Health and environmental factors

Objective:
Due to increasing worldwide prevalence of patients with renal failure of unknown origin, putting a huge pressure on the medical insurance coverage systems in many countries, another research mission to be pursued at the OncoGen Centre is study of the etiology of chronic kidney disease (BEN) in relation with various environmental factors.

a) Optimizing the prevention methods for the improvement of allergic patient management efficiency, program PNII- Partnerships, 41-011/2007, 2007-2010

Short description:
The PREVALERG national project lasted between 2007 and 2010, and its activities included a multidisciplinary approach: (1) airborne pollen analysis was performed by a team lead by Prof. Ianovici, aerobiology specialist at West University in Timișoara; (2) clinical studies were performed at University of Medicine and Pharmacy Victor Babes Timisoara, and in the ENT Department of Municipal Hospital Timisoara and Allergology Compartment of Victor Babes Hospital Timisoara; (3) fundamental medical research was performed at the Regional Center for Transplant Immunology, the core precursor of OncoGen Institute.

During the duration of the project, the atmosphere pollen concentrations were measured and the information was presented in near real-time on the project website (Fig. 1).

d3a

Fig.1. Screenshot of PREVALERG website, showing pollen concentrations

Studies performed by Prof. Ianovici between 2000 and 2009 showed an increasing trend for ragweed pollen atmosphere concentration (Fig. 2) and the atmosphere pollen counts for 2009 showed that ragweed pollen is the most abundant pollen in the atmosphere, with a peak concentration of 292 particles / m3 in August, in Timisoara. This is correlated with a peak in the number of ragweed allergic patients in August-September, which starts 2 weeks after the increase in ragweed pollen concentration in air (Fig. 3)d3b

Fig.2. Ragweed pollen concentration in Timisoara, between 2000 and 2009

d3cFig.3. Correlation between patients sensitized to ragweed and ragweed pollen concentration, in Timisoara

In the seven years of previous study and its continuation (2008 – 2014), 7194 patients were evaluated, out of which 44.03% were diagnosed with allergic rhinoconjunctivitis or allergic bronchial asthma due to inhaled allergens, according to international guidelines (ARIA, and GINA respectively) (Fig. 4).

d3dFig.4. Distribution of allergic and non-allergic patients 2008 – 2014

Most (61.90%) of the allergic patients were polysensitized to several indoor or outdoor allergens, and out of the polysensitized patients, 60.07% were also sensitized to ragweed pollen (Fig. 5, 6, 7).

d3eFig.5. Distribution of monosensitized and polysensitized patients 2008 – 2014

d3fFig.6. Monosensitized patients 2008 – 2014

d3gFig.7. Ragweed monosensitized patients 2008 – 2014

Out of the monosensitized patients, ragweed allergic patients represented 39.88%, more than any other category of monosensitized patients (the category that was the closest was house dust mite allergic patients, at 27.66%). The proportion of ragweed allergic patients out of all allergic patients did not change significantly during the observed duration of the study (Fig. 8).

d3hFig.8. Distribution of monosensitized patients 2008 – 2014

Between August and November 2013 we selected 84 patients allergic to ragweed pollen, diagnosed by positive skin prick test to ragweed pollen extract and symptoms of allergic rhinoconjunctivitis with or without allergic bronchial asthma, during the ragweed pollen season. Most patients had moderate-severe allergic rhinitis, showcasing the intense effects of ragweed allergens (Fig. 9).

d3iFig.9. Distribution of clinical severity of allergic rhinoconjunctivitis symptoms

Specific serum IgE to 176 allergens was determined by using the ImmunoCAP ISAC microarray (Fig. 10). The results showed that out of the 84 patients with positive skin prick test to ragweed pollen extract, 90% also had increased specific serum IgE levels to the major ragweed allergen, Amb a 1 (5% class 1, 35% class 2, and 45% class 3. Sensitivity and specificity of ImmunoCAP ISAC microarray (Amb a 1) vs. Skin prick test (ragweed pollen extract) was 85.88% (95% CI: 76.63% 92.48%), and 90.91% (95% CI: 58.67% to 98.49%), respectively. However, the IgE class did not correlate significantly to the skin prick test class.

d3jFig.10. Specific IgE to Amb a 1, by ImmunoCAP ISAC microarray

All patients with a disease history older than 10 years had developed allergic asthma (Fig. 11), which raises questions regarding the effects of ragweed allergens on respiratory mucosa, so further studies are required to see their effects on the physical and chemical properties of the respiratory epithelium barrier.

d3kFig.11. Correlation between disease history and severity

Link: http://prevalerg.umft.ro/

Relevant publications:

  1. Ianovici N, Panaitescu Bunu C, Brudiu I. (2013) Analysis of airborne allergenic pollen spectrum for 2009 in Timişoara, Romania, Aerobiologia, 29:95–111 doi: 10.1007/s10453-012-9266-y
  2. Macesanu, S, Bunu Panaitescu, C., (2010) Clinical comparison between the control levels of asthma in elderly and young adult asthmatics; is asthma less controlled in the elderly?, Timisoara Medical Journal. Vol. 60: No. 2: 19-23
  3. Matis, B, Bunu, C, Tanasie, G., Tatu, C, Bojin, F., Tatu, C., Gavriliuc, O., Cernescu, L., Campean, A M., Raica, M., Paunescu, V., (2010) The effect of proinflamatory cytokines on pulmonary fibroblasts phenotype – a key role in airway remodeling in asthma, Timisoara Medical Journal Vol. 60, No. 2 – 3:183-188
  4. Toma, A. O., Fara, L., Poenaru, M., Bunu, C, Sarău, C., Horhat, D., Horhat R., Stanese A M, Mocanu, V., (2010) Evaluation of nasal obstruction with rhinomanometry after nasal provocation in allergic rhinitis., Medicine in Evolution, Volume XVI, No.3, 2010: 37-42
  5. Fara, L., Toma, A. O., Poenaru, M., Panaitescu Bunu, C, Sarău C., Horhat R, Horhat D., Stanese A M., Mocanu V., Horhat F., (2010) The management of the otitis media with effusion in the ENT Clinic Timisoara, Medicine in Evolution, Volume XVI, No.3: 95-99
  6. Cernescu L, Jiga J, Jiga L, Bunu C, Rosca A, Matis B, Cernescu C, Mirea F, Tatu C, Tanasie G, Paunescu V, (2009), Dendritic cells induced Th1/Th2 cytokine balance in response to allergen challenge, Timisoara Medical Journal, Vol. 59, No. 3 – 4:17-22 (Index Copernicus)
  7. Tanasie, G., Bojin, F., Tatu, C., Gavriliuc, O., Tatu, C., Nistor, D., Ionita, H., Bunu, C., Paunescu, V., (2009) Mechanisms Involved in Mesenchymal Stem Cells Differentiation towards the Epithelial Lineage. Effects of Chemical Inductors, Fiziologia –Physiology; 19, 3(63), ISSN 1223-2076, 7-12 (Index Copernicus)
  8. Matis, B., Bunu, C., Tanasie, G., Tatu, C., Bojin, F., Cernescu, L., Tatu, C., Marusciac, L., Paunescu, V., (2009) Establishment, Propagation and maintenance of primary pulmonary fibroblasts, Fiziologia –Physiology; 19, 2(62), ISSN 1223-2076, 17-20
  9. Cernescu, L., Jiga, J., Jiga, L., Bunu, C., Cernescu, C., Matis, B., Bojin, F., Tatu, C., Tanasie, G., Paunescu, V., (2009) Dendritic cells and T cells activation; Fiziologia -Physiology; 19, 2(62), ISSN 1223-2076, 21-24
  10. Panaitescu C., Marusciac L., Tamas T., Perez I., Pineda de la Losa F. (2015) Biological standardization of allergenic ragweed pollen extract, EAACI Online Library, Jun 6, 2015; 104415
  11. Perez I., Pineda F., Panaitescu C., Marusciac L.,Tamas T.P., Ianovici N.I. (2015) Patterns of sensitization to Ambrosia species, EAACI Online Library, Jun 6, 2015; 104571
  12. Panaitescu, C; Ianovici, N; Marusciac, L; Cernescu, LD; Tamas, PT; Lazarovicz, R-A (2014) Sensitisation to Ambrosia pollen and other airborne allergens in the population of the Western region of Romania, Allergy, 69 (Suppl. 99), 434
  13. Panaitescu C., Marusciac L., Cernescu L (2014), Influence of Interleukin-4 and Interleukin-13 on serum immunoglobulin E in house dust mite allergy, Clinical and Translational Allergy, 4( Suppl 2):P22
  14. Panaitescu Bunu C, Cernescu L, Matis B, Marusciac L, Tanasie G, Paunescu V. (2012) GATA-3 gene expression on CD4+T lymphocytes from allergic patients. 31st EAACI Congress, 16-20 June, Allergy 67 (Suppl 96):P 1551
  15. Panaitescu, C., Matis, B., Gavriliuc, O., Cernescu, L., Tanasie, G., Tatu, C., (2011) Fluticasone propionate and Budesonide do not stop the in vitro effect of pro-inflammatory cytokines on pulmonary fibroblasts phenotype, 30th EAACI Congress, 11-15 June,  Allergy and Immunology, Suppl., P 1551
  16. Panaitescu, C, Cernescu, L., Jiga, J., Jiga, L., Lungeanu, D., Rosca, A., Matis, B., Bojin, F., (2011) Serum IgE levels are influenced by both IL-4 and IL-13 in house dust mites allergic patients, 30th EAACI Congress, 11-15 June, Allergy and Immunology, Suppl., P1204
  17. Matis, B., Bunu, C., Tanasie, G., Tatu, C., Cernescu, L., Bălăceanu, A., Igreţ, L., Căpraru, A., (2010) The in vitro effect of corticosteroids on components of airway remodeling, ERS Barcelona Congress, 18-22 Sept., European Respiratory Journal Supplement; P2413, pg. 425s
  18. Bunu, C., Cernescu, L., Jiga, J., Jiga, L., Rosca, A., Tatu, C., Tanasie, G., Matis, B., Bojin, F., Marusciac, L., (2009) Th1/Th2 Cytokine response to in vitro allergen challenge of dendritic cells derived from monocytes, EAACI Pediatric Allergy and Asthma Meeting, 12-14 November, Venice, Italy, Pediatric Allergy and Immunology, Vol. 20, Suppl. 20, pg. 60-61
  19. Bunu, C, Cernescu, L., Jiga, L, Jiga, J., Matis, B., Tatu, C, Tanasie, G, (2009) The physiology of dendritic cells/CD4+ T cells response to allergen challenge, XXXVIth International Union of Physiological Sciences (IUPS), 27 -31 July, Kyoto, Japan, The Journal of Physiological Sciences, Vol 59, Suppl 1; P2PM-2-33; pg 270
  20. Tanasie G, Siska, IR, Tatu, C, Bojin, F., Bunu, C, (2009) The comparison of the in vitro histamine induced airways smooth muscle response in human bronchi and rat trachea, XXXVIth International Union of Physiological Sciences (IUPS), 27 -31 July, Kyoto, Japan, The Journal of Physiological Sciences, Vol 59, Suppl 1; pg 538
  21. Matis, B., Tatu, C., Cernescu, L., Bojin, F., Gavriliuc, O., Tanasie, G, Bunu, C., (2009) Airway fibroblasts phenotype markers after pro-inflammatory cytokines challenge, ERS Vienna 2009 Congress, 12-16 Sept., European Respiratory Journal Supplement; Vol 34; 53; P901, pg. 147
  22. Cernescu, L., Jiga, L, Jiga, J., Matis, B., Rosca, A., Cernescu, C., Tatu, C, Tanasie, G, Bunu, C., (2009) Dendritic cells induced Th1/Th2 cytokine balance in response to allergen stimulation, ERS Vienna 2009 Congress, 12-16 Sept., European Respiratory Journal Supplement; Vol 34; 53; P2144, pg. 369-370
  23. Ianovici, N., Bunu, C., Balaceanu, A., Igret, L., Marusciac, L., The principal airborne and allergenic pollen species in Timisoara, 2008, Simpozion Alergologie, p 147
  24. Bunu, C., Tanasie, G., Tatu, C.A., Matis, B., Tatu, C., Paunescu, V. (2008) In vitro effect of TGF-beta and IL-4 on human bronchial fibroblasts phenotype, European Respiratory Journal

b) Environment and chronic kidney diseases of unknown origin

Short description:
As part of the “Health and Environmental Factors” research mission to be pursued at the OncoGen Centre, a primary topic of study is the etiology of chronic kidney disease in relation with various environmental factors. Chronic kidney diseases of unknown origin are becoming an everyday reality for thousands of people around the globe. The prevalence of patients with renal failure is increasing at an alarming pace worldwide, putting a huge pressure on the medical insurance coverage systems in many countries.

For more than a decade we studied Balkan endemic nephropathy (BEN) as a disease model for chronic renal failure of unknown origin (CKDu). BEN is a tubulointerstitial nephropathy with a geographically constant incidence for over 50 years. The discrete and relatively small size of the affected region, the stable population and the well described clinical aspects of BEN make it especially useful as a model for other chronic disease that may be linked to toxic organic substances exposure, increasingly more present in our daily life. Our current research mission is a complex approach of BEN, from the surroundings area of endemic villages to the patience’s functional state of the cell at DNA level, in an effort to link the environmental factors supposed to have a role in BEN’s etiology (and particularly aristolochic acids derived from Aristolochia plants and Pliocene lignite-derived water organic contaminants) to the onset of BEN, into a detailed view of the perturbation of cellular pathways and mechanisms by the environment. Combining state of the art technologies in air sampling methods and geochemical analyses with new edge technologies like DNA methylation sequencing, biological sampling and analysis of the major metabolites of significance in BEN, our research will attempt to provide all the essential elements required for understanding BEN’s complex etiology. On a practical level, our results may lead to new information for developing preventive strategies, including exposure reduction, as well as pharmacological, dietary or lifestyle interventions not only for BEN’s patients but also for similar chronic kidney disease of unknown origin beyond the Balkan Peninsula.

Relevant publications:

  1. Maharaj SV, Orem WH, Tatu CA, Lerch HE 3rd, Szilagyi DN. Organic compounds in water extracts of coal: links to Balkan endemic nephropathy. Environ Geochem Health. 2014 Feb;36(1):1-17
  2. Maharaj SVM, Orem WH, Tatu CA, Lerch III HE, Szilagyi DN, Organic compounds in water extracts of coal: links to Balkan endemic nephropathy, Environ Geochem Health DOI 2013, 10.1007/s10653-013-9515-1.
  3. Pavlovic NM, Orem WH, Tatu CA, Lerch HE, Bunnell JE, Feder GL, Kostic EN, Ordodi VL The role of lecithin cholesterol acyltransferase and organic substances from coal in the etiology of Balkan endemic nephropathy: a new hypothesis. Food Chem Toxicol. 2008, 46(3):949-54.
  4. Tatu CA, Orem WH, Finkelman RB, Feder GL, The etiology of Balkan endemic nephropathy: still more questions than answers, Environ Health Perspect, 1998, 106(11):689-700.

d3lFig.1. BEN affected areas in the Balkan Peninsula

d3mFig.2. Rural fields contaminated with Aristolochia plants in BEN areas

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