with the presence of IR or MS in chronic hepatitis C patients with genotype 1 or 2 infection. The impact of hepatitis C virus on IR is not dose responsive.
Background: Nephroureterectomy with bladder cuff excision has been the gold standard surgical treatment for upper tract urothelial carcinoma. In this study, we determined the independent prognostic factors for upper tract urothelial carcinoma.
Methods: The records of 285 consecutive patients undergoing nephroureterectomy with bladder cuff excision at our institution between 2003 and 2007 were reviewed. Kaplan-Meier survival curves were used to determine the 5-year cancer-specific survival rates for all patient groups. Cox proportional hazard regression was performed to determine the factors that had an independent impact on the survival of patients with upper tract urothelial carcinoma.
Results: A total of 192 patients matching the inclusion criteria were enrolled in our study. The mean follow-up time was 43.81 months. We found that the female gender, a lower ureter free of invasion, and an adequate bladder cuff excision were independent factors for a better tumor recurrence-free survival rate. The
pathology stage and recurrence (none, intravesical or extravesical) were independent factors for the overall survival rate. A non-adequate ureterectomy including the bladder cuff was associated with a high body mass index (BMI) and the infiltrating tumor pattern of urothelial carcinoma.
Conclusion: Nnephroureterectomy together with adequate bladder cuff excision plays an extremely important role in the surgical treatment of upper urinary tract urothelial carcinoma. Patients with incomplete resections of the bladder cuff are at increased risk of tumor recurrence.
Background: The incidence of colorectal cancer is increasing in Taiwan. Adenomatous polyps are known to be precancerous lesions and need to be removed. New techniques like chromendoscopy, magnifying endoscopy, narrow band imaging and magnifying endoscopy with flexible spectral imaging color enhancement may improve the accuracy of identifying precancerous polyps but are not widely available in the real world. This study analyzed the conventional biopsy method in diagnosing early colon cancer and the necessity for subsequent surgery after polypectomy.
Methods: From January 2002 to December 2007, 1027 adenomatous polypoid specimens taken from 720 patients who received polypectomy by conventional white light colonoscopy were studied. The pathologic reports of 26 specimens of early cancer or high grade dysplasia from 25 patients were analyzed.
Protruding polyps were classified as pedunculated (o-Ip), subpedunculated (o-Isp) and sessile (o-Is).
Results: Fourteen of the 26 specimens were type o-Ip, 10 were type o-Isp, and 2 were type o-Is. The pathologic reports were high grade dysplasia (n = 5), mucosal adenocarcinoma (n = 18) and submucosal adenocarcinoma (n = 3). Among these, 7 lesions from 7 patients received a randomized biopsy instead of
immediate polypectomy. Adenoma was reported in 6 of them with only one malignancy detected (false negative rate: 86%). Eight patients received surgery. The mean follow-up period for these patients was 17 months, and none of them had recurrences.
Conclusions: The randomized biopsy method for adenomatous polyps has a high false negative rate for early colon cancer and high grade dysplasia and is therefore not necessary in cases of protruding type polyps which can be removed by polypectomy. An adequate direct polypectomy may completely remove the
protruding type of early colon cancer.
Background: Hip fractures account for < 1% of all pediatric fractures. Most are caused by a high-energy mechanism. Complications occur at a high rate because the vascular and osseous anatomy of the child's proximal femur is vulnerable to injury. The purposes of this study were to evaluate whether osteonecrosis influences the functional results and to analyze the risk factors for the development of osteonecrosis.
Methods: We conducted a retrospective review of the complications of hip fractures (3 transepiphyseal fractures, 13 transcervical fractures, 6 cervico-trochanteric fractures, and 1 intertrochanteric fracture) in 23 patients (15 boys and 8 girls) between January 1988 and December 1997. Most injuries were caused by falling from a height or a motorcycle accident. The medical records and serial radiographs of all patients were reviewed. The function of the injured site was evaluated using Ratliff's criteria.
Results: The ages of these children at the time of injury ranged from 1.5 to 16 years (average 11.1 years). The mean follow-up was 4.91 years (range, 1 year to 12 years and 7 months). Overall, complications included osteonecrosis in 11 (48%) patients, premature physeal closure in 11 (48%), coxa vara in 3 (13%) and coxa valga in 2 (9%). There was no nonunion. Poor outcomes were related to the development of osteonecrosis. The time to surgery (≤ 12 hours) and the quality of reduction significantly influenced the occurrence of osteonecrosis. The occurrence and severity of femoral head osteonecrosis significantly influenced the functional results (p < 0.001, and p < 0.048,
respectively).
Conclusion: Osteonecrosis is the most severe complication after hip fractures in children and is associated with poor functional results. The time to surgery and the quality of reduction were the significant predictors in our study.
Background: To determine predictors associated with early hospital death, 30-day mortality, and long-term survival after open surgical treatment of ruptured abdominal aortic aneurysms (RAAAs).
Methods: A retrospective chart review of 127 consecutive patients who received open surgical treatment of a RAAA at Chang Gung Memorial Hospital, Taiwan, from February 1994 to May 2007. Data recorded included patient characteristics, medical history, perioperative variables, and outcomes.
Results: There were 104 men and 23 women with a mean age of 70 12 years in the analysis. Patients with RAAAs were classified into two groups; 100 (78.7%) patients were classified as group I (hemodynamically stable), and 27 (21.3%) patients were classified as group II (hemodynamically unstable at arrival). The 30-day mortality was 22% for group I and 74.1% for group II. Multivariate analysis identified age > 75 years old (odds ratio [OR], 0.083; 95% confidence interval [CI] 0.02-0.36), hemodynamically unstable state (OR, 0.081; 95% CI 0.016-0.4), blood transfusion > 5 L (OR, 0.14; 95% CI 0.038-0.54), intraperitoneal rupture (OR, 7.2; 95% CI 1.4-36), urine output < 0.5 mL/kg/min (OR, 22; 95% CI 4.6-110), and suprarenal cross-clamping (OR, 0.083; 95% CI 0.019-0.36) as incremental risk factors for 30-day mortality.
Conclusion: Significant predictors of mortality in patients with RAAAs include hemodynamically unstable state, age > 75 years old, intraperitoneal rupture, low intraoperative urine output, and suprarenal cross-clamping.
The impact of personality on depression among university students in Taiwan
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Shu-Man Chang, Daniel W Law, Her-Kun Chang
Background: Depression in Taiwanese university students is a significant problem in terms of life and financial costs. The purpose of this study was to examine the impact of four selected personality traits, namely interpersonal problems, ideas of being persecuted, social students in introversion, and self depreciation, on the inclination to be depressed among students in Taiwanese university.
Methods: A self-report survey was administered to students at a Taiwanese university and consisted of three parts: demographics, the Chinese version of the Basic Personality Inventory (BPI), and the Taiwanese Depression Questionnaire. The level of depression among students was assessed, and the relationships among the various variables were explored using analysis of variance (ANOVA) and regression.
Results: Altogether, 255 students successfully completed the survey. Overall, 37.62% of students were suffering from depression, including 4.7% who indicated that they were severely depressed, 18.30% who were moderately depressed, and 14% who were mildly depressed. In a multiple-regression model, ideas of being persecuted and self depreciation were both significant when predicting an inclination to be depressed.
Conclusion: Depression is a problem for many university students in Taiwan. Understanding which personality traits are related to depression in Taiwanese students is important for student affair administrators and medical professionals and will help them to prevent and treat this debilitating illness.
Neuroleptic malignant syndrome (NMS) is a rare but lethal complication of neuroleptics. Its incidence ranges between 0.02% and 3%. Amisulpride, a second generation neuroleptic, was associated with rhabdomyolysis in one report and NMS in 2 reports. Although the precise pathogenesis is still unclear, dopamine receptor blockade is theorized to play a central role. Conventional presentations include hyperthermia, muscle rigidity, and elevated creatine kinase concentrations. However, similar to other second generation neuroleptics, amisulpride induces an atypical form of NMS, which presents with lower degrees of hyperthermia and elevation of creatine kinase than the typical form. This phenomenon makes it difficult to identify early signs of NMS. This study describes the first case of amisulprideinduced NMS in Taiwan, together with a review of the current knowledge on NMS. In this case, the correlation between NMS and amisulpride was categorized as "probable" on the Naranjo adverse drug reaction probability scale.
Ruptured aneurysm of the accessory middle cerebral artery associated with moyamoya disease – A Case Report
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Cheng-Chi Lee, Zhuo-Hao Liu, Shih-Ming Jung, Tao-Chieh Yang
The accessory middle cerebral artery can provide collateral blood supply in moyamoya disease. We report a case of unilateral moyamoya disease which demonstrates the anatomy of the right accessory middle cerebral artery and a ruptured peripheral aneurysm on the artery. Our patient was a 56-year-old woman who initially suffered from headache and lethargy. Right caudate nucleus hemorrhage with intraventricular extension and spontaneous subarachnoid hemorrhage were found on brain computed tomography. A ruptured peripheral accessory middle cerebral artery aneurysm associated with unilateral moyamoya disease was diagnosed on cerebral angiography. Surgical intervention to excise the peripheral accessory middle cerebral artery aneurysm assisted by frameless navigation guidance to reduce the risk of damage to collateral vessels was done successfully. Histopathology of excised tissue showed this anomaly was a pseudoaneurysm. The management of an aneurysm in moyamoya disease should be modified based on its location and collateral vessels. Prevention of aneurysm bleeding and preservation of collateral vessels during craniotomy are the critical when managing hemorrhagic moyamoya disease. This case suggests that surgical intervention for ruptured intracranial aneurysms is safe with the use of frameless navigation
guidance to minimize collateral vessel injuries.