Manganese superoxide dismutase attenuates Cisplatin-induced renal injury: importance of superoxide.

Cisplatin is a potent chemotherapeutic agent that is used to treat many human malignancies. Unfortunately, in addition to side effects such as ototoxicity, anaphylaxis, and bone marrow suppression, a significant percentage of patients receiving cisplatin develop severe nephrotoxicity. Mitochondrial dysfunction that is mediated via the generation of reactive oxygen species has been implicated in the pathogenesis of cisplatin-induced renal injury. To address the mechanism, it was hypothesized that overexpression of antioxidant enzymes, such as mitochondria-localized manganese superoxide dismutase (MnSOD) or mitochondria-targeted catalase (mito-Cat), would be cytoprotective in cisplatin-induced cell injury. To this end, human MnSOD or a mito-Cat vector were stably transfected into human embryonic kidney 293 cells. Cells that overexpressed MnSOD exhibited significantly less cell rounding and detachment compared with both mito-Cat and vector controls after exposure to 20 microM cisplatin. Cell injury as assessed by DNA fragmentation and annexin V binding assays was significantly decreased in the cells that overexpressed MnSOD compared with vector alone and mito-Cat. In addition, elevated levels of MnSOD were strongly associated with increased clonogenic potential after cisplatin challenge. Thus, overexpression of MnSOD, and not catalase, protects against cisplatin-induced renal epithelial cell injury. These results demonstrate the importance of reactive oxygen species in the mechanism that underlies cisplatin-induced renal injury and specifically implicate the superoxide radical, and not hydrogen peroxide, as the mediator.     

Total Thyroidectomy for Benign Thyroid Disorders in an Endemic Region

Total thyroidectomy is increasingly being accepted as a treatment of choice for differentiated thyroid cancer. However, because of presumed increased morbidity associated with this procedure, it is still not considered a viable option for management of benign thyroid disorders. To assess the safety and efficacy of total thyroidectomy for management of benign thyroid disorders, we analyzed our data from 127 total thyroidectomies performed for benign thyroid disorders. Demographic details, biochemical findings, indications for operation, specimen weight, and complications were noted. Among these patients, 52 had a toxic goiter and 75 had a nontoxic goiter. The mean duration of the goiters being present was 6.08 ± 6.06 years (0.9–26.0 years), and the mean weight of the specimens was 136.88 ± 120.68 g. The incidence of occult malignancy was 6.3% (n= 8), and those of permanent hypothyroidism and permanent recurrent laryngeal nerve palsy were 1.6% and 0.8%, respectively. Total thyroidectomy should be considered a treatment of choice for multinodular goiter and Graves' disease in a setting of palpable nodule(s) or ophthalmopathy (or both). It is particularly relevant in endemic regions where patients present with a long-standing, large nodular goiter with virtually no normal thyroid tissue. Reoperation for recurrent goiter in such a setting would be fraught with distressing complications.     

Varicocelectomy improves intrauterine insemination success rates in men with varicocele

PURPOSE: We determined whether varicocele treatment before intrauterine insemination significantly affects intrauterine insemination success rates. MATERIALS AND METHODS: A total of 58 infertile couples, of whom the women had normal evaluations and men had abnormal semen analyses and a history of varicocele, were included in this study. They were identified after reviewing the charts of all women undergoing intrauterine insemination for male factor infertility at our center. Of the men 24 participated in 63 intrauterine insemination cycles without varicocele treatment, while in the remaining 34 varicocele was treated before a total of 101 intrauterine insemination cycles. Variables associated with pregnancy or live birth were analyzed using repeat measures logistic regression with generalized estimating equation techniques. An initial stepwise generalized estimating equation was performed without including varicocele treatment status. Subsequently varicocele treatment status and the significant associated factors were included in analysis. The semen characteristics of untreated and treated varicocele groups were compared with repeat measures analysis of variance. RESULTS: On pre-wash semen analysis patients with untreated varicocele had significantly higher mean motility plus or minus standard error than patients whose varicoceles were treated (48.6% +/- 2.3% versus 38.1% +/- 1.8%, p = 0.02). However, no statistically significant difference was noted in the mean post-wash total motile sperm count in the treated and untreated groups (7.2 +/- 1.0 versus 14.8 +/- 2.6, p = 0.1). Despite these findings the pregnancy and live birth rates per cycle were significantly higher in patients in whom varicocele was treated than in those without varicocele treatment (11.8% versus 6.3%, p = 0.04 and 11.8% versus 1.6%, p = 0.007, respectively). CONCLUSIONS: Varicocele treatment may not improve semen characteristics in all men but it appears to improve pregnancy and live birth rates among couples undergoing intrauterine insemination for male factor infertility. A functional factor not measured on routine semen analysis may affect pregnancy rates in this setting. Men should be screened for varicocele before intrauterine insemination is initiated for male factor infertility.     

Safety and Efficacy of Surgical Management of Hyperthyroidism: 15-year Experience from a Tertiary Care Center in a Developing Country

Background Ideal management of toxic goiter still remains elusive. Though surgical management of toxic multinodular goiter (MNG) is well accepted, surgical treatment of Graves’ disease (GD) is still controversial in view of the presumed increased incidence of complications. In this paper, we discuss the experience of the surgical management of hyperthyroidism at a specialized tertiary care endocrine center in a developing country, highlighting the minimal morbidity and satisfactory outcome in experienced hands. Materials and methods We retrospectively reviewed 325 consecutive patients with hyperthyroidism managed surgically from 1990 to 2005. The etiologic diagnoses were Graves’ disease (185), toxic MNG (105), and autonomously functioning thyroid nodules (AFTN) (n = 35). The indications for surgery in Graves’ patients were large goiter, relapse after antithyroid drug therapy (ATD), Graves’ ophthalmopathy, and presence of nodule. The indications for surgery in toxic MNG were retrosternal extension (n = 15), compressive symptoms (n = 20), and large size (grade II). Among the AFTN nodule size, those greater than 4 cm (85%) formed the major indication for surgery. Subjects with GD and toxic MNG were subjected to subtotal thyroidectomy (n = 93 prior to 1995) or total thyroidectomy (n = 205 post-1995). Hemithyroidectomy was the procedure of choice in patients with AFTN. Results Patients with Graves’ disease were younger in age, with shorter mean duration of goiter when compared with the other 2 groups. Eight percent of patients with Graves’ disease without a clinically palpable nodule and 25% of those with nodules had associated differentiated carcinoma, including papillary, follicular, and medullary thyroid cancer. Four percent of patients with toxic MNG had malignancy. Complications included temporary hypocalcemia (24%), permanent hypocalcemia (3%), and permanent vocal-cord palsy (1%). Conclusions Surgery for hyperthyroidism has negligible mortality and acceptable morbidity in experienced hands. It is a definite option in selected cases. Immediate and permanent cure of hyperthyroidism is achieved, with no recurrences, after total thyroidectomy. The cosmetic outcome is good, with excellent patient satisfaction and acceptance.     

Biliary Obstruction in Gall Bladder Cancer Is Not Sine Qua Non of Inoperability

Background The presence of biliary obstruction in patients with gallbladder cancer (GBC) is generally viewed as an indicator of advanced disease, inoperability and poor prognosis. Methods Data was collected from patients with GBC with obstructive jaundice who underwent resection during the period January 2001 to October 2003. Systematic analysis of prospective data was undertaken; patients were analyzed for resectability, post-operative morbidity, mortality and disease-free survival. Results During this period 14 patients with GBC with biliary obstruction underwent resection with curative intent. In these jaundiced patients, the resectability rate was 27.45% (14 of 51). In the jaundiced group the mortality was 7.14% the morbidity rate 50%, the mean disease free survival was 23.46 months (median 26 months and range of 2 to 62 months). Seven patients (50%) survived more than two years. Conclusion Biliary obstruction in gall bladder cancer is not sine qua non of inoperability and resection results in meaningful prolongation of survival.     

Giant cell tumor of bone in children and adolescents

BACKGROUND: There are very few series that document giant cell tumor of bone (GCT) in the immature skeleton, and the reported incidence in literature varies from 1.8% to 10.6%. The purpose of this study was to document the incidence of GCT in patients with open physis in the Indian population and study the course of the disease with respect to its adult counterpart to see if it behaved any differently. METHODS: Between January 2000 and December 2005, 17 (6%) of 285 surgically treated patients with histologically proven GCT had open physis on imaging. Treatment was directed toward local control without sacrificing joint function, with most lesions treated with intralesional curettage. RESULTS: Fourteen (82%) patients were girls. The most common site was around the knee (53%). Of 15 lesions in tubular bones, 13 were epiphysiometaphyseal in location. An open physis did not prevent GCT from penetrating the epiphyseal cartilage. Histologically, the tumors were typical of GCT. Of 15 patients available for follow-up, 3 (20%) developed local recurrence. CONCLUSIONS: Although the overall incidence of GCT may be higher in the Asian population, the percentage of skeletally immature patients or those nearing skeletal maturity is similar to that described in literature. The biological behavior of the disease is similar to that seen in adults, except a marked female preponderance, principles of treatment, recurrence patterns, and course of the disease mirror the behavior of its adult counterpart.     

Hypertension is harmful to dialysis patients and should be controlled

Managing hypertension is among the commonest and most challenging features of end-stage renal disease and many clinical trials have shown the benefit of treating hypertension in the general population. If associations between blood pressure levels and cardiovascular outcomes in dialysis patients mirrored those seen in general population studies, one could argue that dialysis population-specific antihypertensive trials are unnecessary. Associations between blood pressure levels and outcomes are complex in this population. Naturally, comparisons of observational and experimental findings within intervention in patients with chronic kidney disease often show a surprising degree of disparity. In addition, the possibility of serious unmeasured co-morbid illnesses masking the true causal relationship between blood pressure and outcomes in this population looms large. Unfortunately, therefore, observational studies appear to be highly unreliable guides to identifying the truth regarding optimal management of hypertension. It appears, then, that controlled trials, alone, can inform appropriate treatment. Of late, intervention trials of antihypertensives in dialysis patients have begun to emerge. Though mostly small, less than definitive, and heterogeneous regarding patient selection, interventions and outcomes, several suggest net benefit and none suggests net harm. As dialysis patients are at vast cardiovascular risk, these findings suggest that aggressive treatment of hypertension should be the default approach, until large clinical trials show otherwise.     

Association of methylenetetrahydrofolate reductase genetic polymorphisms with atlantoaxial dislocation

OBJECT: Genetic mechanisms of atlantoaxial dislocation (AAD) have not previously been elucidated. The authors studied association of polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, which encodes enzymes of the folate pathway (implicated in causation of neural tube defects [NTDs]), in patients with AAD. METHODS: Molecular analysis of MTHFR polymorphisms (677C-->T, cytosine to thymine and, 1298A-->C, adenine to cytosine, substitutions) was carried out using polymerase chain reaction and restriction enzyme digestion in 75 consecutive patients with AAD and in their reducible (nine patients, 12%) and irreducible (66 patients, 88%) subgroups. Controls were 60 age- and sex-matched patients of the same ethnicity. Comparisons of genotype and allele frequencies were performed using a chi-square test (with significance at p < 0.05). RESULTS: The CT genotype frequency of MTHFR 677C-->T polymorphism was significantly increased in the full group of patients with AAD (odds ratio [OR] 3.00, 95% confidence interval [CI] 1.28-7.14, p = 0.005) as well as in the irreducible subgroup (OR 2.81, 95% CI 1.17-6.86, p = 0.01). The frequency of T alleles was also higher in the AAD group (25.3%) than in controls (15%). The comparison of the combined frequency of CT and TT genotypes with the frequency of the CC genotype again showed significant association in AAD (OR 2.63, 95% CI 1.98-5.90, p = 0.009) and the irreducible (OR 2.5, 95% CI 1.1-5.74, p = 0.016) subgroup. There was, however, no significant association of MTHFR 1298A-->C polymorphism with AAD. CONCLUSIONS: Both MTHFR 677C-->T polymorphism and higher T allele frequency have significant associations with AAD, especially the irreducible variety. Perhaps adequate supplementation of periconceptional folic acid to circumvent effects of this missense mutation (as is done for prevention of NTDs) would reduce the incidence of AAD.     

Adeno-Associated Viral Vector-Mediated Interleukin-10 Prolongs Allograft Survival in a Rat Kidney Transplantation Model

Interleukin-10 (IL-10) is a pleiotropic cytokine that plays a pivotal role in the regulation of immune responses. Hence, we evaluated the effects of a recombinant adeno-associated viral vector 1 (rAAV1) encoding rat IL-10 (rAAV1-IL-10) in a rat model of kidney allograft rejection. Dark Agouti rat kidneys were transplanted into Wistar-Furth (WF) rats 8 weeks following a single intramuscular administration of either rAAV1-IL-10 or rAAV1-green fluorescence protein (GFP). Isografts (WF-WF) served as an additional experimental control. Both allograft and isograft recipients received daily cyclosporine (10 mg/kg) for 14 days after transplantation. Serum IL-10 levels increased at 8, 12 and 16 weeks following vector administration in rAAV1-IL-10-treated animals, but not in rAAV1-GFP and isograft groups. rAAV1-IL-10 treatment resulted in lower BUN and creatinine levels (p<0.001), as well as increased allograft survival rates from 22% to 90%. Allograft histological abnormalities were significantly attenuated in the rAAV1-IL-10-treated rats compared with those of rAAV1-GFP controls. Serum levels of proinflammatory cytokines such as growth-related oncogene were also significantly higher in the rAAV1-GFP group than in the rAAV1-IL-10 group. These data suggest delivery of IL-10 using a rAAV1 vector improves renal function and prolongs graft survival in a rat model of kidney transplant rejection.