Chronic Dietary Exposure to Aristolochic Acid and Kidney Function in Native Farmers from a Croatian Endemic Area and Bosnian Immigrants

Background and objectives

Improvements in agricultural practices in Croatia have reduced exposure to consumption of aristolochic acid-contaminated flour and development of endemic (Balkan) nephropathy. Therefore, it was hypothesized that Bosnian immigrants who settled in an endemic area in Croatia 15–30 years ago would be at lower risk of developing endemic nephropathy because of reduced exposure to aristolochic acid. To test this hypothesis, past and present exposure to aristolochic acid, proximal tubule damage as a hallmark of endemic nephropathy, and prevalence of CKD in Bosnian immigrants were analyzed.

Design, setting, participants, & measurements

In this cross-sectional observational study from 2005 to 2010, 2161 farmers were divided into groups: indigenous inhabitants from endemic nephropathy and nonendemic nephropathy villages and Bosnian immigrants; α-1 microglobulin-to-creatinine ratio >31.5 mg/g and eGFR<60 ml/min per 1.73 m² were considered to be abnormal.

Results

CKD and proximal tubule damage prevalence was significantly lower in Bosnian immigrants than inhabitants of endemic nephropathy villages (6.9% versus 16.6%; P<0.001; 1.3% versus 7.3%; P=0.003, respectively); 20 years ago, Bosnian immigrants observed fewer Aristolochia clematitis in cultivated fields (41.9% versus 67.8%) and fewer seeds among wheat seeds (6.1% versus 35.6%) and ate more purchased than homemade bread compared with Croatian farmers from endemic nephropathy villages (38.5% versus 14.8%, P<0.001). Both Croatian farmers and Bosnian immigrants observe significantly fewer Aristolochia plants growing in their fields compared with 15–30 years ago. Prior aristolochic acid exposure was associated with proximal tubule damage (odds ratio, 1.64; 95% confidence interval, 1.04 to 2.58; P=0.02), whereas present exposure was not (odds ratio, 1.31; 95% confidence interval, 0.75 to 2.30; P=0.33). Furthermore, immigrant status was an independent negative predictor of proximal tubule damage (odds ratio, 0.40; 95% confidence interval, 0.19 to 0.86; P=0.02).

Conclusions

Bosnian immigrants and autochthonous Croats residing in endemic areas are exposed significantly less to ingestion of aristolochic acid than in the past. The prevalence of endemic nephropathy and its associated urothelial cancers is predicted to decrease over time.     

Light, nutrients, and food-chain length constrain planktonic energy transfer efficiency across multiple trophic levels

The efficiency of energy transfer through food chains [food chain efficiency (FCE)] is an important ecosystem function. It has been hypothesized that FCE across multiple trophic levels is constrained by the efficiency at which herbivores use plant energy, which depends on plant nutritional quality. Furthermore, the number of trophic levels may also constrain FCE, because herbivores are less efficient in using plant production when they are constrained by carnivores. These hypotheses have not been tested experimentally in food chains with 3 or more trophic levels. In a field experiment manipulating light, nutrients, and food-chain length, we show that FCE is constrained by algal food quality and food-chain length. FCE across 3 trophic levels (phytoplankton to carnivorous fish) was highest under low light and high nutrients, where algal quality was best as indicated by taxonomic composition and nutrient stoichiometry. In 3-level systems, FCE was constrained by the efficiency at which both herbivores and carnivores converted food into production; a strong nutrient effect on carnivore efficiency suggests a carryover effect of algal quality across 3 trophic levels. Energy transfer efficiency from algae to herbivores was also higher in 2-level systems (without carnivores) than in 3-level systems. Our results support the hypothesis that FCE is strongly constrained by light, nutrients, and food-chain length and suggest that carryover effects across multiple trophic levels are important. Because many environmental perturbations affect light, nutrients, and food-chain length, and many ecological services are mediated by FCE, it will be important to apply these findings to various ecosystem types.     

Myosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion disease

Microvillus inclusion disease (MVID) is a severe form of congenital diarrhea that arises from inactivating mutations in the gene encoding myosin Vb (MYO5B). We have examined the association of mutations in MYO5B and disruption of microvillar assembly and polarity in enterocytes. Stable MYO5B knockdown (MYO5B-KD) in CaCo2-BBE cells elicited loss of microvilli, alterations in junctional claudins, and disruption of apical and basolateral trafficking; however, no microvillus inclusions were observed in MYO5B-KD cells. Expression of WT MYO5B in MYO5B-KD cells restored microvilli; however, expression of MYO5B-P660L, a MVID-associated mutation found within Navajo populations, did not rescue the MYO5B-KD phenotype but induced formation of microvillus inclusions. Microvilli establishment required interaction between RAB8A and MYO5B, while loss of the interaction between RAB11A and MYO5B induced microvillus inclusions. Using surface biotinylation and dual immunofluorescence staining in MYO5B-KD cells expressing mutant forms of MYO5B, we observed that early microvillus inclusions were positive for the sorting marker SNX18 and derived from apical membrane internalization. In patients with MVID, MYO5B-P660L results in global changes in polarity at the villus tips that could account for deficits in apical absorption, loss of microvilli, aberrant junctions, and losses in transcellular ion transport pathways, likely leading to the MVID clinical phenotype of neonatal secretory diarrhea.     

Patterns of survival in lymphoplasmacytic lymphoma/waldenström macroglobulinemia: A population‐based study of 1,555 patients diagnosed in Sweden from 1980 to 2005

Clinical management of lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) has changed considerably over recent years, reflected in the use of new therapeutic agents (purine analogs, monoclonal antibodies, thalidomide‐ and bortezomib‐based therapies). No population‐based studies and few randomized trials have been performed to assess survival in newly diagnosed LPL/WM. We performed a large population‐based study in Sweden including 1,555 LPL/WM patients diagnosed from 1980 to 2005. Relative survival ratios (RSRs) and excess mortality rate ratios (EMRR) were computed as measures of survival. Survival of LPL/WM patients has improved significantly (P = 0.007) over time with 5‐year RSR = 0.57 (95% confidence interval [CI] 0.46–0.68), 0.65 (0.57–0.73), 0.74 (0.68–0.80), 0.72 (0.66–0.77), and 0.78 (0.71–0.85) for patients diagnosed during the calendar periods 1980–1985, 1986–1990, 1991–1995, 1996–2000, and 2001–2005, respectively. Improvement in 1‐ and 5‐year relative survival was found in all age groups and for LPL and WM separately. Patients with WM had lower excess mortality compared to LPL (EMRR = 0.38; 95% CI 0.30–0.48). Older age at diagnosis was associated with a poorer survival (P < 0.001). Taken together, we found a significant improvement in survival in LPL/WM over time. Despite this progress, new effective agents with a more favourable toxicity profile are needed to further improve survival in LPL/WM, especially in the elderly. Am. J. Hematol. 2013. © 2012 Wiley Periodicals, Inc.     

Extraosseous Ewing's sarcoma versus primitive rhabdomyosarcoma: diagnostic criteria and clinical correlation

A light and electron microscopic study of 51 cases of Ewing's sarcoma of bone (ESB) and 33 soft tissue sarcomas (carrying a variety of light microscopic diagnoses, including primitive rhabdomyosarcoma) in children and young adults was performed to clarify the similarities and differences among these tumors. Ultrastructural criteria were developed to evaluate the neoplasms. Remarkable ultrastructural uniformity was found in the cases of ESB. In contrast, the soft tissue sarcomas could be divided into two distinct groups on the basis of the ultrastructural criteria: those closely resembling primitive areas of otherwise differentiated rhabdomyosarcomas, and those indistinguishable from ESB. It is proposed that the diagnosis of soft tissue Ewing's sarcoma be reserved for lesions identical to ESB by both light and electron microscopy. The first group of sarcomas may be histogenetically related to rhabdomyosarcoma and should be distinguished from extraosseous Ewing's sarcoma, as their clinical behavior appears to be quite different.     

Early anthropometric measures and reproductive factors as predictors of body mass index and obesity among older women

OBJECTIVE: To examine whether early anthropometric measures and reproductive factors were associated with body mass index (BMI), overweight, and obesity. DESIGN: Cross-sectional, observational study. SUBJECTS: In all, 18 109 healthy women who participated in the Swedish Mammography Cohort aged 49-83 y. MEASUREMENTS: Early anthropometric (birthweight and body shape at age 10 y) and reproductive (age at menarche, age at the birth of the first child, and parity) variables were our predictors and current BMI, overweight (BMI 25-29.99 kg/m(2)), and obesity (BMI > or =30 kg/m(2)) were our outcomes. RESULTS: In multivariate-adjusted polytomous logistic regression analysis, risk of overweight and obesity increased with increasing body shape at age 10 y and decreased with increasing age at menarche and age at first birth (P for trend <0.0001). A U-shaped relation with birthweight was observed. In our tests for effect modification of the relation with overweight/obesity (ow/ob; BMI > or =25 kg/m(2)), we detected significant interactions between body shape at 10 y and age (P<0.0001); body shape at 10 y and physical activity (P<0.0001); age at first birth and smoking (P=0.02); and parity and physical activity (P=0.004). The increased risk of ow/ob among women who reported a larger childhood body shape was reduced as women moved from the lowest to highest quartile of physical activity in adulthood. Likewise, the increasing risk of ow/ob among women with greater parity was reduced with increased physical activity. CONCLUSION: Early anthropometric measures and reproductive factors are significantly associated with BMI, overweight, and obesity among older women. The effects of childhood body weight, age at first birth, and parity may be modified by adult lifestyle choices, as well as age.     

The interspinous method of posterior atlantoaxial arthrodesis

Thirty-six patients underwent C1-2 posterior wiring and fusion procedures over a 5-year period for unstable C-2 fractures (eight cases), unstable atlas-axis combination fractures (six cases), rheumatoid C1-2 instability (14 cases), os odontoideum (four cases), traumatic C1-2 ligamentous instability (three cases), or instability secondary to a C-2 tumor (one case). In each case, the atlantoaxial arthrodesis utilized sublaminar wire at C-1 and incorporated an iliac-crest strut-graft positioned between the posterior arches of C-1 and C-2, held in place by securing wire around the base of the spinous process of the axis. Follow-up examination was performed in all patients after a mean postoperative duration of 33.7 months. The technical aspects and clinical merits of this fusion procedure, which led to a 97% union rate (one nonunion) and minimal morbidity and mortality rates, are presented.