RAR‐related orphan receptor A: One gene with multiple functions related to migraine

AimsRAR‐related orphan receptor (RORA) involves in regulation of several biological processes including inflammation and circadian rhythm that probably are involved in migraine pathophysiology. In the current study, the association between RORA rs11639084 and rs4774388 variants and susceptibility to migraine were investigated in a sample of Iranian migraine patients for the first time.MethodsIn a case‐control study including 400 participants, 200 migraineurs and 200 healthy controls, genotyping of RORA rs4774388 and rs11639084 polymorphisms was performed using tetra‐primer amplification refractory mutation system–polymerase chain reaction (TP‐ARMS‐PCR).ResultsThe distribution of rs4774388 C/T and T/T genotypes differed significantly between the studied groups. Moreover, an association was observed between rs4774388 and migraine under the recessive mode of inheritance (P = 0.002; OR = 1.89.; CI = 1.25‐2.87). The distribution of rs11639084 alleles and genotypes was not significantly different between migraineurs and healthy controls.ConclusionCurrent results suggest RORA, as a molecular link, may explain inflammation and circadian rhythm dysfunction in migraine. Further studies in different ethnicities are required to confirm the function of RORA in migraine development.     

Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy

INTRODUCTION AND OBJECTIVES: Progression of prostate cancer to androgen independence (AI) results in part from the upregulation of anti-apoptotic genes following androgen withdrawal, and androgen-independent disease remains the primary obstacle to improved survival. Testosterone-repressed prostate message-2 (TRPM-2) encodes the anti-apoptotic protein clusterin, which is upregulated in response to cellular compromise as observed in normal and malignant tissues undergoing apoptosis. Systemic administration of antisense clusterin oligonucleotides in prostate cancer xenograft models delays progression to AI and enhances chemosensitivity. The objective of this study was to define changes in clusterin expression following neoadjuvant hormone therapy (NHT) in prostate cancer patients. MATERIALS AND METHODS: Archival radical prostatectomy (RP) specimens were obtained for 128 patients who received either no NHT or treatment for 2-8 weeks, 3 months, or 8 months. Paired needle biopsy specimens were acquired for 30 patients and all tissues were subjected to clusterin immunohistochemistry. Western blot analysis was performed on frozen tissue from 5 untreated and 5 treated patients. RESULTS: Clusterin expression in malignant prostatic tissue was significantly greater in patients who underwent preoperative NHT (P < 0.001). Needle biopsies obtained prior to NHT consistently demonstrated lower staining intensity than corresponding RP specimens (P < 0.001). Western blot analysis confirmed clusterin levels increased 17-fold beginning within 4 weeks after androgen withdrawal. CONCLUSIONS: Upregulation of clusterin levels following androgen ablation therapy may represent an adaptive cell survival response following apoptotic signals like androgen withdrawal. These findings support clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced prostate cancer.     

A decade experience with infrainguinal revascularization in a dialysis-dependent patient population

OBJECTIVE: Although previous series have reported outcomes of lower extremity (LE) revascularization in patients with end-stage renal disease, the issue of LE bypass for limb salvage in this group has not been resolved. We herein present the largest series to date of a 10-year single-institution experience with LE bypass in patients with dialysis dependence. METHODS: With prospectively entered data from a university teaching hospital's vascular registry, we reviewed the records of all patients with dialysis dependence who underwent LE arterial bypass between January 1, 1990, and May 31, 1999. RESULTS: A total of 146 consecutive patients (177 limbs) underwent infrainguinal revascularization, of whom nearly all (92%) had diabetes and tissue loss (91%). The in-hospital mortality rate was 3% (five patients). The rates for perioperative congestive heart failure, myocardial infarction, arrhythmia, and wound infection were 2%, 3%, 5%, and 10%, respectively. The actuarial graft primary and secondary patency rates at 1 and 3 years were 84% and 85%, and 64% and 68%, respectively. The limb salvage rates were 80% and 80% at 1 and 3 years. The 1-year and 3-year cumulative survival rates were 60% and 18%, respectively. At 5 years, survival was poor with only 5% of the entire cohort of 146 patients still alive. Multivariate logistic regression analysis at 6 months identified age (odds ratio, 0.96, 0.91) and number of years on dialysis (odds ratio, 0.79, 0.74) as significant (P <.05) negative predictors of both limb salvage and survival, respectively. CONCLUSION: Infrainguinal arterial reconstruction can be performed on patients with dialysis dependence with acceptable rates of limb salvage given the high incidence rate of perioperative complications and poor longevity of this patient group. Advanced age and number of years on dialysis seem to correlate with poorer outcome.     

Iatrogenic femoral pseudoaneurysms: thrombin injection after failed US-guided compression

Fifteen iatrogenic femoral pseudoaneurysms failed ultrasonography (US)-guided compression treatments. Despite concomitant antiplatelet or anticoagulation treatment, the 15 pseudoaneurysms were successfully and definitively treated without complication with US-guided thrombin injection. Results in this preliminary study suggest US-guided thrombin injection is a safe, expeditious, low-cost, and comfortable definitive treatment for femoral pseudoaneurysms that has advantages over both US-guided compression and open surgical repair.     

Oxidized LDL metabolites with high family risk for premature cardiovascular disease

Objective: Considering the importance of primary prevention of Cardiovascular Disease (CVD) from childhood, especially in children with high family risk for premature atherosclerosis, and also the importance of oxidized LDL in the process of atherosclerosis, the main metabolites of ox-LDL i.e. Malondialdehyde (MDA) and Conjugated diene (CDE) have been measured in children of high risk families and compared with a control group.Methods: Children and adolescents (6–18 years) of parents with premature myocardial infarction (Ml ≤ 55y in men and ≤ 65y in women), were selected as the case group. The control group included neighbors of the case group matched for age and socioeconomic status. All samples have been selected by simple random sampling. Both the case and control groups were divided in two subgroups : those with a total cholesterol and/or LDL-C ≥95th centile and those with normal lipid levels. Each subgroup consisted of 32 subjects, so 128 subjects were studied (64 in the case and 64 in the control group). MDA and CDE were measured by spectrophotometry using molar absorbivity. Data were analyzed by SPSS_v10/Win software using ANOVA, Bon-ferroni, Scheffe-Duncan, Tukey-HSD, and the Student’s t-test.Result: The mean MDA value in the case and control groups was significantly different (1.84 ± 0.43 vs. 1.67 ± 0.41 Μmol/L, p=0.03), but this difference was not significant regarding the mean CDE level (0.50 ± 0.05 vs. 0.47 ± 0.04 Μmol/ L, p>0.05). The mean MDA level in the case group with hyperlipidemia was significantly higher than that in the case group without hyperlipidemia (1.985 ± 0.516 vs. 1.690 ± 0.366, Μmol/L, P=0.02) and also higher than control group with or without hyperiipidemia (1.985 ± 0.516 vs. 1.720 ± 0.389,1.615 ± 0.429 Μmol/L respectivety, P<0.05). The mean CDE level in the case group with hyperiipidemia was significantly higher than the case group without hyperlipidemia (0.542 ± 0.034 vs. 0.494 ± 0.049 Μmol/L, P=0.04) and higher than the control group with or without hyperiipidemia (0.542 ± 0.034 vs. 0.464 ± 0.051, 0.484 ±0.048 Μmol/L respectively, p<0.05). In case boys with hyperiipidemia, the mean MDA (2.03 ± 0.2 Μmol/L) and the mean of CDE (0.56 ± 0.04 Μmol/L) was significantly higher than other subgroups (P<0.05).Conclusion: Considering the increased susceptibility of LDL to oxidation in children with high family risk for premature CVD, special attention should be paid to consumption of foods and seasoning containing antioxidants from childhood especially in high risk families.     

Effect of folic acid in women with and without insulin resistance who have hyperhomocysteinemic polycystic ovary syndrome.

OBJECTIVE: To study the effect of folic acid on homocysteine (Hcy) levels in women with insulin resistance and polycystic ovary syndrome (PCOS) in a prospective clinical trial. METHOD: Of 210 women with PCOS, 70 were hyperhomocysteinemic; and of these, 32 were insulin resistant and 38 were not. The 70 women were treated with folic acid for 3 months. Baseline and serum levels of Hcy and insulin were measured in both groups. RESULTS: In both groups Hcy concentrations were significantly decreased following folic acid supplementation. The mean+/-SD levels before and after treatment were 14.03+/-1.5 micromol/L and 12.53+/-1.72 micromol/L in group 1 (P<0.001), and they were 12.07+/-0.87 micromol/L and 8.83+/-0.78 micromol/L in group 2 (P<0.001). CONCLUSION: The Hcy levels of hyperhomocysteinemic women with PCOS were reduced after 3 months of folic acid supplementation, and the rate of reduction was higher among women without insulin resistance. No change was found in fasting insulin levels.     

Effects of nitric oxide on gentamicin toxicity in isolated perfused rat kidneys

BACKGROUND: There have been many studies in recent years concerning the role of nitric oxide (NO) in acute renal failure (ARF). In this study, the effects of the inhibition or the induction of NO synthase (NOS) on gentamicin-induced ARF was investigated in isolated perfused rat kidneys. METHODS: Kidneys from male Sprague-Dawley rats were perfused in situ for 90 min. Perfusion was conducted in the presence of inulin (60 mg/dL in perfusion buffer) as a glomerular filtration rate (GFR) marker. Six groups (total: 42 rats) were studied: group 1, controls with no treatment; group 2, L-arginine (2 mM in perfusate); group 3, L-nitro-arginine-methyl ester (L-NAME, 0.1 mM in perfusate); group 4, gentamicin (GM, 0.5 mg/mL in perfusate); group 5, GM + L-arginine (same dose as groups 2 and 4) and; group 6, GM + L-NAME (same dose as groups 3 and 4). Cell injury was assessed by measuring N-acetyl-beta-D-glucosaminidase (NAG), lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) activity in urine. RESULTS: L-arginine prevented, whereas L-NAME enhanced, GM-induced enzyme release and GFR reduction. Histological studies showed that GM-treated kidneys had clear signs of tubular damage and this damage was increased by simultaneous L-NAME and GM administration. CONCLUSION: This study suggests that NO formation could prevent the GM-induced nephrotoxicity in this ARF model.