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1.  Balkan endemic nephropathy: an update on its aetiology 
Archives of Toxicology  2016;90(11):2595-2615.
Balkan endemic nephropathy (BEN) is a unique, chronic renal disease frequently associated with upper urothelial cancer (UUC). It only affects residents of specific farming villages located along tributaries of the Danube River in Bosnia-Herzegovina, Croatia, Macedonia, Serbia, Bulgaria, and Romania where it is estimated that ~100,000 individuals are at risk of BEN, while ~25,000 have the disease. This review summarises current findings on the aetiology of BEN. Over the last 50 years, several hypotheses on the cause of BEN have been formulated, including mycotoxins, heavy metals, viruses, and trace-element insufficiencies. However, recent molecular epidemiological studies provide a strong case that chronic dietary exposure to aristolochic acid (AA) a principal component of Aristolochia clematitis which grows as a weed in the wheat fields of the endemic regions is the cause of BEN and associated UUC. One of the still enigmatic features of BEN that need to be resolved is why the prevalence of BEN is only 3–7 %. This suggests that individual genetic susceptibilities to AA exist in humans. In fact dietary ingestion of AA along with individual genetic susceptibility provides a scenario that plausibly can explain all the peculiarities of BEN such as geographical distribution and high risk of urothelial cancer. For the countries harbouring BEN implementing public health measures to avoid AA exposure is of the utmost importance because this seems to be the best way to eradicate this once mysterious disease to which the residents of BEN villages have been completely and utterly at mercy for so long.
doi:10.1007/s00204-016-1819-3
PMCID: PMC5065591  PMID: 27538407
Balkan endemic nephropathy; Disease aetiology; Upper urothelial cancer; Environmental and genetic factors; Aristolochic acid nephropathy; Aristolochic acid
2.  Evaluating Weight of Evidence in the Mystery of Balkan Endemic Nephropathy 
Balkan Endemic Nephropathy (BEN) is a chronic, progressive wasting disease of the kidneys, endemic in certain rural regions of the Balkan nations Croatia, Serbia, Bulgaria, and Romania. It is irreversible, and ultimately fatal. Though this disease was first described in the 1920s, its causes have been a mystery and a source of much academic and clinical contention. Possible etiologic agents that have been explored include exposure to metals and metalloids, viruses and bacteria, and the environmental toxins aristolochic acid (AA) and ochratoxin A (OTA). Aristolochic acid is a toxin produced by weeds of the genus Aristolochia, common in Balkan wheat fields. Aristolochia seeds may intermingle with harvested grains and thus inadvertently enter human diets. Ochratoxin A is a mycotoxin (fungal toxin) common in many foods, including cereal grains. In this study, we analyzed the weight of evidence for each of the suspected causes of BEN using the Bradford Hill Criteria (BHC): nine conditions that determine weight of evidence for a causal relationship between an agent and a disease. Each agent postulated to cause BEN was evaluated using the nine criteria, and for each criterion was given a rating based on the strength of the association between exposure to the substance and BEN. From the overall available scientific evidence for each of these suspected risk factors, aristolochic acid is the agent with the greatest weight of evidence in causing BEN. We describe other methods for testing causality from epidemiological studies, which support this conclusion of AA causing BEN.
doi:10.1111/risa.12239
PMCID: PMC4199864  PMID: 24954501
Balkan Endemic Nephropathy; Bradford Hill Criteria; aristolochic acid; ochratoxin A; weight of evidence
3.  Balkan endemic nephropathy—current status and future perspectives 
Clinical Kidney Journal  2013;6(3):257-265.
Balkan endemic nephropathy (BEN), originally described in 1956, is a unique familial, chronic renal disease encountered with a high-prevalence rate in Serbia, Bulgaria, Romania, Croatia and Bosnia and Herzegovina. The most prominent features of the disease are its endemic nature, long-incubation period, familial clustering of the disease and an unusually high incidence of associated upper urothelial cancer (UUC). There are no clear-cut data on BEN incidence and prevalence, since the studies carried out in different endemic areas yielded contradictory information. In spite of intermittent variations, the incidence of new cases has remained stable over time. It has been estimated that almost 100 000 people are at risk of BEN, whereas 25 000 have the disease. The clinical signs and symptoms of BEN are non-specific and often remain unrecognized for years. There are no pathognomonic diagnostic features of BEN, but the set of epidemiological, clinical and biochemical data along with the pattern of pathologic injury in the absence of any other renal diseases are highly suggestive of this entity. Although the aetiology has been extensively studied, fostering the publication of various hypotheses, only one of them has provided conclusive evidence related to the aetiology of BEN. Studies conducted over the past decade have provided particularly strong arguments that BEN and UUC are caused by chronic poisoning with aristolochic acids (AAs). In light of these later studies, one can raise the question whether AAs could be responsible for previously and currently widespread unrecognized global renal disease and UUC.
doi:10.1093/ckj/sft049
PMCID: PMC4400492  PMID: 26064484
aristolochic acid; Balkan endemic nephropathy; aetiology; hypothesis; urothelial cancer
4.  Is Increased Susceptibility to Balkan Endemic Nephropathy in Carriers of Common GSTA1 (*A/*B) Polymorphism Linked with the Catalytic Role of GSTA1 in Ochratoxin A Biotransformation? Serbian Case Control Study and In Silico Analysis 
Toxins  2014;6(8):2348-2362.
Although recent data suggest aristolochic acid as a putative cause of Balkan endemic nephropathy (BEN), evidence also exists in favor of ochratoxin A (OTA) exposure as risk factor for the disease. The potential role of xenobiotic metabolizing enzymes, such as the glutathione transferases (GSTs), in OTA biotransformation is based on OTA glutathione adducts (OTHQ-SG and OTB-SG) in blood and urine of BEN patients. We aimed to analyze the association between common GSTA1, GSTM1, GSTT1, and GSTP1 polymorphisms and BEN susceptibility, and thereafter performed an in silico simulation of particular GST enzymes potentially involved in OTA transformations. GSTA1, GSTM1, GSTT1 and GSTP1 genotypes were determined in 207 BEN patients and 138 non-BEN healthy individuals from endemic regions by polymerase chain reaction (PCR). Molecular modeling in silico was performed for GSTA1 protein. Among the GST polymorphisms tested, only GSTA1 was significantly associated with a higher risk of BEN. Namely, carriers of the GSTA1*B gene variant, associated with lower transcriptional activation, were at a 1.6-fold higher BEN risk than those carrying the homozygous GSTA1*A/*A genotype (OR = 1.6; p = 0.037). In in silico modeling, we found four structures, two OTB-SG and two OTHQ-SG, bound in a GSTA1 monomer. We found that GSTA1 polymorphism was associated with increased risk of BEN, and suggested, according to the in silico simulation, that GSTA1-1 might be involved in catalyzing the formation of OTHQ-SG and OTB-SG conjugates.
doi:10.3390/toxins6082348
PMCID: PMC4147586  PMID: 25111321
Balkan endemic nephropathy; biotransformation; glutathione transferase A1; ochratoxin A; polymorphism
5.  MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy 
BioMed Research International  2016;2016:7450461.
Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups.
doi:10.1155/2016/7450461
PMCID: PMC4863087  PMID: 27218105
6.  Metals and kidney markers in adult offspring of endemic nephropathy patients and controls: a two-year follow-up study 
Environmental Health  2008;7:11.
Background
The etiology of Balkan Endemic Nephropathy, (BEN), a tubulointerstitial kidney disease, is unknown. Although this disease is endemic in rural areas of Bosnia, Bulgaria, Croatia, Romania, and Serbia, similar manifestations are reported to occur in other regions, for instance Tunisia and Sri Lanka. A number of explanations have been stated including lignites, aristolochic acid, ochratoxin A, metals, and metalloids. Etiologic claims are often based on one or a few studies without sound scientific evidence. In this systematic study, we tested whether exposures to metals (cadmium and lead) and metalloids (arsenic and selenium) are related to Balkan Endemic Nephropathy.
Methods
In 2003/04 we recruited 102 adults whose parents had BEN and who resided in one of three communities (Vratza, Bistretz, or Beli Izvor, Bulgaria). A control group comprised of 99 adults having non-BEN hospitalized parents was enrolled in the study during the same time. We conducted face-to-face interviews, ultrasound kidney measurements, and determined kidney function in two consecutive investigations (2003/04 and 2004/05). Metals and metalloids were measured in urine and blood samples. To assess the agreement between these consecutive measurements, we calculated intraclass correlation coefficients. Repeated measurement data were analyzed using mixed models.
Results
We found that cadmium and arsenic were associated with neither kidney size nor function. Lead had a significant but negligible effect on creatinine clearance. Selenium showed a weak but significant negative association with two of the four kidney parameters, namely creatinine clearance and β2-microglobulin. It was positively related to kidney length. These associations were not restricted to the offspring of BEN patients. Adding credence to these findings are reports showing comparable kidney effects in animals exposed to selenium.
Conclusion
The findings of this 2-year follow-up study indicate that metals and metalloids do not play a role in the etiology of Balkan Endemic Nephropathy. Against the assumption in the literature, selenium was not protective but a risk factor. Since comparable associations were observed in animals, future studies are needed to explore whether selenium may have adverse renal effects in humans.
doi:10.1186/1476-069X-7-11
PMCID: PMC2323372  PMID: 18387186
7.  Pro- and Antiapoptotic Markers in Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy 
TheScientificWorldJournal  2011;11:1699-1711.
The role of aristolochic acid in the etiology of Balkan endemic nephropathy (BEN) and associated upper-tract urothelial carcinoma (UTUC) has been recently confirmed. The aim of this study was to determine apoptosis-related marker(s) specific for BEN-associated UTUC. Present investigation included 105 patients with UTUC, 44 from BEN region and 61 control tumors. Altered expression of Survivin was more often present in BEN UTUC with high grade and solid growth (P < 0.005; P < 0.05) than in control tumors. Significantly lower expression of proapoptotic marker Bax was found in BEN tumors with high grade, high stage, necrosis, and without metaplastic change (P < 0.05; 0.05; 0.05; 0.05) compared to control tumors with the same features. Group (BEN-related/control), stage, growth pattern, and caspase 3 activity were significantly associated with the expression of Bax (P = 0.002, 0.034, 0.047, 0.028, resp.,). This investigation identifies Bax as specific marker of BEN-associated UTUC. Decrease of pro-apoptotic protein Bax together with alteration of Survivin may be indicative for specific disturbances of intrinsic apoptotic pathway in UTUC arising in endemic areas.
doi:10.1100/2011/752790
PMCID: PMC3201692  PMID: 22125429
Balkan endemic nephropathy; upper tract urothelial carcinoma; apoptosis; Survivin; Bcl-2; Bax; Fas; Caspase 3
8.  Receptor Polymorphism and Genomic Structure Interact to Shape Bitter Taste Perception 
PLoS Genetics  2015;11(9):e1005530.
The ability to taste bitterness evolved to safeguard most animals, including humans, against potentially toxic substances, thereby leading to food rejection. Nonetheless, bitter perception is subject to individual variations due to the presence of genetic functional polymorphisms in bitter taste receptor (TAS2R) genes, such as the long-known association between genetic polymorphisms in TAS2R38 and bitter taste perception of phenylthiocarbamide. Yet, due to overlaps in specificities across receptors, such associations with a single TAS2R locus are uncommon. Therefore, to investigate more complex associations, we examined taste responses to six structurally diverse compounds (absinthin, amarogentin, cascarillin, grosheimin, quassin, and quinine) in a sample of the Caucasian population. By sequencing all bitter receptor loci, inferring long-range haplotypes, mapping their effects on phenotype variation, and characterizing functionally causal allelic variants, we deciphered at the molecular level how a subjects’ genotype for the whole-family of TAS2R genes shapes variation in bitter taste perception. Within each haplotype block implicated in phenotypic variation, we provided evidence for at least one locus harboring functional polymorphic alleles, e.g. one locus for sensitivity to amarogentin, one of the most bitter natural compounds known, and two loci for sensitivity to grosheimin, one of the bitter compounds of artichoke. Our analyses revealed also, besides simple associations, complex associations of bitterness sensitivity across TAS2R loci. Indeed, even if several putative loci harbored both high- and low-sensitivity alleles, phenotypic variation depended on linkage between these alleles. When sensitive alleles for bitter compounds were maintained in the same linkage phase, genetically driven perceptual differences were obvious, e.g. for grosheimin. On the contrary, when sensitive alleles were in opposite phase, only weak genotype-phenotype associations were seen, e.g. for absinthin, the bitter principle of the beverage absinth. These findings illustrate the extent to which genetic influences on taste are complex, yet arise from both receptor activation patterns and linkage structure among receptor genes.
Author Summary
Human bitter taste is believed to protect us from the ingestion of poisonous substances, thereby shaping food rejections. Bitter perception differs, however, across individuals, due to genetic variations in the ~25 bitter taste receptor (TAS2R) genes. A famous example known since the 1930s is the inherited bitter taste sensitivity to phenylthiocarbamide, which is associated with genetic polymorphisms in a single TAS2R gene. Yet, such simple receptor-substance associations do not reflect the full complexity of bitter perception, since individual bitter substances frequently activate several TAS2Rs. Here, we provide an in-depth analysis of the genetic variability influencing human bitter taste. While each study subject carried a different set of genetic polymorphisms, we found that most variations reside in just six blocks, each harboring only one to five haplotypes. Thus, besides simple associations between taste and TAS2R gene polymorphisms, we revealed complex associations dependent on linkage between several high- and low-sensitivity alleles. Indeed, subjects carried either sensitive or insensitive alleles for receptors sensitive to grosheimin, a bitter compound in artichoke, or at least one sensitive allele for receptors specific for absinthin, the bitter principle of absinth. In short, simple associations and complex genomic linkage determine sensitivity to selected dietary bitter compounds.
doi:10.1371/journal.pgen.1005530
PMCID: PMC4583475  PMID: 26406243
9.  Increased blood pressure in adult offspring of families with Balkan Endemic Nephropathy: a prospective study 
BMC Nephrology  2006;7:12.
Background
Previous studies have linked smaller kidney dimensions to increased blood pressure. However, patients with Balkan Endemic Nephropathy (BEN), whose kidneys shrink during the course of the disease, do not manifest increased blood pressure. The authors evaluated the relationship between kidney cortex width, kidney length, and blood pressure in the offspring of BEN patients and controls.
Methods
102 offspring of BEN patients and 99 control offspring of non-BEN hospital patients in the Vratza District, Bulgaria, were enrolled in a prospective study and examined twice (2003/04 and 2004/05). Kidney dimensions were determined using ultrasound, blood pressure was measured, and medical information was collected. The parental disease of BEN was categorized into three groups: mother, father, or both parents. Repeated measurements were analyzed with mixed regression models.
Results
In all participants, a decrease in minimal kidney cortex width of 1 mm was related to an increase in systolic blood pressure of 1.4 mm Hg (p = 0.005). There was no association between kidney length and blood pressure. A maternal history of BEN was associated with an increase in systolic blood pressure of 6.7 mm Hg (p = 0.03); paternal BEN, +3.2 mm Hg (p = 0.35); or both parents affected, +9.9 mm Hg (p = 0.002). There was a similar relation of kidney cortex width and parental history of BEN with pulse pressure; however, no association with diastolic blood pressure was found.
Conclusion
In BEN and control offspring, a smaller kidney cortex width predisposed to higher blood pressure. Unexpectedly, a maternal history of BEN was associated with average increased systolic blood pressure in offspring.
doi:10.1186/1471-2369-7-12
PMCID: PMC1560117  PMID: 16928270
10.  The role of a parental history of Balkan endemic nephropathy in the occurrence of BEN: a prospective study 
Balkan endemic nephropathy (BEN) is a chronic kidney disease that affects persons living in the Balkans. Despite the unique geographical specificity of this disease, its etiology has remained unclear. Even if a positive family history of BEN has been identified, it is still uncertain how the disease develops in offspring. In this paper, we examine clinical mechanisms related to the onset of BEN in individuals who have a parental history of BEN to identify early detection of the disease and formulate interventions. We conducted a 5-year prospective study, using markers in years one and three to predict new cases of BEN in year five. New cases of BEN were defined based on three criteria: parental history of BEN, reduced kidney size, and reduced kidney function. Incident cases were divided into (1) probable, (2) definite, and (3) combined labeled total incidence. We evaluated parental history in relation to BEN and tested the potentially intervening effects of kidney length, kidney cortex width, β2-microglobulin, C-reactive protein, and creatinine clearance, using path analyses. The findings of the path analyses suggested that parental history of BEN had both direct and indirect effects. The direct effect was significant for all three modes of parental history (biparental, maternal, and paternal; odds ratios 71.5, 52.3, and 50.1, respectively). The indirect effects of maternal BEN acted via kidney length and creatinine clearance. Biparental BEN was mediated by (1) kidney length and creatinine clearance, and (2) creatinine clearance alone. Paternal BEN had three indirect effects: (1) through kidney length and creatinine clearance, (2) via kidney cortex width and creatinine clearance, and (3) via kidney cortex width only. In conclusion, a family history of BEN led to reduced kidney length and cortex width, and a decline in creatinine clearance, which in turn predicted the onset of BEN.
doi:10.2147/IJNRD.S30615
PMCID: PMC3333804  PMID: 22536083
Balkan endemic nephropathy; incidence of BEN; parental history of BEN; kidney size; β2-microglobulin; creatinine clearance
11.  Do polymorphisms in chemosensory genes matter for human ingestive behavior? 
Food quality and preference  2013;30(2):202-216.
In the last decade, basic research in chemoreceptor genetics and neurobiology have revolutionized our understanding of individual differences in chemosensation. From an evolutionary perspective, chemosensory variations appear to have arisen in response to different living environments, generally in the avoidance of toxins and to better detect vital food sources. Today, it is often assumed that these differences may drive variable food preferences and choices, with downstream effects on health and wellness. A growing body of evidence indicates chemosensory variation is far more complex than previously believed. However, just because a genetic polymorphism results in altered receptor function in cultured cells or even behavioral phenotypes in the laboratory, this variation may not be sufficient to influence food choice in free living humans. Still, there is ample evidence to indicate allelic variation in TAS2R38 predicts variation in bitterness of synthetic pharmaceuticals (e.g., propylthiouracil) and natural plant compounds (e.g., goitrin), and this variation associates with differential intake of alcohol and vegetables. Further, this is only one of 25 unique bitter taste genes (TAS2Rs) in humans, and emerging evidence suggests other TAS2Rs may also contain polymorphisms that a functional with respect to ingestive behavior. For example, TAS2R16 polymorphisms are linked to the bitterness of naturally occurring plant compounds and alcoholic beverage intake, a TAS2R19 polymorphism predicts differences in quinine bitterness and grapefruit bitterness and liking, and TAS2R31 polymorphisms associate with differential bitterness of plant compounds like aristolochic acid and the sulfonyl amide sweeteners saccharin and acesulfame-K. More critically with respect to food choices, these polymorphisms may vary independently from each other within and across individuals, meaning a monolithic one-size-fits-all approach to bitterness needs to be abandoned. Nor are genetic differences restricted to bitterness. Perceptual variation has also been associated with polymorphisms in genes involved in odors associated with meat defects (boar taint), green/grassy notes, and cilantro, as well as umami and sweet tastes (TAS1R1/2/3). Here, a short primer on receptor genetics is provided, followed by a summary of current knowledge, and implications for human ingestive behavior are discussed.
doi:10.1016/j.foodqual.2013.05.013
PMCID: PMC3714112  PMID: 23878414
12.  Kidney length in healthy members of Balkan endemic nephropathy families 
Hippokratia  2015;19(4):304-308.
Background: Kidney size may differ between healthy members of Balkan endemic nephropathy (BEN) and non-BEN families. The present study was designed to elucidate this, in comparison with values for BEN patients.
Methods: A total of 71 BEN patients (34 males, 64.4 ± 12.0 years), 74 healthy BEN family members (39 males, 49.1 ± 12.2 years), and 59 non-BEN family members (19 males, 49.2 ± 12.3 years) were involved. We measured the longest craniocaudal length and minimal parenchymal thickness on each kidney of all examined subjects using ultrasound.
Results: No significant difference was found between the kidney length of healthy subjects from BEN (11.0 ± 0.8 cm) and non-BEN families (10.9 ± 0.8 cm), but kidneys were significantly longer than in BEN patients (9.9 ± 1.3 cm). Minimal parenchymal thickness was similar in all three groups. When subjects from each group were divided according to estimated glomerular filtration rate (eGFR), kidney length of the healthy groups was significantly longer than in BEN patients both in stage 1 (p =0.039) and stage 2 (p =0.044) of chronic kidney disease. The parental history of BEN was not associated with kidney dimensions, eGFR, or urinary excretion of albumin and alpha1-microglobulin.
Conclusion: Kidneys of BEN patients were significantly shorter than in healthy members of both BEN and non-BEN families, but no difference was found in kidney length and parenchymal thickness between healthy members of BEN and non-BEN families. No significant association was found between parental history of BEN and kidney size and function either in BEN patients or in healthy members from BEN families. Hippokratia 2015; 19 (4): 304-308.
PMCID: PMC5033139  PMID: 27688693
Balkan endemic nephropathy; kidney length; ultrasound
13.  Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels 
British Journal of Pharmacology  2016;173(10):1639-1652.
Background and Purpose
Aristolochic acid (AristA) is found in plants used in traditional medicines to treat pain. We investigated the action of AristA on TREK and TRESK, potassium (K2P) channels, which are potential therapeutic targets in pain. Balkan endemic nephropathy (BEN) is a renal disease associated with AristA consumption. A mutation of TASK‐2 (K2P5.1) channels (T108P) is seen in some patients susceptible to BEN, so we investigated how both this mutation and AristA affected TASK‐2 channels.
Experimental Approach
Currents through wild‐type and mutated human K2P channels expressed in tsA201 cells were measured using whole‐cell patch‐clamp recordings in the presence and absence of AristA.
Key Results
TREK‐1‐ and TREK‐2‐mediated currents were enhanced by AristA (100 μM), whereas TRESK was inhibited. Inhibition of TRESK did not depend on the phosphorylation of key intracellular serines but was completely blocked by mutation of bulky residues in the inner pore (F145A_F352A). The TASK‐2_T108P mutation markedly reduced both current density and ion selectivity. A related mutation (T108C) had similar but less marked effects. External alkalization and application of flufenamic acid enhanced TASK‐2 and TASK‐2_T108C current but did not affect TASK‐2_T108P current. AristA (300 μM) produced a modest enhancement of TASK‐2 current.
Conclusions and Implications
Enhancement of TREK‐1 and TREK‐2 and inhibition of TRESK by AristA may contribute to therapeutically useful effects of this compound in pain. Whilst AristA is unlikely to interact directly with TASK‐2 channels in BEN, loss of functional TASK‐2 channels may indirectly increase susceptibility to AristA toxicity.
doi:10.1111/bph.13465
PMCID: PMC4842925  PMID: 26914156
14.  Baicalin Protects Mice from Aristolochic Acid I-Induced Kidney Injury by Induction of CYP1A through the Aromatic Hydrocarbon Receptor 
Exposure to aristolochic acid I (AAI) can lead to aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and urothelial cancer. The induction of hepatic CYP1A, especially CYP1A2, was considered to detoxify AAI so as to reduce its nephrotoxicity. We previously found that baicalin had the strong ability to induce CYP1A2 expression; therefore in this study, we examined the effects of baicalin on AAI toxicity, metabolism and disposition, as well as investigated the underlying mechanisms. Our toxicological studies showed that baicalin reduced the levels of blood urea nitrogen (BUN) and creatinine (CRE) in AAI-treated mice and attenuated renal injury induced by AAI. Pharmacokinetic analysis demonstrated that baicalin markedly decreased AUC of AAI in plasma and the content of AAI in liver and kidney. CYP1A induction assays showed that baicalin exposure significantly increased the hepatic expression of CYP1A1/2, which was completely abolished by inhibitors of the Aromatic hydrocarbon receptor (AhR), 3ʹ,4ʹ-dimethoxyflavone and resveratrol, in vitro and in vivo, respectively. Moreover, the luciferase assays revealed that baicalin significantly increased the luciferase activity of the reporter gene incorporated with the Xenobiotic response elements recognized by AhR. In summary, baicalin significantly reduced the disposition of AAI and ameliorated AAI-induced kidney toxicity through AhR-dependent CYP1A1/2 induction in the liver.
doi:10.3390/ijms160716454
PMCID: PMC4519959  PMID: 26204831
aristolochic acid; kidney injury; baicalin; aromatic hydrocarbon receptor; CYP1A
15.  Resting State Brain Entropy Alterations in Relapsing Remitting Multiple Sclerosis 
PLoS ONE  2016;11(1):e0146080.
Brain entropy (BEN) mapping provides a novel approach to characterize brain temporal dynamics, a key feature of human brain. Using resting state functional magnetic resonance imaging (rsfMRI), reliable and spatially distributed BEN patterns have been identified in normal brain, suggesting a potential use in clinical populations since temporal brain dynamics and entropy may be altered in disease conditions. The purpose of this study was to characterize BEN in multiple sclerosis (MS), a neurodegenerative disease that affects millions of people. Since currently there is no cure for MS, developing treatment or medication that can slow down its progression represents a high research priority, for which validating a brain marker sensitive to disease and the related functional impairments is essential. Because MS can start long time before any measurable symptoms and structural deficits, assessing the dynamic brain activity and correspondingly BEN may provide a critical way to study MS and its progression. Because BEN is new to MS, we aimed to assess BEN alterations in the relapsing-remitting MS (RRMS) patients using a patient versus control design, to examine the correlation of BEN to clinical measurements, and to check the correlation of BEN to structural brain measures which have been more often used in MS studies. As compared to controls, RRMS patients showed increased BEN in motor areas, executive control area, spatial coordinating area, and memory system. Increased BEN was related to greater disease severity as measured by the expanded disability status scale (EDSS) and greater tissue damage as indicated by the mean diffusivity. Patients also showed decreased BEN in other places, which was associated with less disability or fatigue, indicating a disease-related BEN re-distribution. Our results suggest BEN as a novel and useful tool for characterizing RRMS.
doi:10.1371/journal.pone.0146080
PMCID: PMC4699711  PMID: 26727514
16.  Whole genome methylation array analysis reveals new aspects in Balkan endemic nephropathy etiology 
BMC Nephrology  2013;14:225.
Background
Balkan endemic nephropathy (BEN) represents a chronic progressive interstitial nephritis in striking correlation with uroepithelial tumours of the upper urinary tract. The disease has endemic distribution in the Danube river regions in several Balkan countries.
DNA methylation is a primary epigenetic modification that is involved in major processes such as cancer, genomic imprinting, gene silencing, etc. The significance of CpG island methylation status in normal development, cell differentiation and gene expression is widely recognized, although still stays poorly understood.
Methods
We performed whole genome DNA methylation array analysis on DNA pool samples from peripheral blood from 159 affected individuals and 170 healthy individuals. This technique allowed us to determine the methylation status of 27 627 CpG islands throughout the whole genome in healthy controls and BEN patients. Thus we obtained the methylation profile of BEN patients from Bulgarian and Serbian endemic regions.
Results
Using specifically developed software we compared the methylation profiles of BEN patients and corresponding controls and revealed the differently methylated regions. We then compared the DMRs between all patient-control pairs to determine common changes in the epigenetic profiles.
SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs. The CpG islands of all 3 genes were hypomethylated compared to controls. This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions and in both genders.
Conclusion
Our data propose a new hypothesis that immunologic dysregulation has a place in BEN etiopathogenesis.
doi:10.1186/1471-2369-14-225
PMCID: PMC3852817  PMID: 24131581
Epigenetics; Whole genome array analysis; Balkan endemic nephropathy
17.  7th Drug hypersensitivity meeting: part two 
Elera, Javier Dionicio | Boteanu, Cosmin | Blanco, Maria Aranzazu Jimenez | Gonzalez-Mendiola, Rosario | García, Irene Carrasco | Alvarez, Antonio | Martinez, Jose Julio Laguna | Garrido, Jaume Martí | Barona, Carla Torán | Chorda, Carolina Perales | Salgueiro, Ramón López | Palacios, Miguel Díaz | De Rojas, Dolores Hernández Fernández | Acar, Emre Ali | Aktas, Ayse | Ermertcan, Aylin Türel | Temiz, Peyker | Lin, Chien-Yio | Hui, Chung-Yee Rosaline | Chang, Ya-Ching | Yang, Chih-Hsun | Chung, Wen-Hung | Carolino, Fabrícia | Silva, Diana | De Castro, Eunice Dias | Cernadas, Josefina R. | Ensina, Luis Felipe | Aranda, Carolina | Nunes, Ines Camelo | Lacerda, Alex | Martins, Ana Maria | Goudouris, Ekaterini | Ribeiro, Marcia | Da Silva Franco, José Francisco | Queiroz, Leandra | Solé, Dirceu | Dalgiç, Ceyda Tunakan | Sin, Aytül Zerrin | Günsen, Fatma Düsünür | Bulut, Gökten | Ardeniz, Fatma Ömür | Gülbahar, Okan | Gökmen, Emine Nihal Mete | Kokuludag, Ali | De Francisco, Ana M. Montoro | De Vicente Jiménez, Talía Mª | Mendoza Parra, Adriana M. | Burgos Pimentel, Angella M. | Luque, Amelia García | Amaral, Luis | Leão, Leonor Carneiro | Pinto, Nicole | Belo, Joana | Marques, João | Carreiro-Martins, Pedro | Leiria-Pinto, Paula | Chaabane, Amel | Romdhane, Haifa Ben | Fredj, Nadia Ben | Chadly, Zohra | Boughattas, Naceur A. | Aouam, Karim | Uyttebroek, Astrid P. | Bridts, Chris H. | Romano, Antonino | Ebo, Didier G. | Sabato, Vito | Lopes, Anabela | Cosme, Joana | Aguiar, Rita | Lourenço, Tatiana | Paes, Maria-João | Spínola-Santos, Amélia | Pereira-Barbosa, Manuel | Cruz, Cíntia Rito | Dos Reis, Rute Pereira | Tomaz, Elza | Pires, Ana Paula | Inácio, Filipe | Benito-Garcia, Filipe | Mota, Inês | Correia, Magna | Gaspar, Ângela | Chambel, Marta | Piedade, Susana | Morais-Almeida, Mário | Nakonechna, Alla | Antipkin, Yurij | Umanets, Tetiana | Pineda, Fernando | Arribas, Francisca | Lapshyn, Volodymyr | Miranda, Pablo Andrés | De La Cruz Hoyos, Bautista | Blanco, Aranzazu Jimenez | Del Pozo, Marta | Vultaggio, Alessandra | Nencini, Francesca | Pratesi, Sara | Matucci, Andrea | Maggi, Enrico | Cegec, Ivana | Nahal, Danica Juricic | Turk, Viktorija Erdeljic | Aumiler, Matea Radacic | Ausperger, Ksenija Makar | Kraljickovic, Iva | Simic, Iveta | Yamaguchi, Yukie | Watanabe, Tomoya | Satoh, Megumi | Tanegashima, Tomohiko | Oda, Kayoko | Wada, Hidefumi | Aihara, Michiko | Lee, Jaechun Jason | Choi, Jay Chol | Lee, Hwa Young | Fernandes, Rosa-Anita Rodrigues | Faria, Emília | Pita, Joana | Sousa, Nuno | Ribeiro, Carmelita | Carrapatoso, Isabel | Bom, Ana Todo | Rodolfo, Ana | Dias-Castro, Eunice | Voronova, Marina | Valle, Diana Kury | Coronel, Verónica Pacheco | Chordá, Carolina Perales | Madamba, Roselle Catherine Yu | Ferrer, Marta | Goikoetxea, Maria Jose | D’Amelio, Carmen | Bernad, Amalia | Vega, Olga | Gastaminza, Gabriel | Bibián, Beatriz Pola | Salazar, Marina Lluncor | Vilà-Nadal, Gemma | Roman, Ana María Fiandor | Ortega, Javier Dominguez | Muñoz, Miguel Gonzalez | Gancedo, Santiago Quirce | Moreno, Maria Rosario Cabañas | Hofmeier, Kathrin Scherer | Barzylovych, Vladyslava | Pola, Beatriz | Lluncor, Marina | Fiandor, Ana | Bellón, Teresa | Domínguez, Javier | Quirce, Santiago | Yang, Min-Suk | Kim, Sun-Sin | Kim, Sae-Hoon | Kang, Hye-Ryun | Park, Heung-Woo | Cho, Sang-Heon | Min, Kyung-Up | Chang, Yoon-Seok | Delahaye, Clémence | Flabbee, Jenny | Waton, Julie | Bauvin, Olivia | Barbaud, Annick | Fadhel, Najah Ben | Gulin, Sandra Jerkovic | Chiriac, Anca | Cardoso, Bárbara Kong | Viseu, Regina | Moreira, Ana | Cadinha, Susana | Neves, Ana Castro | Barreira, Patrícia | Malheiro, Daniela | Da Silva, J. P. Moreira | Jurakic-Toncic, Ružica | Ljubojevic, Suzana | Turcic, Petra | Gilissen, Liesbeth | Huygens, Sara | Goossens, An | Andreu, Inmaculada | Romero, Alicia Martinez | Cabezas, Pau Gomez | Parejo, Pedro Ayuso | Del Carmen Plaza-Serón, Maria | Doña, Inmaculada | Blanca-López, Natalia | Flores, Carlos | Galindo, María Luisa | Molina, Ana | Perkins, James Richard | Cornejo-García, José Antonio | García-Agúndez, José Augusto | García-Martín, Elena | Campo, Paloma | Canto, María Gabriela | Blanca, Miguel | Guéant-Rodríguez, Rosa María | Jurado-Escobar, Raquel | Barrionuevo, Esther | Salas, María | Canto, Gabriela | Guéant, Jean-Louis | Usui, Toru | Tailor, Arun | Faulkner, Lee | Farrell, John | Alfirevic, Ana | Kevin Park, B. | Naisbitt, Dean J. | Trelles, Oswaldo | Guerrero, María Auxiliadora | Upton, Alex | Ueta, Mayumi | Sawai, Hiromi | Sotozono, Chie | Tokunaga, Katushi | Kinoshita, Shigeru | Sukasem, Chonlaphat | Satapornpong, Patompong | Tempark, Therdpong | Rerknimitr, Pawinee | Pairayayutakul, Kulprapat | Klaewsongkram, Jettanong | Koomdee, N. | Jantararoungtong, T. | Santon, S. | Puangpetch, A. | Intusoma, U. | Tassaneeyakul, W. | Theeramoke, V. | Ramirez, Elena | Borobia, Alberto Manuel | Tong, Hoi | Castañer, Jose Luis | De Abajo, Francisco José | Galvao, Violeta Régnier | Pavlos, Rebecca | Mckinnon, Elizabeth | Williams, Kristina | Beeghly-Fadiel, Alicia | Redwood, Alec | Phillips, Elizabeth | Castells, Mariana | Boni, Elisa | Russello, Marina | Mauro, Marina | Ue, Kok Loong | Rutkowski, Krzysztof | Gomis, Victor Soriano | Ferre, Jorge Frances | Rodriguez, Angel Esteban | Reig, Vicente Cantó | Sanchez, Javier Fernandez | Breynaert, Christine | Van Hoeyveld, Erna | Schrijvers, Rik | Blanco, Aranzazu Jimenez | Irigoyen, Raquel Fuentes | Collado, Daniel | Vida, Yolanda | Najera, Francisco | Perez-Inestrosa, Ezequiel | Mesa-Antunez, Pablo | Mayorga, Cristobalina | Torres, María José | Tannert, Line K. | Mortz, Charlotte G. | Skov, Per Stahl | Bindslev-Jensen, Carsten | Pfützner, Wolfgang | Dörnbach, Hannah | Visse, Johanna | Rauber, Michele | Möbs, Christian | Elzagallaai, Abdelbaset A. | Chow, Lindsey | Abuzgaia, Awatif M. | Rieder, Michael J. | Trubiano, Jason | Woolnough, Emily | Stautins, Kaija | Cheng, Christina | Kato, Kenichi | Azukizawa, Hiroaki | Hanafusa, Takaaki | Katayama, Ichiro | Fujiyama, Toshiharu | Hashizume, Hideo | Umayahara, Takatsune | Ito, Taisuke | Tokura, Yoshiki | Silar, Mira | Zidarn, Mihaela | Rupnik, Helena | Korosec, Peter | Redwood, Alec James | Strautins, Kaija | White, Katie | Chopra, Abha | Konvinse, Katherine | Leary, Shay | Mallal, Simon | Cabañas, Rosario | Fiandor, Ana María | Sullivan, Andrew | Whitaker, Paul | Peckham, Daniel | Haw, Wei Yann | Polak, Marta E. | Mcguire, Carolann | Ardern-Jones, Michael R. | Aoyama, Yumi | Shiohara, Tetsuo | Correia, Sara | Gelincik, Asli | Demir, Semra | Sen, Fatma | Bozbey, Hamza Ugur | Olgac, Muge | Unal, Derya | Coskun, Raif | Colakoglu, Bahauddin | Buyuozturk, Suna | Çatin-Aktas, Esin | Deniz, Gunnur | Laguna, Jose Julio | Dionicio, J. | Fernandez, Tahia | Olazabal, I. | Ruiz, Maria Dolores | Torres, Maria José | Lafuente, Alberto | Núñez, Jorge | Fernández, Tahia Diana | Palomares, Francisca | Fernández, Rubén | Sanchez, Maria Isabel | Fernandez, Tahía | Ruiz, Arturo | Ariza, Adriana | Alonso, Amalia Bernad | Garófalo, Carmen D’Amelio | Matute, Olga Vega | Puga, Marta Ferrer | Lapresa, María José Goikoetxea | Lasarte, Gabriel Gastaminza | Thinnes, Antonia | Merk, Hans F. | Baron, Jens Malte | Leverkus, Martin | Balakirski, Galina | Gibson, Andrew | Ogese, Monday | Al-Attar, Zaid | Yaseen, Fiazia | Meng, Xiaoli | Jenkins, Rozalind | Farrel, John | Alhilali, Khetam | Xue, Yanni | Illing, Patricia | Mifsud, Nicole | Fettke, Heidi | Lai, Jeffrey | Ho, Rebecca | Kwan, Patrick | Purcell, Anthony | Ogese, Monday O. | Betts, Catherine | Thomson, Paul | Alhaidari, Mohammad | Berry, Neill | O’Neill, Paul M. | Alzahrani, Abdulaziz | Azoury, Marie Eliane | Fili, Lucia | Bechara, Rami | Scornet, Noémie | Nhim, Cathy | Weaver, Richard | Claude, Nancy | Joseph, Delphine | Maillere, Bernard | Parronchi, Paola | Pallardy, Marc | Villani, Axel Patrice | Rozières, Aurore | Bensaïd, Benoît | Tardieu, Mathilde | Albert, Floriane | Mutez, Virginie | Baysal, Tugba | Maryanski, Janet | Nicolas, Jean-François | Kanagawa, Osami | Vocanson, Marc | Hung, Shuen-Iu | Harrison, Caroline J. | Jenkins, Rosalind E. | French, Neil S. | Montañez, Maria Isabel | Fernandez, Tahia D. | Martin-Serrano, Angela | Torres, Maria Jose | Molina, Noemi | Wood, Sally | Pirmohamed, Munir | Montañez, María Isabel | Martín-Serrano, Ángela | Pérez-Inestrosa, Ezequiel | Pérez-Sala, Dolores | Guzmán, Antonio E. | Ko, Tai-Ming | Chen, Yuan-Tsong | Wu, Jer-Yuarn | Sánchez-Gómez, Francisco J. | González-Morena, Juan M. | Torres, María J. | Arreola, Alejandra Monroy | Corona, Jesus Agustin Badillo | Flores, Silvia Mendez | Cherit, Judith Dominguez | Figueroa, Noe Valentin Duran | Flores, Jose Luis Castrejon | Perkins, James | Pérez-Alzate, Diana | Bogas, Gador | Torres, María J | Marti, Luis Mario Tubella | De La Losa, Fernando Pineda | Poves, Francisca Arribas | Lopez, Jaime Tubella | Santiago, Teodora Lopez
Table of contents
Poster walk 11: miscellaneous drug hypersensitivity 2 (P92–P94, P96–P101)
P92 16 years of experience with proton pump inhibitors (PPIs)
Javier Dionicio Elera, Cosmin Boteanu, Maria Aranzazu Jimenez Blanco, Rosario Gonzalez-Mendiola, Irene Carrasco García, Antonio Alvarez, Jose Julio Laguna Martinez
P93 Allergy evaluation of quinolone induced adverse reactions
Jaume Martí Garrido, Carla Torán Barona, Carolina Perales Chorda, Ramón López Salgueiro, Miguel Díaz Palacios, Dolores Hernández Fernández De Rojas
P94 Bupropion-induced acute urticaria and angioedema, a case report
Emre Ali Acar, Ayse Aktas, Aylin Türel Ermertcan, Peyker Temiz
P96 Delayed type hypersensitivity and study of cross-reactivity between proton-pump inhibitors
Chien-Yio Lin, Chung-Yee Rosaline Hui, Ya-Ching Chang, Chih-Hsun Yang, Wen-Hung Chung
P97 Diagnostic work-up in suspected hypersensitivity to proton-pump inhibitors: looking at cross-reactivity
Fabrícia Carolino, Diana Silva, Eunice Dias De Castro, Josefina R. Cernadas
P98 Management of infusion-related hypersensitivity reactions to enzyme replacement therapy for lysosomal diseases
Luis Felipe Ensina, Carolina Aranda, Ines Camelo Nunes, Alex Lacerda, Ana Maria Martins, Ekaterini Goudouris, Marcia Ribeiro, José Francisco Da Silva Franco, Leandra Queiroz, Dirceu Solé
P99 Management of insulin allergy with continuous subcutaneous insulin infusion
Ceyda Tunakan Dalgiç, Aytül Zerrin Sin, Fatma Düsünür Günsen, Gökten Bulut, Fatma Ömür Ardeniz, Okan Gülbahar, Emine Nihal Mete Gökmen, Ali Kokuludag
P100 Off-label use of icatibant for management of serious angioedema associated with angiotensin inhibitors
Ana M. Montoro De Francisco, Talía Mª De Vicente Jiménez, Adriana M. Mendoza Parra, Angella M. Burgos Pimentel, Amelia García Luque
P101 Thiocolchicoside anaphylaxis: an unusual suspect?
Luis Amaral, Fabricia Carolino, Leonor Carneiro Leão, Eunice Castro, Josefina Cernadas
Poster walk 12: betalactam hypersensitivity (P102–P111)
P102 A curious delayed reading: a case report of a β-lactam allergy in a child
Nicole Pinto, Joana Belo, João Marques, Pedro Carreiro-Martins, Paula Leiria-Pinto
P103 Betalactam-induced hypersensitivity: a 10-years’ experience
Amel Chaabane, Haifa Ben Romdhane, Nadia Ben Fredj, Zohra Chadly, Naceur A. Boughattas, Karim Aouam
P104 Cefazolin hypersensitivity: towards optimized diagnosis
Astrid P. Uyttebroek, Chris H. Bridts, Antonino Romano, Didier G. Ebo, Vito Sabato
P105 Clavulanic acid allergy: two cases report
Anabela Lopes, Joana Cosme, Rita Aguiar, Tatiana Lourenço, Maria-João Paes, Amélia Spínola-Santos, Manuel Pereira-Barbosa
P106 Diagnosis of betalactam allergy in an allergy department
Cíntia Rito Cruz, Rute Pereira Dos Reis, Elza Tomaz, Ana Paula Pires, Filipe Inácio
P107 Diagnostic work-up of 410 patients with suspicion of betalactam antibiotic hypersensitivity
Filipe Benito-Garcia, Inês Mota, Magna Correia, Ângela Gaspar, Marta Chambel, Susana Piedade, Mário Morais-Almeida
P108 Immediate selective hypersensitivity reactions to clavulanic acid
Alla Nakonechna, Yurij Antipkin, Tetiana Umanets, Fernando Pineda, Francisca Arribas, Volodymyr Lapshyn
P109 Prevalence and incidence of penicillin hypersensitivity reactions in Colombia
Pablo Andrés Miranda, Bautista De La Cruz Hoyos
P110 Selective sensitization to amoxicilin and clavulanic acid
Jose Julio Laguna Martinez, Aranzazu Jimenez Blanco, Javier Dionicio Elera, Cosmin Boteanu, Rosario Gonzalez-Mendiola, Marta Del Pozo
P111 Infliximab-specific T cells are detectable also in treated patients who have not developed anti-drug antibodies
Alessandra Vultaggio, Francesca Nencini, Sara Pratesi, Andrea Matucci, Enrico Maggi
Poster walk 13: biologicals, local anesthetics, others (P112–P118)
P112 A case report of allergic immediate systemic reaction to adalimumab and certolizumab
Ceyda Tunakan Dalgiç, Fatma Düsünür Günsen, Gökten Bulut, Fatma Ömür Ardeniz, Okan Gülbahar, Emine Nihal Mete Gökmen, Aytül Zerrin Sin, Ali Kokuludag
P113 Allergy to local anesthetics: negative predictive value of skin tests
Ivana Cegec, Danica Juricic Nahal, Viktorija Erdeljic Turk, Matea Radacic Aumiler, Ksenija Makar Ausperger, Iva Kraljickovic, Iveta Simic
P114 Cutaneous adverse reactions of molecular targeted agents: a retrospective analysis in 150 patients in our department
Yukie Yamaguchi, Tomoya Watanabe, Megumi Satoh, Tomohiko Tanegashima, Kayoko Oda, Hidefumi Wada, Michiko Aihara
P115 Generalized paralysis induced by local lidocaine injection
Jaechun Jason Lee, Jay Chol Choi, Hwa Young Lee
P116 Hypersensitivity to local anaesthetics: a 10 year review
Rosa-Anita Rodrigues Fernandes, Emília Faria, Joana Pita, Nuno Sousa, Carmelita Ribeiro, Isabel Carrapatoso, Ana Todo Bom
P117 Local anaesthetics: a rare culprit in hypersensitivity reactions
Ana Rodolfo, Eunice Dias-Castro, Josefina Cernadas
P118 Stevens–Johnson syndrome in clinical practice: a variant of clinical course
Marina Voronova
Poster walk 14: RCM (P119–P128)
P119 13 cases of severe anaphylactic reactions due to radiocontrast media
Jaume Martí Garrido, Ramon Lopez Salgueiro, Diana Kury Valle, Verónica Pacheco Coronel, Carolina Perales Chordá, Dolores Hernandez Fernandez De Rojas
P120 Anaphylactic shock after administration of iodinated contrast medium during cardiac catheterization
Roselle Catherine Yu Madamba, Marta Ferrer, Maria Jose Goikoetxea, Carmen D’Amelio, Amalia Bernad, Olga Vega, Gabriel Gastaminza
P121 Anaphylactic shock and cardiac arrest induced by gadolinium-based contrast agents
Beatriz Pola Bibián, Marina Lluncor Salazar, Gemma Vilà Nadal, Ana María Fiandor Roman, Javier Dominguez Ortega, Miguel Gonzalez Muñoz, Santiago Quirce Gancedo, Maria Rosario Cabañas Moreno
P122 Anaphylaxis to gadobenate and cross-reactivity to other gadolinium-based contrast agents in two patients
Kathrin Scherer Hofmeier
P123 Anaphylaxis to glatiramer acetate in a patient with multiple sclerosis
Fabrícia Carolino, Vladyslava Barzylovych, Josefina R. Cernadas
P124 Delayed hypersensitivity reaction to radiocontrast media
Fabrícia Carolino, Diana Silva, Leonor Leão, Josefina R. Cernadas
P125 Drug reaction with eosinophilia and systemic symptoms induced by iodixanol
Gemma Vilà-Nadal, Beatriz Pola, Marina Lluncor, Ana Fiandor, Teresa Bellón, Javier Domínguez, Santiago Quirce
P126 Electronic consultation support system for radiocontrast media hypersensitivity changes clinician’s behavior
Min-Suk Yang, Sun-Sin Kim, Sae-Hoon Kim, Hye-Ryun Kang, Heung-Woo Park, Sang-Heon Cho, Kyung-Up Min, Yoon-Seok Chang
P127 Hypersensitivity reactions to iodinated contrast media: skin testing and follow-up
Danica Juricic Nahal, Ivana Cegec, Viktorija Erdeljic Turk, Iva Kraljickovic, Matea Radacic Aumiler, Ksenija Makar Ausperger, Iveta Simic
P128 Would iodine allergy exist?
Clémence Delahaye, Jenny Flabbee, Julie Waton, Olivia Bauvin, Annick Barbaud
Poster walk 15: MPE/type 4 (P129–P137)
P129 Delayed hypersensitivity cutaneous reactions: a case/control study from a tunisian database
Karim Aouam, Najah Ben Fadhel, Zohra Chadly, Nadia Ben Fredj, Naceur A. Boughattas, Amel Chaabane
P130 Delayed hypersensitivity reactions to cephalosporins: a review of seven cases
Joana Cosme, Anabela Lopes, Amélia Spínola-Santos, Manuel Pereira-Barbosa
P131 Diclofenac induced allergic contact dermatitis: case series of four patients
Sandra Jerkovic Gulin, Anca Chiriac
P132 Late-onset maculopapular rash to irbesartan
Bárbara Kong Cardoso, Elza Tomaz, Regina Viseu, Filipe Inácio
P133 Nonimmediate hypersensitivity reactions to betalactams: a retrospective analysis
Ana Moreira, Susana Cadinha, Ana Castro Neves, Patricia Barreira, Daniela Malheiro, J. P. Moreira Da Silva
P134 Occupational airborne contact dermatitis to omeprazole
Ružica Jurakic-Toncic, Suzana Ljubojevic, Petra Turcic
P135 Ornidazole-induced fixed drug eruption confirmed by positive patch test on a residual pigmented lesion
Liesbeth Gilissen, Sara Huygens, An Goossens
P136 Repeated delayed reaction induced by amoxicillin and amoxicillin clavulanate
Inmaculada Andreu, Ramon Lopez-Salgueiro, Alicia Martinez Romero, Pau Gomez Cabezas
P137 Systemic photosensitivity from fenofibrate in a patient photo-sensitized to ketoprofen
Liesbeth Gilissen, An Goossens
Poster walk 16: HLA genetics (P138–P146)
P138 A copy number variation in ALOX5 and PTGER1 is associated with nonsteroidal anti-inflammatory drugs induced urticaria and/or angioedema
Pedro Ayuso Parejo, Maria Del Carmen Plaza-Serón, Inmaculada Doña, Natalia Blanca López, Carlos Flores, Luisa Galindo, Ana Molina, James Richard Perkins, Jose Antonio Cornejo-García, José Augusto García-Agúndez, Elena García-Martín, Paloma Campo, María Gabriela Canto, Miguel Blanca
P139 Association of galectin-3 (LGALS3) single nucleotide polymorphisms with non-steroidal anti-inflammatory drugs-induced urticaria/angioedema
José Antonio Cornejo-Garcia, Inmaculada Doña, Rosa María Guéant-Rodríguez, Natalia Blanca-López, María Carmen Plaza-Serón, Raquel Jurado-Escobar, Esther Barrionuevo, María Salas, María Luisa Galindo, Gabriela Canto, Miguel Blanca, Jean-Louis Guéant
P140 Detection of T cell responses to ticlopidine using peripheral blood mononuclear cells from HLA-A*33:03+ healthy donors
Toru Usui, Arun Tailor, Lee Faulkner, John Farrell, Ana Alfirevic, B. Kevin Park, Dean J. Naisbitt
P141 Epistasis approaches to identify novel genes potentially involved in NSAIDs hypersensitivity
James Richard Perkins, Jose Antonio Cornejo García, Oswaldo Trelles, Inmaculada Doña, Esther Barrionuevo, María Salas, María Auxiliadora Guerrero, Miguel Blanca, Alex Upton
P142 Genetic predisposition of cold medicine related SJS/TEN with severe ocular complications
Mayumi Ueta, Hiromi Sawai, Chie Sotozono, Katushi Tokunaga, Shigeru Kinoshita
P143 HLA-B*13:01 and dapsone induced hypersensitivity in Thai population
Chonlaphat Chonlaphat Sukasem, Patompong Satapornpong, Therdpong Tempark, Pawinee Rerknimitr, Kulprapat Pairayayutakul, Jettanong Klaewsongkram
P144 HLA-B*15:02 alleles and lamotrigine-induced cutaneous adverse drug reactions in Thai
Chonlaphat Sukasem, N. Koomdee, T. Jantararoungtong, S. Santon, A. Puangpetch, U. Intusoma, W. Tassaneeyakul, V. Theeramoke
P145 HLA-B*38:01 and HLA-A*24:02 allele frequencies in Spanish patients with lamotrigine-induced SCARs
Teresa Bellón, Elena Ramirez, Alberto Manuel Borobia, Hoi Tong, Jose Luis Castañer, Francisco José De Abajo
P146 Overrepresentation of a class II HLA haplotype in severe hypersensitivity type I reactions to carboplatin
Violeta Régnier Galvao, Rebecca Pavlos, Elizabeth Mckinnon, Kristina Williams, Alicia Beeghly-Fadiel, Alec Redwood, Elizabeth Phillips, Mariana Castells
Poster walk 17: in vivo diagnosis + sIgE (P147–P154)
P147 Absence of specific Ig-e against beta-lactams 9 months after an allergic reaction to amoxicillin-clavulanic acid
Elisa Boni, Marina Russello, Marina Mauro
P148 Drug provocation tests in suspected opioid allergy
Kok Loong Ue, Krzysztof Rutkowski
P149 Improvement to the specific IgE cut-off in the assess of β-lactamic allergy
Victor Soriano Gomis, Jorge Frances Ferre, Angel Esteban Rodriguez, Vicente Cantó Reig, Javier Fernandez Sanchez
P150 Initial false negative specific IgE to gelatin in a patient with gelatin-induced anaphylaxis
Christine Breynaert, Erna Van Hoeyveld, Rik Schrijvers
P151 Inmediate reactions to beta-lactam antibiotics: pattern of skin test response over the time
Jose Julio Laguna Martinez, Rosario Gonzalez Mendiola, Javier Dionicio Elera, Cosmin Boteanu, Aranzazu Jimenez Blanco, Marta Del Pozo, Raquel Fuentes Irigoyen
P152 New fluorescent dendrimeric antigens for the evaluation of dendritic cell maturation as a test to detect allergy reactions to amoxicillin
Daniel Collado, Yolanda Vida, Francisco Najera, Ezequiel Perez-Inestrosa, Pablo Mesa-Antunez, Cristobalina Mayorga, María José Torres, Miguel Blanca
P153 Positive skin test or positive specific IgE to penicillin does not predict penicillin allergy
Line K. Tannert, Charlotte G. Mortz, Per Stahl Skov, Carsten Bindslev-Jensen
P154 Significance of skin testing and in vitro-analysis of neuromuscular blocking agents in diagnosis of perioperative drug hypersensitivity: evaluation of a negative control population
Wolfgang Pfützner, Hannah Dörnbach, Johanna Visse, Michele Rauber, Christian Möbs
Poster walk 18: in vitro/ex vivo (P155–P158, P160–P164)
P155 Diagnostic value of the lymphocyte toxicity assay (LTA) and the in vitro platelet toxicity assay (IPTA) for β-lactam allergy
Abdelbaset A. Elzagallaai, Lindsey Chow, Awatif M. Abuzgaia, Michael J. Rieder
P156 Enzyme linked immunospot assay used in the diagnosis of severe cutaneous adverse reactions to antimicrobials
Alec Redwood, Jason Trubiano, Rebecca Pavlos, Emily Woolnough, Kaija Stautins, Christina Cheng, Elizabeth Phillips
P157 Evaluation of in vitro diagnostic methods for identifying the culprit drugs in drug hypersensitivity
Kenichi Kato, Hiroaki Azukizawa, Takaaki Hanafusa, Ichiro Katayama
P158 Ex-vivo expanded skin-infiltrating T cells from severe drug eruptions are reactive with causative drugs: a possible novel method for determination of causative drugs
Toshiharu Fujiyama, Hideo Hashizume, Takatsune Umayahara, Taisuke Ito, Yoshiki Tokura
P160 In vitro release of IL-2, IL-5 and IL-13 in diagnosis of patients with delayed-type nickel hypersensitivity
Mira Silar, Mihaela Zidarn, Helena Rupnik, Peter Korosec
P161 Single cell analysis of drug responsive T cells; identification of candidate drug reactive T cell receptors in abacavir and carbamazepine hypersensitivity
Alec James Redwood, Kaija Strautins, Katie White, Abha Chopra, Katherine Konvinse, Shay Leary, Rebecca Pavlos, Simon Mallal, Elizabeth Phillips
P162 Specificity and sensitivity of LTT in DRESS: analysis of agreement with the Spanish pharmacovigilance system probability algorithm
Rosario Cabañas, Elena Ramirez, Ana María Fiandor, Teresa Bellón
P163 The role of interleukin-22 in β-lactam hypersensitivity
Andrew Sullivan, Paul Whitaker, Daniel Peckham, B. Kevin Park, Dean J. Naisbitt
P164 Vancomycin-specific T cell responses and teicoplanin cross-reactivity
Wei Yann Haw, Marta E. Polak, Carolann Mcguire, Michael R. Ardern-Jones
Poster walk 19: BAT and biomarkers (P165–P173)
P165 A combination of early biomarkers useful for the prediction of severe ADRs
Yumi Aoyama, Tetsuo Shiohara
P166 Basophil activation test in the diagnostic approach of reactions during general anaesthesia
Ana Moreira, Susana Cadinha, Patrícia Barreira, Ana Castro Neves, Daniela Malheiro, Sara Correia, J. P. Moreira Da Silva
P167 IL-10 can be related to successful desensitization
Asli Gelincik, Semra Demir, Fatma Sen, Hamza Ugur Bozbey, Muge Olgac, Derya Unal, Raif Coskun, Bahauddin Colakoglu, Suna Buyuozturk, Esin Çatin-Aktas, Gunnur Deniz
P168 Immediate reactions to proton pump inhibitors: value of basophil activation test
Maria Salas, Jose Julio Laguna, Esther Barrionuevo, J. Dionicio, Tahia Fernandez, R. Gonzalez-Mendiola, I. Olazabal, Maria Dolores Ruiz, Miguel Blanca, Cristobalina Mayorga, Maria José Torres
P169 Improvement of the elevated tryptase criterion to discriminate IgE from non-IgE mediated allergic reactions
Gabriel Gastaminza, Alberto Lafuente, Carmen D’Amelio, Amalia Bernad, Olga Vega, Roselle Catherine Madamba, M. Jose Goikoetxea, Marta Ferrer, Jorge Núñez
P170 Low expression of Tim-3 could serve as a biomarker for control and diagnose maculopapular exanthema induced by drugs
Tahia Diana Fernández, Inmaculada Doña, Francisca Palomares, Rubén Fernández, Maria Salas, Esther Barrionuevo, Maria Isabel Sanchez, Miguel Blanca, Maria José Torres, Cristobalina Mayorga
P171 Role of basophil activation test using two different activation markers for the diagnosis of allergy to fluoroquinolones
Esther Barrionuevo, Tahía Fernandez, Arturo Ruiz, Adriana Ariza, Maria Salas, Inmaculada Doña, Ana Molina, Miguel Blanca, Maria Jose Torres, Cristobalina Mayorga
P172 The importance of basophil activation test in anaphylaxis due to celecoxib
Amalia Bernad Alonso, Carmen D’Amelio Garófalo, Olga Vega Matute, Marta Ferrer Puga, María José Goikoetxea Lapresa, Roselle Catherine Yu Madamba, Gabriel Gastaminza Lasarte
P173 The role of basophil activation test in the diagnosis of immediate type drug hypersensitivity to betalactam antibiotics
Antonia Thinnes, Hans F. Merk, Jens Malte Baron, Martin Leverkus, Galina Balakirski
Poster walk 20: TCR recognition, cellular (P174–P183)
P174 Characterisation of the effect of co-inhibitory signalling on the activation of drug-derived antigen-specific T-cells
Andrew Gibson, Monday Ogese, Lee Faulkner, B. Kevin Park, Dean J. Naisbitt
P175 Characterization of drug hapten-specific T cell responses in piperacillin hypersensitive patients
Zaid Al-Attar, Fiazia Yaseen, Xiaoli Meng, Rozalind Jenkins, Paul Whitaker, Daniel Peckham, Lee Faulkner, John Farrel, Kevin Park, Dean Naisbitt
P176 Characterization of the response of T-cells to telaprevir and its metabolite in normal volunteers
Zaid Al-Attar, Khetam Alhilali, Yanni Xue, John Farrell, Lee Faulkner, Kevin Park, Dean Naisbitt
P177 Characterization of the T cell receptor signatures of drug-responsive T cells
Patricia Illing, Nicole Mifsud, Heidi Fettke, Jeffrey Lai, Rebecca Ho, Patrick Kwan, Anthony Purcell
P178 Defining the signals between hepatocytes and immune cells in idiosyncratic drug-induced liver injury (DILI)
Monday O. Ogese, Lee Faulkner, B. Kevin Park, Catherine Betts, Dean J. Naisbitt
P179 Development of novel chemicals that do not bind to HLA-B*57:01 or activate CD8 + T-cells through modification of the 6-amino cyclopropyl group of abacavir
Paul Thomson, John Farrell, Mohammad Alhaidari, Neill Berry, Paul M. O’Neill, B. Kevin Park, Dean J. Naisbitt
P180 Generation and characterization of dapsone- and nitroso-dapsone-specific T-cell clones using lymphocytes from healthy volunteers
Abdulaziz Alzahrani, Monday O. Ogese, John Farrell, Lee Faulkner, Andrew Gibson, Arun Tailor, B. Kevin Park, Dean J. Naisbitt
P181 Identification of benzylpenicillin-hapten peptides responsible for naïve T-cell activation and immunization of allergic patients to penicillin
Marie Eliane Azoury, Lucia Fili, Rami Bechara, Noémie Scornet, Cathy Nhim, Richard Weaver, Nancy Claude, Delphine Joseph, Bernard Maillere, Paola Parronchi, Marc Pallardy
P182 Massive expansion of clonotypic and polycytotoxic CD8+ T cells in toxic epidermal necrolysis
Axel Patrice Villani, Aurore Rozières, Benoît Bensaïd, Mathilde Tardieu, Floriane Albert, Virginie Mutez, Tugba Baysal, Marc Pallardy, Janet Maryanski, Jean-François Nicolas, Osami Kanagawa, Marc Vocanson
P183 Pharmaco-immunological synapse of HLA-drug-TCR in SCAR
Shuen-Iu Hung
Poster walk 21: new in vitro methods, haptens, etc. (P184–P194)
P184 Amoxicillin-clavulanate forms distinct multiple haptenic structures on human serum albumin in patients
Xiaoli Meng, Arun Tailor, Caroline J. Harrison, Rosalind E. Jenkins, Paul Whitaker, Neil S. French, Dean J. Naisbitt, B. Kevin Park
P185 Dendrimeric antigens for studying the influence of penicillin determinants orientation on IgE recognition
Maria Isabel Montañez, Cristobalina Mayorga, Francisco Najera, Adriana Ariza, Tahia D. Fernandez, Maria Salas, Angela Martin-Serrano, Miguel Blanca, Ezequiel Perez-Inestrosa, Maria Jose Torres
P186 Dendrimeric antigens on solid supports: designed materials for IgE quantification
Yolanda Vida, Maria Isabel Montañez, Noemi Molina, Daniel Collado, Francisco Najera, Adriana Ariza, Maria Jose Torres, Cristobalina Mayorga, Ezequiel Perez-Inestrosa
P187 Development of a screening assay for drug hypersensitivity using naïve T cells from donors with seven different HLA class I risk alleles
Lee Faulkner, Sally Wood, Ana Alfirevic, Munir Pirmohamed, Dean J. Naisbitt, B. Kevin Park
P188 Different patterns of recognition of structures derived from amoxicillin by IgE antibodies from patients with immediate hypersensitivity reactions to betalactams
Adriana Ariza, Cristobalina Mayorga, María Isabel Montañez, María Salas, Inmaculada Doña, Ángela Martín-Serrano, Ezequiel Pérez-Inestrosa, Dolores Pérez-Sala, Miguel Blanca, Antonio E. Guzmán, María José Torres
P189 High-resolution typing of HLA polymorphism and T-cell receptor repertoire for severe adverse drug reactions based on the cost-effective next-generation sequencing approaches
Tai-Ming Ko, Yuan-Tsong Chen, Jer-Yuarn Wu
P190 Identification and fate of intracellular proteins haptenated by amoxicillin
Francisco J. Sánchez-Gómez, Juan M. González-Morena, Yolanda Vida, Ezequiel Pérez-Inestrosa, Miguel Blanca, María J. Torres, Dolores Pérez-Sala
P191 In vitro detection of terbinafine protein adducts
Arun Tailor, Toru Usui, Yanni Xue, Xiaoli Meng, Dean J. Naisbitt, B. Kevin Park
P192 MicroRNAs dysregulation in PBMCs from drug hypersensitivity patients during drug challenge in vitro
Alejandra Monroy Arreola, Jesus Agustin Badillo Corona, Silvia Mendez Flores, Judith Dominguez Cherit, Dean J. Naisbitt, Noe Valentin Duran Figueroa, Jose Luis Castrejon Flores
P193 NSAIDs-exacerbated cutaneous disease: high throughput gene expression profiling
José Antonio Cornejo-García, James Perkins, Natalia Blanca-López, Diana Pérez-Alzate, Raquel Jurado-Escobar, Inmaculada Doña, Gador Bogas, María J. Torres, Gabriela Canto, Miguel Blanca
P194 Utility of skin tests in non-immediate reactions to amoxicillin
Luis Mario Tubella Marti, Fernando Pineda De La Losa, Francisca Arribas Poves, Jaime Tubella Lopez, Teodora Lopez Santiago
doi:10.1186/s13601-016-0122-y
PMCID: PMC5009521
18.  Genetic and Environmental Determinants of Bitter Perception and Sweet Preferences 
Pediatrics  2005;115(2):e216-e222.
Objective
Flavor is the primary dimension by which young children determine food acceptance. However, children are not merely miniature adults because sensory systems mature postnatally and their responses to certain tastes differ markedly from adults. Among these differences are heightened preferences for sweet-tasting and greater rejection of bitter-tasting foods. The present study tests the hypothesis that genetic variations in the newly discovered TAS2R38 taste gene as well as cultural differences are associated with differences in sensitivity to the bitter taste of propylthiouracil (PROP) and preferences for sucrose and sweet-tasting foods and beverages in children and adults.
Design
Genomic DNA was extracted from cheek cells of a racially and ethnically diverse sample of 143 children and their mothers. Alleles of the gene TAS2R38 were genotyped. Participants were grouped by the first variant site, denoted A49P, because the allele predicts a change from the amino acid alanine (A) to proline (P) at position 49. Henceforth, individuals who were homozygous for the bitter-insensitive allele are referred to as AA, those who were heterozygous for the bitter-insensitive allele are referred to as AP, and those who were homozygous for the bitter-sensitive allele are referred to as PP. Using identical procedures for children and mothers, PROP sensitivity and sucrose preferences were assessed by using forced-choice procedures that were embedded in the context of games that minimized the impact of language development and were sensitive to the cognitive limitations of pediatric populations. Participants were also asked about their preferences in cereals and beverages, and mothers completed a standardized questionnaire that measured various dimensions of their children’s temperament.
Results
Genetic variation of the A49P allele influenced bitter perception in children and adults. However, the phenotype-genotype relationship was modified by age such that 64% of heterozygous children, but only 43% of the heterozygous mothers, were sensitive to the lowest concentration (56 micromoles/liter) of PROP. Genotypes at the TAS2R38 locus were significantly related to preferences for sucrose and for sweet-tasting beverages and foods such as cereals in children. AP and PP children preferred significantly higher concentrations of sucrose solutions than did AA children. They were also significantly less likely to include milk or water as 1 of their 2 favorite beverages (18.6% vs 40%) and were more likely to include carbonated beverages as 1 of their most preferred beverages (46.4% vs 28.9%). PP children liked cereals and beverages with a significantly higher sugar content. There were also significant main effects of race/ ethnicity on preferences and food habits. As a group, black children liked cereals with a significantly higher sugar content than did white children, and they were also significantly more likely to report that they added sugar to their cereals.
Unlike children, there was no correspondence between TAS2R38 genotypes and sweet preference in adults. Here, the effects of race/ethnicity were the strongest determinants, thus suggesting that cultural forces and experience may override this genotype effect on sweet preferences. Differences in taste experiences also affected mother–child interaction, especially when the 2 resided in different sensory worlds. That is, children who had 1 or 2 bitter-sensitive alleles, but whose mothers had none, were perceived by their mothers as being more emotional than children who had no bitter-sensitive alleles.
Conclusion
Variations in a taste receptor gene accounted for a major portion of individual differences in PROP bitterness perception in both children and adults, as well as a portion of individual differences in preferences for sweet flavors in children but not in adults. These findings underscore the advantages of studying genotype effects on behavioral outcomes in children, especially as they relate to taste preferences because cultural forces may sometimes override the A49P genotypic effects in adults. New knowledge about the molecular basis of food likes and dislikes in children, a generation that will struggle with obesity and diabetes, may suggest strategies to overcome diet-induced diseases.
doi:10.1542/peds.2004-1582
PMCID: PMC1397914  PMID: 15687429
children; genetic predisposition; racial differences; taste; temperament; PTC, phenylthiocarbamide; PROP, propylthiouracil
19.  Role of Exposure Analysis in Solving the Mystery of Balkan Endemic Nephropathy 
Croatian medical journal  2007;48(3):300-311.
We evaluated the role of exposure analysis in assessing whether ochratoxin A aristolochic acid are the agents responsible for causing Balkan endemic nephropathy. We constructed a framework for exposure analysis using the lessons learned from the study of endemic goiter within the context of an accepted general model. We used this framework to develop an exposure analysis model for Balkan endemic nephropathy, evaluated previous findings from the literature on ochratoxin A and aristolochic acid in the context of this model, discussed the strength of evidence for each, and proposed approaches to address critical outstanding questions. The pathway for exposure to ochratoxin A is well defined and there is evidence that humans have ingested ochratoxin A. Factors causing differential exposure to ochratoxin A and how ochratoxin A is implicated in Balkan endemic nephropathy are not defined. Although there is evidence of human exposure to aristolochic acid and that its effects are consistent with Balkan endemic nephropathy, a pathway for exposure to aristolochic acid has been suggested but not demonstrated. Factors causing differential exposure to aristolochic acid are not known. Exposure analysis results suggest that neither ochratoxin A nor aristolochic acid can be firmly linked to Balkan endemic nephropathy. However, this approach suggests future research directions that could provide critical evidence on exposure, which when linked with findings from the health sciences, may be able to demonstrate the cause of this disease and provide a basis for effective public health intervention strategies. One of the key unknowns for both agents is how differential exposure can occur.
PMCID: PMC2080532  PMID: 17589972
20.  CatM Regulation of the benABCDE Operon: Functional Divergence of Two LysR-Type Paralogs in Acinetobacter baylyi ADP1 
Two LysR-type transcriptional regulators, BenM and CatM, control benzoate consumption by the soil bacterium Acinetobacter baylyi ADP1. These homologs play overlapping roles in the expression of multiple genes. This study focuses on the benABCDE operon, which initiates benzoate catabolism. At this locus, BenM and CatM each activate transcription in response to the catabolite cis,cis-muconate. BenM, but not CatM, additionally responds to benzoate as an effector. Regulation by CatM alone is insufficient for growth on benzoate as the sole carbon source. However, three point mutations independently increased CatM-activated benA transcription and enabled growth on benzoate without BenM. Two mutations generate variants with one amino acid change in the 303-residue CatM, CatM(V158M) and CatM(R156H). These substitutions affected regulation of benA differently than that of catB, another CatM-regulated gene involved in benzoate catabolism. In relation to CatM, CatM(V158M) increased cis,cis-muconate-dependent transcription of benA but decreased that of catB. CatM(R156H) increased effector-independent expression of catB compared to CatM. In contrast, cis,cis-muconate was required with CatM(R156H) to activate unusually high benA expression. Thus, induction by cis,cis-muconate depends on both the sequence of CatM and the promoter. A point mutation at position −40 of the benA promoter enhanced CatM-activated gene expression and altered regulation by CatM(R156H). BenM and CatM bound to the same locations on ben region DNA. The frequency with which spontaneous mutations allow CatM to substitute for BenM might predict that one regulator would be sufficient for controlling benzoate consumption. This prediction is discussed in light of current and previous studies of the BenM-CatM regulon.
doi:10.1128/AEM.72.3.1749-1758.2006
PMCID: PMC1393229  PMID: 16517618
21.  Comparative 1H NMR Metabolomic Urinalysis of People Diagnosed with Balkan Endemic Nephropathy, and Healthy Subjects, in Romania and Bulgaria: A Pilot Study  
Toxins  2011;3(7):815-833.
1H NMR spectroscopy of urine has been applied to exploring metabolomic differences between people diagnosed with Balkan endemic nephropathy (BEN), and treated by haemodialysis, and those without overt renal disease in Romania and Bulgaria. Convenience sampling was made from patients receiving haemodialysis in hospital and healthy controls in their village. Principal component analysis clustered healthy controls from both countries together. Bulgarian BEN patients clustered separately from controls, though in the same space. However, Romanian BEN patients not only also clustered away from controls but also clustered separately from the BEN patients in Bulgaria. Notably, the urinary metabolomic data of two people sampled as Romanian controls clustered within the Romanian BEN group. One of these had been suspected of incipient symptoms of BEN at the time of selection as a ‘healthy’ control. This implies, at first sight, that metabolomic analysis can be predictive of impending morbidity before conventional criteria can diagnose BEN. Separate clustering of BEN patients from Romania and Bulgaria could indicate difference in aetiology of this particular silent renal atrophy in different geographic foci across the Balkans.
doi:10.3390/toxins3070815
PMCID: PMC3202861  PMID: 22069742
Balkan nephropathy;  metabolomics;  urinalysis;  haemodialysis;  ochratoxin A;  aristolochic acid
22.  Angiogenesis in upper tract urothelial carcinoma associated with Balkan endemic nephropathy 
Upper tract urothelial carcinoma (UTUC) associated with Balkan endemic nephropathy (BEN) is characterized by a number of aberrations in cell-cycle regulation and apoptosis. The aim of this study was to detect angiogenesis-related marker(s) specific for BEN UTUC, and to examine the influence of HIF 1α upon angiogenesis and apoptosis in UTUC. Present investigation included 110 patients with UTUC, 50 from BEN region and 60 control tumors. Altered expression of VEGFR1 was more often present in control UTUC than in BEN tumors (p<0.005). It was associated with high grade, low and high stage, solid growth, and metaplastic change of control UTUC. Microvessel density assessed by CD31 (MVD CD31) was significantly higher in UTUC with lymphovascular invasion (p<0.05), and in BEN tumors with papillary growth (p<0.05). Discriminant analysis indicated that BEN and control tumors do not differ significantly in expression of angiogenesis related markers. The most important discriminant variable that determined control UTUC was expression of VEGFR1 (p=0.002). HIF 1α in UTUC significantly correlated with the low stage, papillary growth and expression of Bcl-2, Caspase-3 index, and MVD CD34 (p<0.001; 0.0005; 0.01; 0.005; 0.01, respectively). HIF-1α may be helpful marker in evaluation of UTUC, especially when combined with angiogenesis and apoptosis.
PMCID: PMC3438770  PMID: 22977664
Balkan endemic nephropathy; upper tract urothelial carcinoma; angiogenesis; VEGF; VEGFR1; VEGFR2; CD31; CD34; HIF 1α; apoptosis
23.  Offspring of parents with Balkan Endemic Nephropathy have higher C-reactive protein levels suggestive of inflammatory processes: a longitudinal study 
BMC Nephrology  2009;10:10.
Background
Despite the characteristic extensive tubulointerstitial fibrosis, Balkan Endemic Nephropathy (BEN) is usually considered a non-inflammatory disease.
Methods
We examined a marker of inflammation, C-reactive protein (CRP), in the offspring of patients with BEN, a population at risk for BEN, prior to development of established disease to determine if an inflammatory process could be identified in the early stages of the disease. In 2003/04, 102 adult offspring whose parents had BEN and a control group of 99 adult offspring of non-BEN patients were enrolled in this prospective study. This cohort was re-examined yearly for four consecutive years. Levels of serum CRP were measured in years 3 and 4 and compared between groups. The data were analyzed with mixed models.
Results
Compared to controls, offspring of BEN parents had statistically higher CRP levels in two consecutive years, suggestive of early inflammatory reactivity. Whenever the mother was affected by BEN (both parents, or mother only), serum CRP was significantly increased, but not if only the father had BEN. CRP was inversely related to kidney cortex width but not to markers or renal function.
Conclusion
Early stages of BEN may involve inflammatory processes. The observation of a maternal involvement supports the concept of fetal programming, which has been implicated in the pathogenesis of other chronic kidney diseases.
doi:10.1186/1471-2369-10-10
PMCID: PMC2681460  PMID: 19400955
24.  Limitations and plausibility of the Pliocene lignite hypothesis in explaining the etiology of Balkan endemic nephropathy 
Background:
Balkan endemic nephropathy (BEN) is a chronic, tubulointerstitial renal disease often accompanied by urothelial cancer that has a lethality of nearly 100%.
Introduction:
One of the many factors that have been proposed to play an etiological role in BEN is exposure to organic compounds from Pliocene lignite coal deposits via the drinking water in endemic areas.
Objectives:
The objective of this study was to systematically evaluate the role of the tenets of the Pliocene lignite hypothesis in the etiology of BEN in order to provide an improved understanding of the hypothesis for colleagues and patients alike.
Methods:
A comprehensive compilation of the possible limitations of the hypothesis, with each limitation addressed in turn is presented.
Results:
The Pliocene lignite hypothesis can best account for, is consistent with, or has the potential to explain the evidence associated with the myriad of factors related to BEN.
Conclusions:
Residents of endemic areas are exposed to complex mixtures containing hundreds of organic compounds at varying doses and their potentially more toxic (including nephrotoxic) and/or carcinogenic metabolites; however, a multifactorial etiology of BEN appears most likely.
doi:10.1179/2049396713Y.0000000046
PMCID: PMC4137802  PMID: 24075451
BEN; Coal; Drinking water; Environmental medicine; Geochemistry; Human health; Medical geology; Organic compounds
25.  p53 mutations as fingerprints for aristolochic acid - an environmental carcinogen in endemic (Balkan) nephropathy 
Mutation research  2009;663(1-2):1-6.
The activation of protooncogenes and inactivation of tumor suppressor genes are considered to be the main molecular events in the multistep process of carcinogenesis. Mutations of the TP53 tumor suppressor gene have been found in nearly all tumor types and are estimated to contribute to more than 50% of all cancers. Most mutations lead to the synthesis of highly stable, inactive proteins that accumulate in the nucleus of cancer cells. Among the 393 codons of the human p53 gene, 222 are targets of 698 different types of mutations. Alterations of codons 175, 248, 273 and 282 correspond to 19 % of all mutations and are considered general hot spot mutations. Dietary exposure to aristolochic acid (AA), an established nephrotoxin and human carcinogen found in all Aristolochia species was shown to be the causative agent of aristolochic acid nephropathy (previously called Chinese herbs nephropathy). This syndrome is characterized by proximal tubular damage, renal interstitial fibrosis, slow progression to the end stage renal disease and a high prevalence of upper urinary tract urothelial carcinoma (otherwise a highly unusual location). AA preferentially binds to purines in DNA and is associated with a high frequency of A → T transversions in the p53 gene. Rats treated with AA develop A:T → T:A mutations in codon 61. The pathological and clinical features of endemic (Balkan) nephropathy closely resemble those associated with aristolochic acid nephropathy except for the slower progression to end stage renal disease and longer cumulative period before the appearance of urothelial cancer. Recently, we reported the presence of AA-DNA adducts in renal cortex and A → T p53 mutations in tumor tissue of patients from Croatia and Bosnia with endemic nephropathy. These data support the hypothesis that dietary exposure to AA is a major risk factor for endemic (Balkan) nephropathy.
doi:10.1016/j.mrfmmm.2009.01.005
PMCID: PMC2729401  PMID: 19428366
environmental carcinogen; aristolochic acid; p53 mutations; DNA adducts; endemic nephropathy; aristolochic acid nephropathy

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