Oxidative stress in rat kidneys due to 3,4-methylenedioxymetamphetamine (ecstasy) toxicity

AIM: The mechanism of MDMA (3,4-methylenedioxymethamphetamine)-induced toxicity is believed to be, in part, due to enhanced oxidative stress. As MDMA is eliminated via the kidney, the aim of this study was to investigate whether MDMA created conditions of oxidative stress within rat kidney. METHODS: Adult male Wistar rats were divided into three groups, control treatment (water), acute MDMA administration (single oral dose: 5, 10, 20 or 40 mg/kg body weight) and subacute MDMA administration (5, 10, or 20 mg/kg body weight per day during 14 days). Animals were sacrificed 8 h after the single oral MDMA administration in the acute MDMA administration group and after the last MDMA administration in the subacute MDMA administration group. Rectal temperature measurements, oxidative stress status parameters and histological examinations were performed. RESULTS: In all MDMA-administered rats, rectal temperature markedly increased peaking approximately 1 h after MDMA ingestion. Superoxide dismutase activity and thiobarbituric acid reactive substances increased after MDMA administration. Histological examinations of the kidney revealed dose-dependent disruption of tissue structure in subacute MDMA-administered rats. The latter was not observed in acute MDMA-administered rats.     

Evaluation of negative emotional care experiences in burn care

Aim and objective. To assess recollection of negative emotional experiences during burn care. Background. Patients in intensive care frequently report negative emotional experiences. Patients with severe burns who are treated in intensive care units undergo painful care procedures, but there have been no recent evaluations of their care experiences. Design. Former burn patients (n = 42) were randomly assigned to three groups: postal questionnaire, telephone interview and face‐to‐face interview. Methods. Assessments included negative care experiences (feelings of uncertainty, powerlessness, being afraid, insecure, being a nuisance, or neglected), severity of injury, patient satisfaction, personality traits and psychological symptoms. Results. Overall, the degree of recalled negative experiences was low and associated with greater severity of injury, more symptoms of post‐traumatic stress disorder and lower satisfaction with care. The feeling of powerlessness was the most common, as 67% of participants had such feelings to some extent. Conclusions. Overall, negative care experiences were uncommon and most prevalent among the severely injured. Such experiences were also associated with psychological symptoms and lower patient satisfaction. Relevance to clinical practice. Although relatively uncommon, negative emotional care experiences should be monitored more closely during care.     

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Preclinical studies have shown that nitric oxide (NO)-donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NO-deprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatin-resistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting.     

Effects of electrical stimulation in C2C12 muscle constructs

Electrical stimulation affects the deposition of extracellular matrices and cellular differentiation. Type I collagen is one of the most abundant extracellular matrix proteins; however, not much is known about the effects of electrical stimulation on collagen type I deposition in C2C12 cells. Thus, we studied the effects of electrical voltage and stimulation frequency in 3D cultured C2C12 muscle cells in terms of metabolic activity, type I collagen deposition and cell morphology. Electrically excitable C2C12 muscle cells were seeded in collagen scaffolds and stimulated with rectangular signals of voltage (2, 5, 7 V) and frequency (1, 2 Hz), using parallel carbon electrodes spaced 1 cm apart. Metabolic activity was quantified by the glucose:lactate concentration ratio in the medium. Apoptotic activity was assessed by TUNEL staining and changes in collagen deposition were identified by immunohistology. The ultrastructure of the tissue was examined by TEM. Glucose and lactate analysis indicated that all groups had similar metabolic activity. TUNEL stain showed no significant difference in apoptotic damage induced by electrical stimulation compared to the control. Samples stimulated at 2 Hz exhibited reduced collagen deposition compared to the control and 1 Hz stimulated samples. Muscle-protein marker desmin was highly expressed in constructs stimulated with 1 Hz/5 V sample. TEM revealed that the stimulated samples developed highly organized sarcomeres, which coincided with improved contractile properties in the 1 Hz/5 V- and 2 Hz/5 V-stimulated groups. Our data implicate that a specific electrical frequency may modulate type I collagen accumulation and a specific voltage may affect the differentiation of muscle sarcomeres in excitable cells.     

Microalbuminuria in children with vesicoureteral reflux

Vesicoureteral reflux (VUR) is a common congenital anomaly of the urinary tract that may be inherited. Reflux of infected urine may cause scarring in susceptible kidneys with the potential to compromise renal function. The aim of the study was to evaluate the possible influence of different grades of VUR on glomerular damage using microalbuminuria as a parameter. Children with VUR detected by voiding cystourethrography (VCUG) were investigated. According to the grade of VUR, patients were separated into three groups. The first group included 12 children with VUR grade I-II. The second group consisted of 12 children with grade III of VUR. Patients with VUR grade IV-V (n = 11) were members of the third group. The control group consisted of 17 healthy children. Microalbuminuria was examined in samples of morning urine specimens using a microalbumin/creatinine reagent kit. Serum urea, creatinine levels and creatinine clearance (CCR) were measured as markers of renal function. The mean value of microalbumin excretion in the third group showed a statistically significant increase (p < 0.001) compared to all other groups. CCR in the third group was statistically significantly decreased (p < 0.05) in comparison to the group of healthy children. There were no statistically significant changes of microalbumin excretion and CCR in the first and second group compared to control values. We discussed the presence of microalbuminuria and decrease of CCR in children with high grade of VUR as a possible consequence of retrograde urine flow (intrarenal reflux), glomerulosclerosis, and consecutive hyperfiltration.     

Generalized regression neural networks in prediction of drug stability

This study had two aims. Firstly, we wanted to model the effects of the percentage of Eudragit RS PO and compression pressure as the most important process and formulation variables on the time course of drug release from extended-release matrix aspirin tablets. Secondly, we investigated the possibility of predicting drug stability and shelf-life using an artificial neural network (ANN). Ten types of matrix aspirin tablets were prepared as model formulations and were stored in stability chambers at 60 degrees C, 50 degrees C, 40 degrees C and 30 degrees C and controlled humidity. Samples were removed at predefined time points and analysed for acetylsalicylic acid (ASA) and salicylic acid (SA) content using stability-indicating HPLC. The decrease in aspirin content followed apparent zero-order kinetics. The amount of Eudragit RS PO and compression pressure were selected as causal factors. The apparent zero-order rate constants for each temperature were chosen as output variables for the ANN. A set of output parameters and causal factors were used as training data for the generalized regression neural network (GRNN). For two additional test formulations, Arrhenius plots were constructed from the experimentally observed and GRNN-predicted results. The slopes of experimentally observed and predicted Arrhenius plots were tested for significance using Student's t-test. For test formulations, the shelf life (t(95%)) was then calculated from experimentally observed values (t(95%) 82.90 weeks), as well as from GRNN-predicted values (t(95%) 81.88 weeks). These results demonstrate that GRNN networks can be used to predict ASA content and shelf life without stability testing for formulations in which the amount of polymer and tablet hardness are within the investigated range.     

On the origin of schizophrenia: Testing evolutionary theories in the post‐genomic era

Considering the relatively high heritability of schizophrenia and the fact that it significantly reduces the reproductive fitness of affected individuals, it is not clear how the disorder is still maintained in human populations at a disproportionally high prevalence. Many theories propose that the disorder is a result of a trade‐off between costs and benefits of the evolution of exclusively human adaptations. There have also been suggestions that schizophrenia risk alleles are accompanied with increase in fitness of affected persons or their relatives in both past and current social contexts. The discoveries of novel schizophrenia‐related genes and the advancements in comparative genomics (especially comparisons of the human genome and the genomes of related species, such as chimpanzees and extinct hominids) have finally made certain evolutionary theories testable. In this paper, we review the current understanding of the genetics of schizophrenia, the basic principles of evolution that complement our understanding of the subject, and the latest genetic studies that examine long‐standing evolutionary theories of schizophrenia using novel methodologies and data. We find that the origin of schizophrenia is complex and likely governed by different evolutionary mechanisms that are not mutually exclusive. Furthermore, the most recent evidence implies that schizophrenia cannot be comprehended as a trait that has elevated fitness in human evolutionary lineage, but has been a mildly deleterious by‐product of specific patterns of the evolution of the human brain. In other words, novel findings do not support previous hypotheses stating that schizophrenia risk genes have an evolutionary advantage.     

Diabetes mellitus type 2 as an underlying,comorbid or consequent state of mental disorders

Somatic disturbances that occur in parallel with psychiatric diseases are a major challenge in clinical practice. Various factors contribute to the development of mental and somatic disorders. Type 2 diabetes mellitus (T2DM) is a significant health burden worldwide, and the prevalence of diabetes in adults is increasing. The comorbidity of diabetes and mental disorders is very common. By sharing a bidirectional link, both T2DM and mental disorders influence each other in various manners, but the exact mechanisms underlying this link are not yet elucidated. The potential mechanisms of both mental disorders and T2DM are related to immune and inflammatory system dysfunction, oxidative stress, endothelial dysfunction, and metabolic disturbances. Moreover, diabetes is also a risk factor for cognitive dysfunction that can range from subtle diabetes-associated cognitive decline to pre-dementia and dementia. A complex re-lationship between the gut and the brain also represents a new therapeutic approach since gut-brain signalling pathways regulate food intake and hepatic glucose production. The aim of this minireview is to summarize and present the latest data on mutual pathogenic pathways in these disorders, emphasizing their complexity and interweaving. We also focused on the cognitive performances and changes in neurodegenerative disorders. The importance of implementing integrated approaches in treating both of these states is highlighted, along with the need for individual therapeutic strategies.