Phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate nephrolithiasis.

BACKGROUND: Urinary oxalate is a major risk factor for calcium oxalate stones. Marked hyperoxaluria arises from mutations in 2 separate loci, AGXT and GRHPR, the causes of primary hyperoxaluria (PH) types 1 (PH1) and 2 (PH2), respectively. Studies of null Slc26a6(-/-) mice have shown a phenotype of hyperoxaluria, hyperoxalemia, and calcium oxalate urolithiasis, leading to the hypothesis that SLC26A6 mutations may cause or modify hyperoxaluria in humans. STUDY DESIGN: Cross-sectional case-control. SETTING & PARTICIPANTS: Cases were recruited from the International Primary Hyperoxaluria Registry. Control DNA samples were from a pool of adult subjects who identified themselves as being in good health. PREDICTOR: PH1, PH2, and non-PH1/PH2 genotypes in cases. OUTCOMES & MEASURES: Homozygosity or compound heterozygosity for SLC26A6 variants. Functional expression of oxalate transport in Xenopus laevis oocytes. RESULTS: 80 PH1, 6 PH2, 8 non-PH1/PH2, and 96 control samples were available for SLC26A6 screening. A rare variant, c.487C-->T (p.Pro163Ser), was detected solely in 1 non-PH1/PH2 pedigree, but this variant failed to segregate with hyperoxaluria, and functional studies of oxalate transport in Xenopus oocytes showed no transport defect. No other rare variant was identified specifically in non-PH1/PH2. Six additional missense variants were detected in controls and cases. Of these, c.616G-->A (p.Val206Met) was most common (11%) and showed a 30% reduction in oxalate transport. To test p.Val206Met as a potential modifier of hyperoxaluria, we extended screening to PH1 and PH2. Heterozygosity for this variant did not affect plasma or urine oxalate levels in this population. LIMITATIONS: We did not have a sufficient number of cases to determine whether homozygosity for p.Val206Met might significantly affect urine oxalate. CONCLUSIONS: SLC26A6 was effectively ruled out as the disease gene in this non-PH1/PH2 cohort. Taken together, our studies are the first to identify and characterize SLC26A6 variants in patients with hyperoxaluria. Phenotypic and functional analysis excluded a significant effect of identified variants on oxalate excretion.

Delayed patch test reading after 5 days: the Mayo Clinic experience.

BACKGROUND: Some patients may have delayed allergic patch test reactions that are not identified with a typical 5-day reading protocol. OBJECTIVE: To identify allergens with delayed-positive reactions and to determine whether a late reading (day 7-9) can be substituted for the day-5 reading. METHODS: We retrospectively reviewed medical records of patients who underwent patch testing for suspected allergic contact dermatitis from October 1997 through December 2006 and returned for delayed readings between days 7 and 10 or beyond. (This cohort was predominantly patients with suspected allergies to metals and corticosteroids). RESULTS: A total of 36,064 individual reactions (471 allergens, 372 patients) were interpreted on day 5 and at least once during days 7 through 21. We analyzed the 170 allergens that were each tested in at least 50 patients. The 4 allergens with the highest percentage of delayed-positive reactions were gold sodium thiosulfate 0.5% (delayed-positive reactions in 22/353 patients), dodecyl gallate 0.25% (6/105), palladium chloride 2% (8/194), and neomycin sulfate 20% (10/253). We observed a low number of delayed-positive readings for p-phenylenediamine 1% (1/251) and for corticosteroids. Reactions to certain preservative and fragrance allergens dissipated after the day-5 reading. Most reactions that dissipated after day 5 were mild, whereas the reactions that became apparent after day 5 were strong. LIMITATIONS: This was a retrospective study. Most patients had suspected allergies to metals and corticosteroids. CONCLUSION: Late patch test readings (day 7 or beyond) were useful when interpreting reactions to metals and topical antibiotics, but it was not useful in the diagnosis of reactions to other allergens, including topical corticosteroids. Because reactions to certain fragrance and preservative allergens may dissipate after 5 days, patch test reactions therefore are optimally read at days 3 and 5, but an additional reading on day 7 or beyond is useful if patch tests to metals and topical antibiotics are performed.

Outcomes of melanoma in recipients of solid organ transplant.

BACKGROUND: There is concern that the immunologic tumor malignant melanoma (MM) may have worse outcomes in immunosuppressed hosts than in the general population. OBJECTIVE: We sought to describe outcomes of MM in immunosuppressed solid organ transplant recipients and compare them with the general population. METHODS: We conducted a retrospective review of medical charts and pathology slides of cases of MM and solid organ transplantation between 1978 and 2007, with comparison of outcomes. RESULTS: In all, 48 MMs were identified in 43 transplant recipients. No patient with MM before transplant receipt had melanoma recurrence, subsequent metastasis, or death caused by melanoma. Of patients with MM diagnosed after transplantation, metastases developed in 3 patients, and two patients died of melanoma. LIMITATIONS: Retrospective review and low number of cases are limitations. CONCLUSIONS: Outcomes of MM in immunosuppressed transplant recipients appeared similar to those in prognostically matched nonimmunosuppressed hosts. The small number of cases limited statistical comparisons.

Sinonasal melanoma: a clinicopathologic review of 61 cases.

OBJECTIVE: To review the Mayo Clinic experience with sinonasal melanoma. STUDY DESIGN: Retrospective review (case series). SUBJECTS AND METHODS: We identified 61 patients who had melanoma arising from the nasal cavity, paranasal sinuses, or both. All were treated at our institution from 1955 through 2003. Clinical and pathologic data were summarized, and survival curves were generated. RESULTS: The most common symptoms at presentation were epistaxis and nasal congestion. The most common treatment was excision only (48%). The cancer-specific survival rate (ie, rate of death due to disease) was 48.9% and 22.1% at 3 and 5 years, respectively. Median time between diagnosis and death due to disease was 19 months. CONCLUSION: Sinonasal melanoma is a rare but devastating disease. Wide local excision is the treatment of choice, and some patients may benefit from postoperative radiotherapy. Local recurrence and distant metastasis are common. Improved survival depends on better systemic therapies.

Incidence of cutaneous lupus erythematosus, 1965-2005: a population-based study.

OBJECTIVES: To assess trends in the cutaneous variants of lupus erythematosus (CLE) and to ascertain the incidence of CLE over the past 4 decades. DESIGN: Retrospective population-based study. SETTING: Community-based epidemiology project. PATIENTS: All Olmsted County, Minnesota, residents with any subtype of CLE between January 1965 and December 2005. MAIN OUTCOME MEASURES: Incidence of CLE and disease progression to systemic LE (SLE). RESULTS: A total of 156 patients with newly diagnosed CLE (100 females and 56 males) were identified between 1965 and 2005. The incidence rate (age and sex adjusted to the 2000 US white population) was 4.30 (95% confidence interval [CI], 3.62-4.98) per 100,000. The age- and sex-adjusted prevalence as of January 1, 2006, was 73.24 (95% CI, 58.29-88.19) per 100,000. Nineteen patients with CLE had disease progression to SLE: cumulative incidence at 20 years, 19%; mean (SD) length to progression, 8.2 (6.3) years. Compared with a previously reported incidence of 2.78 (95% CI, 2.08-3.49) per 100,000 for SLE among Rochester, Minnesota, residents in 1965 through 1992, the incidence of CLE in Rochester was 3.08 (95% CI, 2.32-3.83) per 100,000 in 1965 through 1992. CONCLUSIONS: The incidence of CLE is comparable to the published incidence of SLE. Our findings double the incidence of the root designation of the disease process known as LE (SLE and CLE).

Photopatch testing of 182 patients: a 6-year experience at the Mayo Clinic.

BACKGROUND: Photopatch testing is important for diagnosing photoallergic contact dermatitis. Although results of photopatch testing have been presented from many European centers, there have been few reports of the results of photopatch testing in the United States. OBJECTIVE: To review the Mayo Clinic's recent experience with photopatch testing, identify common photoallergens, and compare our current and previous findings. METHODS: We retrospectively reviewed records of patients who underwent photopatch testing at the Mayo Clinic between January 1, 2000, and December 31, 2005 (N = 182). RESULTS: Fifty-four patients (29.7%) had photoallergic contact reactions, and 29 (15.9%) had allergic contact reactions. The most common photoallergens were medications, sunscreen agents, fragrances, and antiseptics. CONCLUSION: Photopatch testing is the technique useful in identifying photoallergens. The series of allergens used must be constantly updated to reflect newly identified and outdated photoallergens. We present a 6-year experience with photopatch testing. Medications, sunscreen agents, fragrances, and antiseptics were the most frequently identified photoallergens.

Changing trends and allergens in the patch test standard series: a mayo clinic 5-year retrospective review, january 1, 2001, through december 31, 2005.

OBJECTIVE: To present and interpret results of patch testing with the Mayo Clinic standard series over 5 years. DESIGN: Retrospective study. A standardized patch testing technique was used. Data were recorded on a standardized computer program from January 1, 2001, to December 31, 2005, and analyzed. SETTING: Tertiary referral center. PATIENTS: Patients who were referred for patch testing. INTERVENTION: Patch testing with the "standard series," ie, a standard series of allergens used by most clinicians to identify the most common offending allergens in patients with allergic contact dermatitis. MAIN OUTCOME MEASURES: Number of patients patch tested, allergens used over this period, and rates of allergic patch test reactions to allergens. RESULTS: A total of 3854 patients (mean age, 55.1 years; age range, 6.2-99.4 years; 2576 female [66.8%]) were tested. All dermatologists in the department performed patch testing. The mean number of allergens included was 69.3 (range, 6-87). There were 2664 patients with at least 1 positive reaction (69.1%) and 1933 with 2 or more positive reactions (50.2%). Metals, fragrances, topical antibiotics, preservatives, and individual allergens used in hair-care products, topical corticosteroids, glues, plastics, and rubber were still the most common allergen groups associated with allergic patch test reactions. CONCLUSIONS: We describe the structure of the patch testing service at our referral center. Ongoing analysis of our patch test reaction rates allows us to recommend broad, clinically relevant, and up-to-date allergens for testing.

Urachal anomalies: a longitudinal study of urachal remnants in children and adults.

PURPOSE: Urachal anomalies are often recognized in children but they may persist into adulthood and cause considerable morbidity. We reviewed the clinical findings associated with these embryological structures and evaluated risk factors for cancer to define the optimal timing for intervention. MATERIALS AND METHODS: We examined the medical records of 176 patients diagnosed with a urachal anomaly between 1951 and 2005. Association of clinicopathological features with malignancy for adults was evaluated using univariate and multivariate logistic regression studies. RESULTS: Urachal remnants were identified in 46 children and 130 adults. Of the 46 children 20 (43%) presented with umbilical drainage and 23 (50%) could be diagnosed by physical examination. A total of 34 children (74%) underwent simple excision. In contrast, 65 of the 130 adults (50%) presented with hematuria, 78 (60%) required cystoscopy and 53 (41%) required computerized tomography. A total of 66 adults (51%) required more extensive surgical intervention with partial or radical cystectomy. Of adult urachal anomalies 66 (51%) were malignant. Patient age 55 years or older and hematuria were the strongest predictors of urachal malignancy (each p <0.001). Cancer risk increased with advancing adult age. CONCLUSIONS: Urachal anomalies present and progress differently in pediatric and adult populations. Adults are at high risk for urachal cancer but children usually incur lower morbidity. Urachal lesions noted early in childhood should be excised to prevent problems in adulthood.

Diabetes mellitus and hypertension associated with shock wave lithotripsy of renal and proximal ureteral stones at 19 years of followup.

PURPOSE: SWL has revolutionized the management of nephrolithiasis and it is a preferred treatment for uncomplicated renal and proximal ureteral calculi. Since its introduction in 1982, conflicting reports of early adverse effects have been published. However, to our knowledge the long-term medical effects associated with SWL are unknown. We evaluated these adverse medical effects associated with SWL for renal and proximal ureteral stones. MATERIALS AND METHODS: Chart review identified 630 patients treated with SWL at our institution in 1985. Questionnaires were sent to 578 patients who were alive in 2004. The response rate was 58.9%. Respondents were matched by age, sex and year of presentation to a cohort of patients with nephrolithiasis who were treated nonsurgically. RESULTS: At 19 years of followup hypertension was more prevalent in the SWL group (OR 1.47, 95% CI 1.03, 2.10, p = 0.034). The development of hypertension was related to bilateral treatment (p = 0.033). In the SWL group diabetes mellitus developed in 16.8% of patients. Patients treated with SWL were more likely to have diabetes mellitus than controls (OR 3.23, 95% CI 1.73 to 6.02, p <0.001). Multivariate analysis controlling for change in body mass index showed a persistent risk of diabetes mellitus in the SWL group (OR 3.75, 95% CI 1.56 to 9.02, p = 0.003). Diabetes mellitus was related to the number of administered shocks and treatment intensity (p = 0.005 and 0.007). CONCLUSIONS: At 19 years of followup SWL for renal and proximal ureteral stones was associated with the development of hypertension and diabetes mellitus. The incidence of these conditions was significantly higher than in a cohort of conservatively treated patients with nephrolithiasis.

Time-dependent variations in inflammation and scar formation of six different pubovaginal sling materials in the rabbit model.

OBJECTIVES: To provide pathologic evidence, using six different sling materials, of the findings from rabbit model studies demonstrating loss of tensile strength and stiffness in porcine and cadaveric sling materials. METHODS: Ten rabbits randomized into two survival groups (6 and 12 weeks of age) each had human cadaveric fascia, porcine dermis, porcine small intestine submucosa, polypropylene mesh, and autologous fascia implanted on their anterior rectus fascia. At harvest, hematoxylin-eosin and immunohistochemical staining for CD3, CD20, and MIB-I were performed. A pathologist unaware of the content of the slides quantified the degree of inflammation and fibrosis of each. RESULTS: Significant differences were found for inflammation (P = 0.016), eosinophil infiltrate (P = 0.035), and inflammatory rind (P = 0.027) at 12 weeks, with polypropylene mesh having the lowest degree. At 12 weeks, differences were found in the presence of fibrosis/scar formation (P = 0.010) and degree of fibrosis/scar (P = 0.009). Although polypropylene mesh, cadaveric fascia, and porcine dermis all demonstrated a high presence of fibrosis/scar, polypropylene mesh had the greatest overall degree of scar formation at 12 weeks. CONCLUSIONS: The inflammation with the cadaveric fascia and porcine materials may cause rapid clinical deterioration compared with autologous fascia and polypropylene mesh. These data provide a possible explanation for prior biomechanical studies demonstrating variations in tensile strength and stiffness of the different materials. The fibrosis and scarring noted with polypropylene mesh may also contribute to a more lasting repair.

Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas.

The epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of many tumors. To analyze the expression of EGFR and activated EGFR in well-differentiated neuroendocrine carcinomas including primary and metastatic gastrointestinal carcinoid tumors and pancreatic endocrine tumors (PET), we examined 58 gastrointestinal carcinoid tumors and 48 PET using immunohistochemistry, Western blotting, and RT-PCR. EGFR and activated EGFR (P-EGFR) were expressed by both gastrointestinal carcinoids and PET in primary and metastatic tumors, although a higher percentage of gastrointestinal carcinoid tumors expressed EGFR and activated EGFR. Western blotting detected a 170 kDa band for both EGFR and activated EGFR in three primary carcinoid tumors and two metastatic carcinoid tumors to the liver. RT-PCR analysis confirmed the expression of EGFR mRNA in both primary and metastatic carcinoid tumors. Patients with activated EGFR expression in their primary PET had a significantly worse prognosis compared to those who did not express activated-EGFR (P = 0.043). These results indicate that gastrointestinal carcinoid tumors as well as PET express EGFR and activated EGFR, and that expression is more common in gastrointestinal carcinoid tumors compared to pancreatic endocrine tumors. These findings implicate the EGFR and P-EGFR signal transduction pathway in the pathogenesis of these neuroendocrine tumors and suggest that targeted therapy directed against the EGFR tyrosine kinase domain may be a useful therapeutic approach in patients with unresectable metastatic gastrointestinal carcinoid tumors and pancreatic endocrine tumors.

International registry for primary hyperoxaluria.

BACKGROUND/AIMS: Primary hyperoxaluria (PH) is an inherited disorder that causes calcium urolithiasis and renal failure. Due to its rarity, experience at most centers with this disease is limited. METHODS: A secure, web-based, institutional review board/ethics committee and American Health Insurance Portability and Accountability Act (HIPAA)-compliant registry was developed to facilitate international contributions to a data base. To date 95 PH patients have been entered. RESULTS: PH type was confirmed in 84/95 (PH1 79%, PH2 9%). Mean age +/- SD at symptom onset was 9.5 +/- 10.2 (median 5.5) years whereas age at diagnosis was 15.0 +/- 15.2 (median 10.0) years. Urolithiasis was present at diagnosis in 90% (mean 7, median 1, stones prior to diagnosis) and nephrocalcinosis in 48%. Surprisingly 15% of the patients were asymptomatic at the time of diagnosis. Nineteen of the 95 patients were first recognized to have PH after they had reached end-stage renal disease, with the diagnosis made only after kidney transplantation in 7 patients. Patients were followed for 12.1 +/- 10.6 (median 9.4) years. Thirty-four of 95 progressed to end-stage renal failure, before (19 patients) or after (15 patients) diagnosis. In the PH1 cohort actuarial renal survival was 64% at 30 years of age, 47% at 40 years, and 29% at 50 years. CONCLUSION: We have developed a PH registry, and demonstrated the feasibility of this secure, web-based approach for data entry. By facilitating accumulation of an increasing cohort of patients, this registry should allow more complete characterization of clinical expression of PH, an appreciation of geographic variability, and identification of treatment outcomes.