Miloš Nikolić

Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides.

Clinical and serological profiles of idiopathic and drug-induced autoimmune diseases can be very similar. We compared data from idiopathic and antithyroid drug (ATD)-induced antineutrophil cytoplasmic antibody (ANCA)-positive patients. From 1993 to 2003, 2474 patients were tested for ANCA in the Laboratory for Allergy and Clinical Immunology in Belgrade. Out of 2474 patients, 72 (2.9%) were anti-proteinase 3 (PR3)- or anti-myeloperoxidase (MPO)-positive and their clinical and serological data were analyzed. The first group consisted of ANCA-associated idiopathic systemic vasculitis (ISV) diagnosed in 56/72 patients: 29 Wegeners granulomatosis (WG), 23 microscopic polyangiitis (MPA) and four Churg-Strauss syndrome. The second group consisted of 16/72 patients who became ANCA-positive during ATD therapy (12 receiving propylthiouracil and four receiving methimazole). We determined ANCA and antinuclear (ANA) antibodies by indirect immunofluorescence; PR3-ANCA, MPO-ANCA, anticardiolipin (aCL) and antihistone antibodies (AHA) by ELISA; and cryoglobulins by precipitation. Complement components C3 and C4, alpha-1 antitrypsin (α1 AT) and C reactive protein (CR-P) were measured by nephelometry. Renal lesions were present in 3/16 (18.8%) ATD-treated patients and in 42/56 (75%) ISV patients (p <0.001). Skin lesions occurred in 10/16 (62.5%) ATD-treated patients and 14/56 (25%) ISV patients (p <0.01). ATD-treated patients more frequently had MPO-ANCA, ANA, AHA, aCL, cryoglobulins and low C4 (p <0.01). ISV patients more frequently had low α1 AT (p = 0.059) and high CR-P (p <0.001). Of 16 ATD-treated patients, four had drug-induced ANCA vasculitis (three MPA and one WG), while 12 had lupus-like disease (LLD). Of 56 ISV patients, 13 died and eight developed terminal renal failure (TRF). There was no lethality in the ATD-treated group, but 1/16 with methimazole-induced MPA developed pulmonary-renal syndrome with progression to TRF. ANCA-positive ISV had a more severe course in comparison with ATD-induced ANCA-positive diseases. Clinically and serologically ANCA-positive ATD-treated patients can be divided into two groups: the first consisting of patients with drug-induced WG or MPA which resemble ISV and the second consisting of patients with LLD. Different serological profiles could help in the differential diagnosis and adequate therapeutic approach to ANCA-positive ATD-treated patients with symptoms of systemic disease.

Transit network design by Bee Colony Optimization

The transit network design problem is one of the most significant problems faced by transit operators and city authorities in the world. This transportation planning problem belongs to the class of difficult combinatorial optimization problem, whose optimal solution is difficult to discover. The paper develops a Swarm Intelligence (SI) based model for the transit network design problem. When designing the transit network, we try to maximize the number of satisfied passengers, to minimize the total number of transfers, and to minimize the total travel time of all served passengers. Our approach to the transit network design problem is based on the Bee Colony Optimization (BCO) metaheuristics. The BCO algorithm is a stochastic, random-search technique that belongs to the class of population-based algorithms. This technique uses a similarity among the way in which bees in nature look for food, and the way in which optimization algorithms search for an optimum of a combinatorial optimization problem. The numerical experiments are performed on known benchmark problems. We clearly show that our approach, based on the BCO algorithm, is competitive with other approaches in the literature, and it can generate high-quality solutions.

Empirical study of the Bee Colony Optimization (BCO) algorithm

The Bee Colony Optimization (BCO) meta-heuristic deals with combinatorial optimization problems. It is biologically inspired method that explores collective intelligence applied by the honey bees during nectar collecting process. In this paper we perform empirical study of the BCO algorithm. We apply BCO to optimize numerous numerical test functions. The obtained results are compared with the results in the literature. The numerical experiments performed on well-known benchmark functions show that the BCO is competitive with other methods and it can generate high-quality solutions within negligible CPU times.

Retroperitoneal round-cell liposarcoma associated with paraneoplastic pemphigus presenting as lichen planus pemphigoides-like eruption

A 59‐year old Caucasian woman refugee from Bosnia had been in good health until a year before admission, when she developed painful erosions and ulcerated lesions in the mouth, anogenital area, hands, and feet. Treatment with topical and systemic antibiotics, acyclovir, and antifungal creams was ineffective. Three months before admission, her skin and mucosal lesions had worsened, resulting in the limitation of walking and her daily activities. She had also experienced significant weight loss.

Generalized Acanthosis Nigricans in Early Childhood

Abstract: Acanthosis nigricans (AN) is a disorder often accompanied by internal malignancy in adult patients, but in children it is usually benign. Generalized forms of AN, especially in childhood, are extremely rare. We report a 5‐year‐old boy with a 3‐year history of AN who had generalized roughness and hyperpigmentation, numerous skin wrinkles, disseminated skin tags, tripe palms, and intensive pruritus. No clinical evidence of internal disorders, notably of an endocrinologic or neoplastic nature, have been detected thus far.

In vitro anti-quorum sensing activity of phytol

Anti-quorum sensing activity of the diterpene phytol was evaluated in vitro for the first time. This compound (at three sub-MIC concentrations – 0.5, 0.25 and 0.125 MIC, respectively) reduced the formation of Pseudomonas aeruginosa PAO1 biofilm in the range of 74.00–84.33% exhibiting higher activity than the both positive controls used, streptomycin and ampicillin. Phytol (0.5 MIC) also effectively reduced P. aeruginosa twitching and flagella motility. Indeed, the bacteria treated were incapable of producing a twitching zone and had almost round, smooth and regular colony edges. Finally, the tested compound (0.5 MIC) exhibited good P. aeruginosa pyocyanin inhibitory activity (51.94%) practically to the same extent as streptomycin (52.09%). According to the experimental data obtained, this phytol property may inspire design of medical foods targeting P. aeruginosa quorum sensing activity.

Serum DNase I activity in systemic lupus erythematosus: correlation with immunoserological markers, the disease activity and organ involvement.

Abstract Background: Decreased activity of serum desoxyribonuclease I (DNase I) in systemic lupus erythematosus (SLE) has been reported, but its role as a biomarker in SLE is still unelucidated. Methods: Seventy-seven SLE patients (aged 39.6±13.1 years) were studied for serum DNase I activity, levels of antinuclear (ANA), anti-dsDNA [high-avidity ELISA, conventional ELISA and indirect immunofluorescence (IIF)], anti-nucleosome, anti-histone antibodies, complement components C3 and C4. SLE disease activity was evaluated by disease activity index (SLEDAI-2K). Thirty-five patients were serologically and clinically followed for 3–12 months (mean 5.6±2.8). Thirty-seven healthy blood donors were the control group. Results: DNase I activity in SLE patients was lower than in healthy controls (p<0.01). DNase I activity was in positive correlation with SLEDAI-2K (p<0.01), levels of ANA, anti-dsDNA, anti-nucleosome and anti-histone antibodies (p<0.01) and in negative correlation with C3 concentration (p<0.05). The highest correlation was found between DNase I activity and anti-dsDNA concentrations determined by high-avidity ELISA (r=0.624), followed by IIF (r=0.541) and conventional ELISA (r=0.405). In the follow-up study, DNase I activity also correlated with SLEDAI-2K (p<0.01). SLE patients with low DNase I activity more frequently had SLE-specific cutaneous lesions (p<0.05). Conclusions: Monitoring of DNase I activity simultaneously with SLEDAI-2K might be a useful tool in the follow-up of SLE. An increase of DNase I activity characterized relapse in most SLE patients, although it did not reach the levels of healthy individuals. A decrease of DNase I activity in SLE flare-ups might be a functional biomarker of a subset of patients with specific dysfunction of apoptotic chromatin degradation.

Further in vitro evaluation of antiradical and antimicrobial activities of phytol

The antiradical activity of phytol was evaluated by electron paramagnetic resonance towards hydroxyl radical (√OH), superoxide anion radical (), methoxy radical (√CH2OH), carbon-dioxide anion radical (), as well as towards nitric-oxide radical (√NO) and 2,2-diphenyl-1-picrylhydrazyl (√DPPH) radical. It reduced the production of all tested radicals showing more promising activity against , √CH2OH and √DPPH radicals (56%, 50% and 48%, respectively) in comparison with √NO, and √OH radicals (38%, 23% and 15%, respectively). The antimicrobial activity of phytol was evaluated by the microdilution method against eight bacterial and eight fungal strains. To varying degrees, it was proven to be active against all tested bacteria and fungi (MIC 0.003–0.038 mg/mL and MBC 0.013–0.052 mg/mL, MIC 0.008–0.016 mg/mL and MFC 0.090–0.520 mg/mL, respectively). According to the obtained results, medical foods containing phytol may support development of new therapies for heart disease.

Toxic epidermal necrolysis following morbilli-parotitis-rubella vaccination

We present the first reported case of toxic epidermal necrolysis (TEN) caused by morbilli‐parotitis‐rubella (MPR) vaccine. A 13‐year‐old girl developed TEN 7 days after she received live, attenuated, triple MPR vaccine. The history of drug intake and any illness was negative. At admission the patient was acutely ill with high fever. The whole body was erythematous. The epidermis was wrinkled and the Nikolsky sign was positive. Numerous erosions were present on the lips and genital region. On the seventh day of illness, the eruption involved 80% of the skin. Systemic corticosteroid therapy was not employed. The skin and mucosal defects completely epithelized by the end of the third week of illness. Mild keratoconjunctivitis sicca remained because of permanent cup cell damage.

Chemical characterization and biological activity of Chaga (Inonotus obliquus), a medicinal “mushroom”

ETHNOPHARMACOLOGICAL RELEVANCE In Russian traditional medicine, an extract from the mushroom Inonotus obliquus (Fr.) Pil´at is used as an anti-tumor medicine and diuretic. It has been reported that Inonotus obliquus has therapeutic effects, such as anti-inflammatory, immuno-modulatory and hepatoprotective effects. This study was designed to investigate the chemical composition and biological properties of aqueous and ethanolic extracts of Inonotus obliquus from Finland, Russia, and Thailand. Their antioxidative, antimicrobial, and antiquorum properties were tested as well as the cytotoxicity on various tumor cell lines. MATERIALS AND METHODS The tested extract was subjected to conventional chemical study to identified organic acids and phenolic compounds. Antioxidative activity was measured by several different assays. Antimicrobial potential of extracts was tested by microdilution method, and antiquorum sensing activity and antibiofilm formation of Inonotus obliquus extracts was tested on Pseudomonas aeruginosa. Cytotoxicity of the extracts was tested on tumor cells (MCF-7, NCI-H460, HeLa and HepG2) and non-tumor liver cells primary cultures. RESULTS Oxalic acid was found as the main organic acid, with the highest amount in the aqueous extract from Russia. Gallic, protocatechuic and p-hydroxybenzoic acids were detected in all samples. Inonotus obliquus extracts showed high antioxidant and antimicrobial activity. Extracts were tested at subMIC for anti-quorum sensing (AQS) activity in Pseudomonas aeruginosa and all extracts showed definite AQS activity. The assays were done using twitching and swarming of bacterial cultures, and the amount of produced pyocyanin as QS parameters. All the extracts demonstrated cytotoxic effect on four tumor cell lines and not on primary porcine liver cells PLP2. CONCLUSIONS As the Inonotus obliquus presence in Chaga conks is limited, further purification is necessary to draw quantitative conclusions. The presence of AQS activity in medicinal mushrooms suggests a broader anti-infectious disease protection than only immunomodulatory effects.