Prevalence of the microbiological causes of canine otitis externa and the antibiotic susceptibility of the isolated bacterial strains.

Otitis externa is a canine disease of multifactorial etiology in which bacteria plays a significant role. Due to the predominant bacterial etiology otitis is usually treated with antibiotics. However, non-prudent use of antibiotics promotes the emergence of antibiotic-resistant bacteria thus compromising the therapy effectiveness. Currently, the increase of antimicrobial resistance (AMR) is one of the biggest threats to global health. For this reason, the aim of the study was to investigate prevalence of the microbiological causes of canine otitis externa and the antibiotic susceptibility of the isolated bacterial strains. The research and sampling were conducted at Veterinary Clinics for small pets in Serbia. Samples were sent to laboratory for bacteriological and mycological testing. Additionally, the sensitivity of the isolated bacteria to antibiotics was evaluated using disc diffusion method. Sixty dogs with otitis externa clinical symptoms were included in the study. Out of a total of 53 positive samples for pathogen presence, bacteria were present in 40. The most prevalent bacteria was Staphylococcus pseudintermedius, followed by Pseudomonas aeruginosa and Proteus spp., while Malassezia pachydermatis was the only isolated yeast pathogen occurring in 36 samples. Generally, the lowest resistance against all bacteria showed enrofloxacin. On the contrary, high resistance to penicillin and amoxicillin was a common finding for G+ and G- bacteria. These results indicate the need for laboratory testing in terms of isolation, identification and antibiotic susceptibility testing, not only in the case of otitis externa in dogs, but in all diseases when it is possible, in order to enhance antimicrobial stewardship and consequently to contribute AMR reduction.

Using the Food and Drug Administration´s Sentinel System for surveillance of TB infection.

BACKGROUND: We examined patterns in care for individuals treated for latent TB infection (LTBI) in the US Food and Drug Administration´s Sentinel System.METHODS: Using administrative claims data, we identified patients who filled standard LTBI treatment prescriptions during 2008-2019. In these cohorts, we assessed LTBI testing, clinical management, and treatment duration.RESULTS: Among 113,338 patients who filled LTBI prescriptions, 80% (90,377) received isoniazid (INH) only, 19% (21,235) rifampin (RIF) only, and 2% (1,726) INH + rifapentine (RPT). By regimen, the proportion of patients with documented prior testing for TBI was 79%, 54%, and 91%, respectively. Median therapy duration was 84 days (IQR 35-84) for the 3-month once-weekly INH + RPT regimen, 60 days (IQR 30-100) for the 6- to 9-month INH regimen, and 30 days (IQR 2-60) for the 4-month RIF regimen.CONCLUSIONS: Among the cohorts, INH-only was the most commonly prescribed LTBI treatment. Most persons who filled a prescription for LTBI treatment did not have evidence of completing recommended treatment duration. These data further support preferential use of shorter-course regimens such as INH + RPT.

Off label use of human approved drugs in treatment of dogs in the Republic of Serbia.

Since drug companies are driven by the need to produce profit they are unwilling to make large investments in the development of new drugs if there is no market large enough to justify such investment. For this reason, veterinarians face a major obstacle - the veterinary drug market is not very profitable, which sometimes leads to not having a licensed drug available for treatment in veterinary practice. In this case, the cascade procedure allows veterinarians to, under certain circumstances, prescribe human approved drugs. The aim of our study was to analyze the pattern of human approved drugs prescription for 150 medical records of dogs participating in the survey. The results show that antimicrobial agents were the most commonly prescribed drugs for animals (50%) of all human approved drugs, and beta-lactams (38.6%) were the most widely used antibiotic classes. The most common general conditions for therapeutic use of antimicrobials in this study were digestive, skin and respiratory disorders. Our study shows that the frequency of bacterial culture, susceptibility testing and cytology was very low. Even though the off-label use of human approved drugs in animal practice is regulated by law, the results of this study indicate the need for more specific strategies and guidelines for such use. This may represent a potential for improvement by raising veterinarians' awareness toward more prudent use of human drugs.

Can an introduced predator select for adaptive sex allocation?

Most species produce equal numbers of sons and daughters, and sex differences in survival after parental care do not usually affect this pattern. Temporary overproduction of the scarcer sex can be adaptive when generations overlap, the sexes differ in life-history expectations, and parents can anticipate future mating opportunities. However, an alternative strategy of maximizing the competitiveness of the more abundant sex in these circumstances remains unexplored. We develop theory showing how mothers can maximize reproductive value when future mate competition will be high by producing more sons in the advantageous early hatching positions within their broods. Our model for optimal birth order was supported by long-term data of offspring sex in a parrot facing catastrophic female mortality caused by introduced predators. Swift parrots (Lathamus discolor) suffer high female mortality due to introduced sugar gliders (Petaurus breviceps) creating fluctuating male-biased adult sex ratios. Offspring hatched early within broods fledged in better condition, and in support of our model were more likely to be male in years with higher adult female mortality. We found a highly significant rank-order correlation between observed and predicted birth sex ratios. Our study shows the potential for mothers to maximize reproductive value via strategic biases in offspring sex depending on the advantages conferred by birth order and the predictability of future mate competition. Our long-term data support the predictions and appear to suggest that sex allocation strategies may evolve surprisingly quickly when anthropogenic pressures on populations are severe.

Hybrid denture acrylic composites with nanozirconia and electrospun polystyrene fibers.

The processing and characterization of hybrid PMMA resin composites with nano-zirconia (ZrO2) and electrospun polystyrene (PS) polymer fibers were presented in this study. Reinforcement was selected with the intention to tune the physical and mechanical properties of the hybrid composite. Surface modification of inorganic particles was performed in order to improve the adhesion of reinforcement to the matrix. Fourier transform infrared spectroscopy (FTIR) provided successful modification of zirconia nanoparticles with 3-Methacryloxypropyltrimethoxysilane (MEMO) and bonding improvement between incompatible inorganic nanoparticles and PMMA matrix. Considerable deagglomeration of nanoparticles in the matrix occurred after the modification has been revealed by scanning electron microscopy (SEM). Microhardness increased with the concentration of modified nanoparticles, while the fibers were the modifier that lowers hardness and promotes toughness of hybrid composites. Impact test displayed increased absorbed energy after the PS electrospun fibers had been embedded. The optimized composition of the hybrid was determined and a good balance of thermal and mechanical properties was achieved.

Effect of postpartum administration of ketoprofen on proinflammatory cytokine concentration and their correlation with lipogenesis and ketogenesis in Holstein dairy cows.

Early lactation period in dairy cows could be harmful to their health since it is challenging and demanding. Proinflammatory cytokine concentrations are increased in the early phase of the inflammatory response and during the early lactation period in cows. The aim of this study was to determine if ketoprofen treatment in the first days following parturition would decrease proinflammatory cytokine concentration and their correlation between lipid mobilization, ketogenesis and metabolic parameters in cows. The study was conducted on 30 cows divided into two groups of 15 cows each. The experimental group was treated with 3 mg × kg.bw.-1 ketoprofen for three consecutive days after parturition. The blood samples were collected on the first day of treatment and in the first and second week postpartum and they were analyzed for biochemical parameters such as non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), glucose, cholesterol and total bilirubine and inflammatory parameters such as tumour necrosis factor-α (TNF-α), interleukin-1α (IL-1α) and interferon-γ (IFN-γ). The results suggested that ketoprofen- treated cows had a significantly lower concentration of TNF-α, IL-1α, IFN-γ, NEFA and BHBA in the first and second postpartum week compared to the control group. Ketoprofen administration increased glucose levels (the first week, p⟨0.05), increased cholesterol levels (the second week, p⟨0.01) and decreased serum total bilirubin levels (second week, p⟨0.01) compared to the control group of cows. A positive correlation was found between TNF-α and NEFA and total bilirubin, significantly more expressed in the control than in experimental group of cows (p⟨0.01) and it was also found between IL-1α and NEFA (p⟨0.01). A negative correlation was found between TNF-α and glucose and cholesterol, significantly more expressed in the control than in experimental group of cows (p⟨0.01). A positive correlation was also found between IL-1α and glucose (p⟨0.01). Ketoprofen given parenterally to Holstein cows immediately after calving could reduce inflammation and decrease the relation between inflammatory response and lipogenesis and ketogenesis in postpartum cows.

Hypothesis related to the regulation of inducible nitric oxide synthase during carotid endarterectomy.

Sudden occlusion of an artery caused by a thrombus or emboli is the most frequent cause of acute brain ischemia (ABI). Carotid endarterectomy (CEA) represents the gold standard for preventing strokes of carotid origin. However, neuronal damage caused by ischemia and/or reperfusion may contribute to a poor clinical outcome after CEA. In response to shear stress caused by hypoxic-ischemic conditions in patients undergoing CEA, stimulation of the hypothalamic-pituitaryadrenal axis leads to biological responses known as hypermetabolic stress, characterized by hemodynamic, metabolic, inflammatory and immunological changes. These changes maintain homeostasis and assist recovery, but an unregulated inflammatory response could lead to further tissue damage and death of neurons. Nitric oxide (NO) is an important signaling molecule involved in several physiological and pathological processes, including ABI. However, an excess of NO could have detrimental effects. We hypothesized that the hypoxic-ischemic state induced by carotid clamping leads to overexpression of inducible NO synthase and that uncontrolled production of NO could adversely affect outcome after CEA.

Association of metabolic and inflammatory markers with milk yield in postpartum dairy cows treated with ketoprofen.

Inflammation together with lipolysis and ketogenesis in early lactation can cause low productivity and may be harmful to the cow health. The objective of the study was to determine if ketoprofen treatment in the first days following parturition would positively affect the milk production and whether it was associated with the metabolic and inflammatory response. The study was conducted on 30 cows divided into two groups of 15 cows each. The experimental group was treated with 3 mg × kg. bw. -1 ketoprofen for three consecutive days after parturition. The blood samples were collected on the first day of treatment and in the first and second week postpartum and they were analyzed for non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHB), tumour necrosis factor-a(TNF-a) and haptoglobin. The results suggested that ketoprofen-treated cows with a higher milk production had a significantly lower concentration of NEFA, BHB, TNF-a and haptoglobin in the first and second week postpartum. No differences were found in the control group in metabolic status regardless of the achieved level of milk production. Ketoprofen administration in postpartum cows can enhance the milk yield. The higher milk yield in the experimental group might be associated with a lower degree of lipolysis, ketogenesis and reduced inflammatory response in the first two weeks postpartum.

Crosstalk between possible cytostatic and antiinflammatory potential of ketoprofen in the treatment of culture of colon and cervix cancer cell lines.

OBJECTIVES: The aim of this study was to test the cytostatic potential of ketoprofen in the in vitro treatment of cells derived from colon and cervix cancer. BACKGROUND: NF-κB and cyclooxygenase can have a role in different stages of the development and progression of cancer. In recent years, special attention has been paid to the possible cytostatic potential of nonsteroidal anti-inflammatory drugs. There are no published data on the use of ketoprofen in pharmacotherapy of the colon and cervical carcinoma. METHODS: We examined the effect of ketoprofen alone or in combination with cisplatin and 5-fluorouracil on proliferation of the two cell lines, HeLa (human cervical carcinoma cells) and Caco-2 (human colon cancer cells) by MTT test. Measurement of the level of NF-κB was also performed in the cells of both cell lines. RESULTS: The results of present study have shown that at least one of the mechanisms of antiproliferating and/or cytostatic effects of different concentrations of ketoprofen on Caco-2 and HeLa cells could include the transcription factor NF-κB. CONCLUSIONS: Since this transcription factor is controlled by the altered expression of COX-2, the inhibition of this enzyme by ketoprofen may represent a significant step in synergistic cascade of the therapy and prevention of colon and cervical cancer (Tab. 4, Ref. 31).

Chemopreventive potential of alpha lipoic acid in the treatment of colon and cervix cancer cell lines.

OBJECTIVES: The nuclear factor κB regulates the expression of genes involved in many processes that play a key role in the development and progression of cancer. The aim of this study was to examine the influence of the alpha lipoic acid in the chemoprevention of colon and cervix carcinoma in vitro. BACKGROUND: In recent years, special attention has been paid to the potential chemopreventive properties of antioxidants. There are no published data on the impact of alpha lipoc acid of chemoprevention of cervix and colon cancer. METHODS: We examined the effect of alpha lipoic acid alone or in combination with cisplatin and 5-fluorouracil on proliferation of the two cell lines, HeLa (human cervical carcinoma cells) and Caco-2 (human colon cancer cells) by MTT test. The measurement of the level of transcription factor NF-κB was also performed in the cells of both cell lines. RESULTS: At least one of the mechanisms of the antiproliferative and/or cytotoxic effect of alpha lipoic acid on Caco-2 and HeLa cells at high concentrations, the transcription factor NF-κB, may be involved, as well as the products of transcription of genes that are under its control. CONCLUSION: The alpha lipoic acid has proven to be a promising candidate in the combat arena against cancer (Tab. 4, Ref. 31).

The feasibility of sentinel lymph node biopsy for gastric cancer: the experience from Serbia.

PURPOSE: The prediction of outcome for patients with gastric cancer is determined largely by the presence of lymph node metastases, which could be detected by sentinel lymph node (SLN) biopsy (SLNB). The purpose of this work was to determine the feasibility of SLNB in patients with gastric cancer for the assessment of regional lymph node status, including performing immunohistochemical (IHC) staining of SLN tissue. METHODS: We reviewed 137 consecutive patients with operable gastric cancer over a 10-year period using a retrospective (to examine skip metastases) and prospective (to evaluate successful mapping) study design. SLNs were mapped, biopsied and subsequently explored by routine hematoxylin & eosin (H&E) staining and by IHC staining using a cytokeratin 8/18 antibody. RESULTS: The retrospective study showed a low incidence of skip metastases (3.7%). Mapping of SLNs in the prospective study was highly successful (98.2%). During the prospective study, IHC examination of SLNs from 56 patients showed statistically significant change in disease stage. CONCLUSION: This study demonstrated highly successful mapping and biopsy of SLNs (98.2%), as well as highest specificity (100%), sensitivity (100%) and accuracy (100%) to predict metastasis in the surrounding lymph nodes of gastric carcinoma. In addition, we believe that IHC study might enable "ultra staging" and additional selection of patients for further cancer treatment.

L-arginine intake effect on adenine nucleotide metabolism in rat parenchymal and reproductive tissues.

L-arginine is conditionally essetcial amino acid, required for normal cell growth, protein synthesis, ammonia detoxification, tissue growth and general performance, proposed in the treatment of men sterility and prevention of male impotence. The aim of the present paper was to estimate the activity of the enzymes of adenine nucleotide metabolism: 5'-nucleotidase (5'-NU), adenosine deaminase (ADA), AMP deaminase, and xanthine oxidase (XO), during dietary intake of L-arginine for a period of four weeks of male Wistar rats. Adenosine concentration in tissues is maintained by the relative activities of the adenosine-producing enzyme, 5'-NU and the adenosine-degrading enzyme-ADA adenosine deaminase. Dietary L-arginine intake directed adenine nucleotide metabolism in liver, kidney, and testis tissue toward the activation of adenosine production, by increased 5'-NU activity and decreased ADA activity. Stimulation of adenosine accumulation could be of importance in mediating arginine antiatherosclerotic, vasoactive, immunomodulatory, and antioxidant effects. Assuming that the XO activity reflects the rate of purine catabolism in the cell, while the activity of AMP deaminase is of importance in ATP regeneration, reduced activity of XO, together with the increased AMP-deaminase activity, may suggest that adenine nucleotides are presumably directed to the ATP regenerating process during dietary L-arginine intake.

Breast MRI: intraindividual comparative study at 1.5 and 3.0T; initial experience.

PURPOSE: To prospectively and intraindividually compare breast magnetic resonance imaging (MRI) at 1.5 Tesla (T) and 3.0T. METHODS: A prospective intraindividual Ethics Committee- approved study was performed in 31 women (average age 58.6±12.3 years), with 114 lesions (9 benign, 105 breast cancers; 24 patients with unilateral and 7 with bilateral cancers). Axial bilateral breast high-spatial resolution contrast-enhanced dynamic MRI was performed at 1.5T using 3 dimensional (3D) dynamic gradient-echo sequences in all patients (spatial resolution 1.1×0.7×2 mm; temporal resolution 41 sec per dynamic acquisition), and after 24-48 h at 3.0T (0.6×0.6×1.7 mm; temporal resolution 65 and 72 sec per dynamic acquisition). Contrast enhancement ratio, number and features of enhancing lesions, image quality and reliability were compared by two radiologists independently. RESULTS: 102 cancer lesions were detected at 1.5T and 105 cancer lesions were detected in 31 patients at 3.0T. One cancer lesion was observed at 1.5T which was missed at 3.0T, and 3 cancer lesions and one high-risk lesion (LCIS) were detected at 3.0T while missed at 1.5T. Enhancement rates were significantly higher at 1.5T (224.5±100.2) compared to 3.0T (133.7±38.3). Better image quality was observed at 3.0T. Interobserver reliability was higher at 3.0T (p= 0.684) compared to 1.5T (p= 0.351). CONCLUSION: Detection of breast cancer shows a trend of better performance at 3.0T than at 1.5T.

Nonlinear optical spectra of intersubband transitions in a CdSe/ZnS/CdSe/SiO2 spherical quantum dot.

In this paper the electronic spectra and optical properties of one-electron spherical quantum dot (QD) are presented. QD is composed of CdSe core surrounded by ZnS shell (barrier) CdSe shell and finally by medium of very high potential barrier (SiO2) compared to CdSe. The energy eigenvalues of s, p and d states and corresponding wave functions were calculated using effective mass approximation. We have calculated oscillator strengths and the linear and third-order nonlinear intersubband optical absorption coefficients as function of the QD dimension, incident photon energy and incident optical intensity for the 1s-1p, 1p-1d and 1p-2s transitions.

The effect of depurinized milk draught diet on rat serum uric acid, lipid status and haematological parameters.

Hyperuricaemia and gout are closely related, but hyperuricaemia is an independent risk factor for endothelial damage, autoinflammation and haemodynamic abnormalities. Milk, generally known as a 'purine-free diet', is an essential protein source for patients suffering from hyperuricaemia and gout. As milk still contains different purine ribonucleotides, the new product, depurinized milk, almost free of purine nucleotides and uric acid, was produced. The potential effect of depurinized milk diet on serum uric acid (SUA) level, lipid parameters and blood haematological parameters was explored in rats after 72 h and 15 days, in relation to standard laboratory chow or the untreated milk diet. The beneficial effect on SUA was achieved when depurinized milk draught was given instead of standard chow for 72 h [28.39 ± 4.76 µm; p < 0.001 vs. standard diet (STD) 47.6 ± 6.12, vs. untreated milk diet 31.55 ± 8.50; p < 0.05] or as a supplement for STD for 15 days experiment (35.38 ± 6.40 µm; p < 0.05 vs. STD only 48.05 ± 4.32; vs. untreated milk + STD 46.02 ± 9.48). Depurinized milk diet significantly decreased the low density lipoproteins/high density lipoproteins (LDL/HDL) ratio (p < 0.001), triglycerides (p < 0.05) and leucocyte count (p < 0.001), while both milk draughts enhanced haemoglobin concentration (p < 0.01). In conclusion, considering the detrimental effect of persisting hyperuricaemia, the depurinized milk draught may meet the demand of healthy dairy product for population under hyperuricaemic risk.

Binding energy of D(0) and D(-) impurity centers in CdTe/ZnTe spherical quantum dot.

Binding energy of neutral (D(0)) and negatively charged (D(-)) hydrogenic impurity located at the center of the CdTe/ZnTe spherical quantum dot has been investigated. Calculations are performed under the effective mass approximation on the basis of exact solution of the Schrödinger and Poisson equations. Eigenfunctions are expressed in terms of the Whittaker and Coulomb wave functions. Calculated results show that D(0) and D(-) impurity binding energies of ground 1s, 1S(1s2) and 2p, 3P(1s2p) excited states strongly depend on CdTe/ZnTe QD size if QD radius is less than one effective Bohr radius.

[Surgical treatment of degenerative cervical spine diseases: analyses of 90 patients clinical study]. / Hirursko lecenje degenerativnih oboljenja cervikalne kicme: analiza klinicke serije od 90 pacijenata.

The effect of degenerative cervical spine surgery depends on good understanding of the pathogenesis and clinical course of disease with a detailed neurological and neuroradiological examination. Surgical approach should be considered separately for each pathological substrate in order to avoid additional morbidity. The aim of our study is to present the results of treatment through analysis of large clinical series focusing on anterior surgical approach with iliac crest graft fusion without cervical plating. The retrospective analysis of 90 patients operated on Neurosurgery of CHC Zemun, from 2008 to 2011, was done. In 81 patients cervical disc herniation was found in one or two levels, and 9 patients had spinal canal stenosis with polydiscopathy. Preoperatively 50 patients had cervical myelopathy, and 40 patients had radiculopathy as dominating clinical sign. Anterior cervical approach was performed in 79 patients, and 11 patients were operated by posterior approach. The treatment outcome was as follows: good outcome 16 (16.8%) patients, improved condition 65 (72.2%), without improvement 6 (6.7%), bad outcome 3 (4.3%). The anterior cervical approach with iliac crest autologous graft fusion, and without additional cervical plating, is reliable treatment option with results comparable to reported clinical series with sintetic graft placement and anterior cervical plate stabilisation.

Molecular typing and antimicrobial resistance of Salmonella Enteritidis isolated from poultry, food, and humans in Serbia.

Molecular typing and resistotyping coupled with gyrA single nucleotide polymorphism (SNP) of 60 Salmonella Enteritidis (SE) isolates originated from poultry, food, and humans in Serbia is described. Molecular fingerprinting was performed by randomly amplified polymorphic DNA (RAPD) using four primers, and the diversity index (D) was 0.688. In combination with resistotyping and gyrA SNP, D increased to 0.828. A total of 23 genetic groups were obtained. When four RAPD primers were combined, epidemic isolates from a fast-food restaurant outbreak were clustered in a distinctive genetic group. Among 60 SE strains, three had multiple resistances to three or more antibiotics. Nine strains were resistant to nalidixic acid (NAL; a non-fluorinated quinolone). The mutations in quinolone resistance-determining region (QRDR) found in NAL-resistant strains were attributed to Asp(87) → Asn in six strains, Asp(87) → Gly in one strain, and Ser(83) → Phe in one strain. One NAL-resistant strain had no mutations in QRDR, suggesting another mechanism of resistance.

Hyperglycemia, oxidative and nitrosative stress affect antiviral, inflammatory and apoptotic signaling of cultured thymocytes.

A high prevalence of various infectious diseases is reported in diabetic patients, which may suggest impaired innate immunity against different pathogen-associated molecular patterns. This study investigated the effects of hyperglycemia, oxidative stress (H(2)O(2)), nitric oxide (NO) and peroxynitrite (ONOO(-)) on the modulation of antiviral (MDA-5, IRF-3 and phospho-IRF-3), inflammatory (NF-kappaB) and pro/anti-apoptotic molecules (Bax and Bcl-2) in BALB/c mice thymocytes. Each of the experimental conditions, except the weakest NO concentration, resulted in down-regulation of MDA-5, IRF-3 and phospho-IRF-3. In contrast, each of the experimental conditions elicited up-regulation of NF-kappaB, Bcl-2 and Bax. These results suggest that hyperglycemia, oxidative and nitrosative stress may contribute to the reduced immunity of the host by altering the MDA-5/IRF-3/phosphoIRF-3 axis, as well as contributing to the mechanisms of inflammatory reaction via increased NF-kappaB, and to augmented turnover rate of thymocyte cells via Bcl2/Bax up-regulation.

Molecular aspects of microcystin-induced hepatotoxicity and hepatocarcinogenesis.

It is known that microcystin (MC) is a cyanotoxin that is a potent environmental inhibitor of eucariotic protein serine/threonine phosphatase 1 and 2A, both in vitro and in vivo. Consequently, these cyanobacterial toxins (MC-IARC group 2B carcinogen, MC extracts-group 3) are potent tumor promoters and there is an indication that they may also act as tumor initiators. The ability of microcystin-LR (MC-LR) to act as a tumor initiator is based on fact that it can induce DNA damage either by direct interaction with DNA or by indirect mechanisms through formation of reactive oxygen species (ROS). Both acute and chronic exposures, to either low or high doses of MC-LR, can activate apoptotic pathways. Chronic exposure to low concentrations of MC-LR contributes to increased risk for cancer development. Epidemiological studies, in certain areas of China, have suggested that MC is one of the risk factors for the high incidence of primary liver cancer (PLC). Recently, we have reported a correlation between PLC and cyanobacterial "blooms" in reservoirs used as a source for drinking water supply in central Serbia. It appears that the combination of acute and chronic exposures to both high and low doses of MC can lead to PLC initiation and promotion. Based on this, we propose that the requirement for the co-factors such as aflatoxin B1 and other mycotoxins, HBV, HCV, alcohol, etc. is not needed for initiation and promotion of PLC by MC-LR as was suggested earlier. The possible mechanisms of the genotoxicity of MC and its role as a hepatocarcinogen are outlined in this review. Furthermore, we show that the exposure of hepatocytes to MC can lead either to malignant proliferation or apoptosis.