Effects of concomitant use of THC and irinotecan on tumour growth and biochemical markers in a syngeneic mouse model of colon cancer.

Clinical treatment with the antineoplastic drug irinotecan (IRI) is often hindered by side effects that significantly reduce the quality of life of treated patients. Due to the growing public support for products with Δ9-tetrahydrocannabinol (THC), even though relevant scientific literature does not provide clear evidence of their high antitumour potential, some cancer patients take unregistered preparations containing up to 80 % THC. This study was conducted on a syngeneic colorectal cancer mouse model to test the efficiency and safety of concomitant treatment with IRI and THC. Male BALB/c mice subcutaneously injected with CT26 cells were receiving 60 mg/kg of IRI intraperitoneally on day 1 and 5 of treatment and/or 7 mg/kg of THC by gavage a day for 7 days. Treatment responses were evaluated based on changes in body, brain, and liver weight, tumour growth, blood cholinesterase activity, and oxidative stress parameters. Irinotecan's systemic toxicity was evidenced by weight loss and high oxidative stress. The important finding of this study is that combining THC with IRI diminishes IRI efficiency in inhibiting tumour growth. However, further studies, focused on more subtle molecular methods in tumour tissue and analytical analysis of IRI and THC distribution in tumour-bearing mice, are needed to prove our observations.

The Rheometric Analysis of the Polymer Modifier's Properties in the Environment of Hydrated Cement.

This paper investigates the effect of polymer modifiers (re-dispersible powder, multifunctional additives, methylhydroxyethylcellulose) on the rheological behavior of emulsions, saturated of calcium hydrosilicates to simulate a hydrating cement structure. The subjects of the study were modified emulsions which had varied concentrations of each additive and they were examined comparatively to a base emulsion. Tests were performed with a CR-rheometer ("Himpribor-1", Tula, Russia) applying the Searle measuring principle at various shear rates to characterize viscosity properties. The performance of modified mixtures within the operating period was analyzed by using two parameters-effective viscosity (η) and the proportion of structural failure (|m|). The test results showed that the most important factor influencing rheological characteristics is the addition of methylhydroxyethylcellulose additive-the higher additive amount in the emulsion, the higher the viscosity. Furthermore it was noted in the work that adding olefin sulfonate sodium salt causes reduced viscosities as well as lower shear moduli. If ethylhydroxyethylcellulose and ethylene vinyl acetate additives are used in the same mixture together, the rate of structural failure |m| can be relatively similar and low regardless of whether the mixture has large or small viscosity values.

Cytotoxic, genotoxic, and oxidative stress-related effects of lysergic acid diethylamide (LSD) and phencyclidine (PCP) in the human neuroblastoma SH-SY5Y cell line.

Lysergic acid diethylamide (LSD) is a classic hallucinogen, widely abused for decades, while phencyclidine (PCP) has increased in popularity in recent years, especially among the adolescents. Very little is known about the general toxicity of these compounds, especially about their possible neurotoxic effects at the cell level. The aim of this study was to address these gaps by assessing the toxic effects of 24-hour exposure to LSD and PCP in the concentration range of 0.39-100 µmol/L in the human neuroblastoma SH-SY5Y cell line. After cell viability was established, cells treated with concentrations that reduced their viability up to 30 % were further subjected to the alkaline comet assay and biochemical assays that enable estimation of oxidative stress-related effects. Treatment with LSD at 6.25 µmol/L and with PCP at 3.13 µmol/L resulted with 88.06±2.05 and 84.17±3.19 % of viable cells, respectively, and led to a significant increase in primary DNA damage compared to negative control. LSD also caused a significant increase in malondialdehyde level, reactive oxygen species (ROS) production, and glutathione (GSH) level, PCP significantly increased ROS but lowered GSH compared to control. Treatment with LSD significantly increased the activities of all antioxidant enzymes, while PCP treatment significantly increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) but decreased catalase (CAT) activity compared to control. Our findings suggest that LSD has a greater DNA damaging potential and stronger oxidative activity than PCP in SH-SY5Y cells.

Human Papillomavirus (HPV) Prevalence, Temporal Dynamics and Association with Abnormal Cervical Cytology Findings in Women from Croatia: Is there a Compounding Effect of Low-Risk/High-Risk HPV Co-Infection?

BACKGROUND: Human papillomavirus (HPV) is a major risk factor for cervical dysplasia and invasive cervical cancer; therefore, regular screening by cervical smear cytology or HPV testing is recommended. We aimed to determine the overall and risk group-specific HPV prevalence, age distribution, and temporal trends and to appraise the correlation of HPV positivity with abnormal cervical cytological findings. METHODS: This retrospective, single-center study involved a total of 751 women (aged 18 - 67) concurrently subjected to HPV DNA testing and cervical cytology evaluation over a 10-year period in Zagreb, Croatia. Digene HC2 HPV DNA test (Qiagen Corporation, USA) was employed in screening specimens for both low-risk and high-risk HPV risk groups. The cytology was reported using the Bethesda system and in accordance with uniform classification of uterine cervix cytological findings in Croatia "Zagreb 2002". Statistical significance was set at p < 0.05. RESULTS: The overall HPV prevalence in our study population was 48.6%, and the 18 - 30 age group presented with the highest infection burden (p = 0.046). A decrease in low-risk and high-risk mono-positivity has been observed over the 10-year period; conversely, there was a significant increase in low-risk/high-risk co-positivity (p = 0.007). Low-risk/high-risk HPV co-infection resulted in a compounding effect which increased the occurrence of abnormal cells, HPV-associated changes and low grade squamous intraepithelial lesions (LSIL/cervical intraepithelial neoplasia grade I) in cervical cytology when compared to mono-infection with either low-risk or high-risk HPV. On the other hand, such effect has not been demonstrated for high grade squamous intraepithelial lesions (HSIL/ cervical intraepithelial neoplasia grades II and III). CONCLUSIONS: The overall HPV prevalence in female outpatients was high, underscored with rising co-positivity rates. Such co-infection with both low-risk and high-risk HPV (predominantly seen in women younger than 30) can exhibit a compounding effect in the occurrence of cytological abnormalities and low grade squamous intra-epithelial lesions (LSIL), which has to be considered in future diagnostic and screening algorithms.

High Doses of Δ9-Tetrahydrocannabinol Might Impair Irinotecan Chemotherapy: A Review of Potentially Harmful Interactions.

This review proposes the hypothesis that the effectiveness of irinotecan chemotherapy might be impaired by high doses of concomitantly administered Δ9-tetrahydrocannabinol (THC). The most important features shared by irinotecan and THC, which might represent sources of potentially harmful interactions are: first-pass hepatic metabolism mediated by cytochrome P450 (CYP) enzyme CYP3A4; glucuronidation mediated by uridine diphosphate glycosyltransferase (UGT) enzymes, isoforms 1A1 and 1A9; transport of parent compounds and their metabolites via canalicular ATP-binding cassette (ABC) transporters ABCB1 and ABCG2; enterohepatic recirculation of both parent compounds, which leads to an extended duration of their pharmacological effects; possible competition for binding to albumin; butyrylcholinesterase (BChE) inhibition by THC, which might impair the conversion of parent irinotecan into the SN-38 metabolite; mutual effects on mitochondrial dysfunction and induction of oxidative stress; potentiation of hepatotoxicity; potentiation of genotoxicity and cytogenetic effects leading to genome instability; possible neurotoxicity; and effects on bilirubin. The controversies associated with the use of highly concentrated THC preparations with irinotecan chemotherapy are also discussed. Despite all of the limitations, the body of evidence provided here could be considered relevant for human-risk assessments and calls for concern in cases when irinotecan chemotherapy is accompanied by preparations rich in THC.

Contrasting Vantage Points between Caregivers and Residents on the Perception of Elder Abuse and Neglect During Long-Term Care.

BACKGROUND: Elder abuse and neglect can be defined as refusing or failing to fulfil a caregiver's obligation to meet the needs of elderly individuals in order to punish or hurt them. We aimed to explore perceptions of elder mistreatment of both caregivers and residents during long-term care, and highlight significant differences in the overall mistreatment perception regarding socio-demographic variables, as well as the type of care facility. SUBJECTS AND METHODS: The study involved 171 caregivers and 245 elderly individuals in stationary facilities. Two structured questionnaires were used - one for caregivers and the other for institutionalized elderly residents, whose initial validation concerning question and factor selection has been based upon exploratory factor analysis and discriminant validity. Parametric and nonparametric tests were employed in the statistical analysis, and statistical significance was set at p<0.05 (two-sided). RESULTS: We found significant differences in the perception of elder abuse and neglect between caregivers and elderly residents. More specifically, caregivers tend to recognize unnecessary or inappropriate medical/care procedures as indicators of elder mistreatment, while the elderly residents emphasize the removal of their personal belongings and inappropriate physical contact. According to the care facility, residents reported abuse/neglect more frequently in extended care units (21.4%), compared to the county-owned nursing home (11.4%) and private nursing home (12.1%) (p=0.001). Similarly, caregivers reported abuse/neglect more frequently in extended care units (75.4%), in comparison to county-owned nursing home (24.6%) and private nursing home (0%) (p=0.039). Shift work was also a significant predictor, as the morning nursing staff perceived abuse/neglect more frequently (p=0.011). CONCLUSIONS: This study has shown that residents and caregivers have contrasting vantage points in relation to elder abuse/neglect perception, which underlines the need for evidence-based standardization of procedures to prevent any type of elder mistreatment.

DNA Damaging Effects, Oxidative Stress Responses and Cholinesterase Activity in Blood and Brain of Wistar Rats Exposed to Δ9-Tetrahydrocannabinol.

Currently we are faced with an ever-growing use of Δ9-tetrahydrocannabinol (THC) preparations, often used as supportive therapies for various malignancies and neurological disorders. As some of illegally distributed forms of such preparations, like cannabis oils and butane hash oil, might contain over 80% of THC, their consumers can become intoxicated or experience various detrimental effects. This fact motivated us for the assessments of THC toxicity in vivo on a Wistar rat model, at a daily oral dose of 7 mg/kg which is comparable to those found in illicit preparations. The main objective of the present study was to establish the magnitude and dynamics of DNA breakage associated with THC exposure in white blood and brain cells of treated rats using the alkaline comet assay. The extent of oxidative stress after acute 24 h exposure to THC was also determined as well as changes in activities of plasma and brain cholinesterases (ChE) in THC-treated and control rats. The DNA of brain cells was more prone to breakage after THC treatment compared to DNA in white blood cells. Even though DNA damage quantified by the alkaline comet assay is subject to repair, its elevated level detected in the brain cells of THC-treated rats was reason for concern. Since neurons do not proliferate, increased levels of DNA damage present threats to these cells in terms of both viability and genome stability, while inefficient DNA repair might lead to their progressive loss. The present study contributes to existing knowledge with evidence that acute exposure to a high THC dose led to low-level DNA damage in white blood cells and brain cells of rats and induced oxidative stress in brain, but did not disturb ChE activities.

A 'pathogenic needle' in a 'commensal haystack': Genetic virulence signatures of Corynebacterium glucuronolyticum that may drive its infectious propensity for the male urogenital system.

The predominance of the genus Corynebacterium in the healthy male urogenital system contributes to the resident microbiome of not only the distal urethra, but potentially the proximal urethra and urinary bladder as well. However, for certain species in this genus, pathogenic potential was described, and the salient representative is Corynebacterium glucuronolyticum (C. glucuronolyticum) implicated in cases of urethritis and prostatitis in men. Nonetheless, some still question whether C. glucuronolyticum can actually be considered pathogenic or rather just a commensal species fortuitously isolated in patients with urogenital symptoms and/or syndromes. Although pathogen/commensal dichotomy is not always clear-cut, we hypothesize that specific genetic markers may expose C. glucuronolyticum as a convincingly pathogenic Corynebacterium. More specifically, characteristic pathogenic gene constellation inherent to this species (most notably the presence of specific sortase/SpaA-type pili gene clusters, but also the augmentative role of type VII secretion system) may significantly facilitate host tissue adhesion, with subsequent suppression/evasion of the immune response and acquisition of vitally important nutrients. Consequently, these genetic markers differentiate C. glucuronolyticum from its commensal counterparts, and give this species a pathogenic facet, which can be even further influenced by the Allee effect. In this paper we also propose a specific methodological approach on how to analyze C. glucuronolyticum epithelial colonization capacity and explore inceptive host cell-pathogen interactions that manipulate host environment and immune responses. This entails moving from approaches based primarily on overall homology of primary sequences towards specific structure-function studies to precisely evaluate all stakeholders involved in pili assemblage, cell adhesion and the expression of other virulence traits. In the era of high precision medicine, the hypothesized roles of C. glucuronolyticum adhesion systems in both virulence and nutrient acquisition may also reveal promising targets for future drug developments.

Proposed dual antagonist approach for the prevention and treatment of urinary tract infections caused by uropathogenic Escherichia coli.

Urinary tract infections are among the most common infectious diseases worldwide, primarily caused by uropathogenic Escherichia coli (UPEC) strains that harbor type I pili and P pili on the surface. Standard E. coli therapy still entails antibiotic consumption, but urinary tract infections tend to recur at a very high rate. Due to the emergence of antibiotic resistant strains of UPEC, as well as high infection recurrence rates, there is a need for new approaches to efficiently treat and prevent urinary tract infections. Since aforementioned adhesive organelles are the principal virulence factors in UPEC, anti-adhesion strategy seems to be the most promising (and hitherto unexplored) treatment option. Here we propose an antiadhesive dual targeting approach towards FimH and PapG adhesive proteins placed on two key virulence factors for UPEC - type I fimbriae and P pili. Such dual antagonists will contain appropriate pharmacophores (mannose and natural cranberry-containing polyphenol) joined together and will more efficiently block the infection and prevent the progression of the disease in comparison to FimH and PapG as isolated targets. More specifically, polyphenol mannosides (due to the structural similarities with the most potent biaryl inhibitors) can act as high-affinity FimH ligands, while cranberry-associated polyphenol moiety can additionally inhibit the PapG-mediated adhesion. Proposed compound may also contribute to the antioxidant capacity of the human organism. In conclusion, this dual-target hypothesis for the prevention and treatment of UPEC infections represents an important foundation for further research on this topic.

Effective anti-adhesives of uropathogenic Escherichia coli.

Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) are among the most common infectious diseases in humans. Due to their frequent occurrence in the community and nosocomial settings, as well as the development of resistance to the commonly prescribed antimicrobial agents, an enormous financial burden is placed on healthcare systems around the world. Therefore, novel approaches to the prevention and treatment of UTIs are needed. Although UPEC may harbour a plethora of virulence factors, type I fimbriae and P pili are two of the most studied adhesive organelles, since the attachment to host cells in the urinary tract is a crucial step towards infection. Design of receptor analogues that competitively bind to UPEC surface adhesins placed at the top of pili organelles led to the development of anti-adhesive drugs that are increasingly recognized as important and promising alternatives to antibiotic treatment of UTIs.

Is the burnout syndrome associated with elder mistreatment in nursing homes: results of a cross-sectional study among nurses.

As this issue has not yet been addressed in Croatia, our aim was to explore the presence of the burnout syndrome in nurses and see how it is related to their perception of elder mistreatment in nursing homes and extended care units. The burnout syndrome was assessed in 171 nursing professionals with a standardised Maslach Burnout Inventory for Human Services Survey (MBI-HSS) for three dimensions: emotional exhaustion (EE), depersonalisation (DP), and personal accomplishment (PA). High EE was reported by 43.9 %, high DP by 22.2 %, and low PA by 39.8 % of the respondents. Their perception of elder abuse and neglect was investigated with two self-completion questionnaires. The answers suggest that elder mistreatment in Croatian nursing homes and extended care units is more common than expected: 55 % witnessed shouting at a resident in anger, 43 % insulting and swearing at a resident, 42 % force-feeding the resident, 39 % ignoring a resident when they called, and 38 % neglecting to turn or move a resident to prevent pressure sores. We also established associations between a number of questionnaire items on perceived abuse and neglect and the burnout syndrome dimensions and determined the items that predicted the type and level of burnout in our respondents. One way to avoid the pitfalls that lead to abuse and neglect is education in schools and at work. We believe our research could contribute to this end.

Biofeedback and neurofeedback application in the treatment of migraine.

INTRODUCTION: Biofeedback is a non-invasive method of measurement of physiological functions. Precise instruments measure the slightest changes of different body functions-which are then in a clear and understandable manner shown in the form of feedback. Person gets an insight into what is going on inside the body and thus learns to change the patterns of behavior to improve health and performance. Any changes that are wanted are rewarded, which leads to learning of the new patterns of behavior. Neurofeedback is a type of biofeedback which uses electrical activity in the brain. Certain disorders are associated with specific patterns of brain activity, and through neurofeedback it is possible to reduce or even remove symptoms of some disorders. In the treatment of migraine different biofeedback methods- such as breathing, training of vasoconstriction/vasodilatation and neurofeedback, may be applied. METHODS: This paper will describe the successful treatment of 25 years old girl who suffered for many years from painful migraine. She had in total 25 treatments during which listed biofeedback methods were used. The first part of the treatment was neurofeedback training on the central sensorimotor area, followed by respiration training and at the end by biofeedback training of vasoconstriction/vasodilatation. RESULTS AND CONCLUSION: The final result of the treatment was significant reduce in the frequency of migraine attacks and the pain reduction. Further study, have to be done with more patients and with placebo group to scientifically prove the effectiveness of the method.

Attitudes and knowledge of parents of preschool children about specific learning disabilities.

INTRODUCTION: Specific learning disorders include dyslexia - reading disorder, dysgraphia - writing disorder, dyspraxia and discoloration - difficulties with mathematical tasks. Along with these disorders, hyperactivity disorder and attention deficit are often associated with these disorders. According to available data, 2/3 of children who have difficulty reading, writing, and counting have a lack of attention. Diagnosing these disorders is an important task for parents, preschools and schools, because it is prerequisite for understanding and treatment. The aim of the research was to gain information how the parents of preschool children get information and knowledge about learning disabilities at children, were they able to recognize the symptoms, what was the main source of their information and whether information was understandable and reliable. METHODS: Five hundred (510) respondents participated in the survey. The survey was conducted from July to August 2016 and was conducted through a "google" application. The survey was placed at different social networks, and the participation in the survey was voluntary and anonymous with the note that parents of preschool and school children were participating. A survey of 10 questions with the offered answers was used in the survey. RESULTS AND CONCLUSION: The results have shown that parents majority of information get from Internet /which is understandable for this sample, because the survey was done through Internet/. Most parents received information through online pages, which did not always mean getting the correct information. They expressed a need for expert education and more public talk about children's learning disabilities. Parents have been interested in this topic, so it is necessary to organize different workshops and lectures that will be led by experts to provide reliable and useful information and to put more professional information on Internet for parents.

Characteristics and Distribution of Penile Lesions in Croatian Men with Laboratory-Confirmed Low-Risk and High-Risk Human Papillomavirus (HPV) Infection.

BACKGROUND: Studies that compare penoscopic evaluation with the results of molecular human papillomavirus (HPV) testing are scarce. This study assessed and compared both type and distribution of various penile lesions using penoscopy (peniscopy) technique in Croatian men with different, laboratory-confirmed HPV status. METHODS: From a large cohort of men attending an outpatient STD clinic for HPV testing, a total of 120 patients were randomly selected and grouped into those positive for low-risk HPV, high-risk HPV, both low-risk and highrisk HPV, and those with negative results. Samples for HPV-DNA detection were taken by penile brushing and tested with the hc2 HPV DNA Test using Hybrid Capture 2 technology. Lesions were observed by photocolposcope after the application of aqueous 5% acetic acid, and classified as flat (macular), papular, papillary, classical condyloma, PIN-suspicious and non-specific lesions. RESULTS: The results have shown that flat and non-specific acetowhite lesions were the most common overall. All groups differed significantly with respect to papular and papillary lesions. A combination of heterogeneous lesions (i.e., a mixed penoscopic pattern) was commonly observed in all HPV-positive groups, but was significantly lower in the HPV-negative group. A majority of lesions were located in the coronal sulcus, and the four groups differed with respect to the location only considering the lesions of the penile shaft. Distribution of lesions in different sites did not appear to be significantly different with respect to the group, although differences within the high-risk HPV group and the group with both low-risk and high-risk HPV were detected. CONCLUSIONS: Penoscopy is relevant, but not a conclusive diagnostic tool for differentiating HPV from non-HPV findings in men - thus combining it with an HPV DNA test represents a more reliable approach.