Oxidative stress in schizophrenia patients treated with long-acting haloperidol decanoate

In this study the role of oxidative stress in schizophrenia was investigated by evaluating the relationship of oxidative stress markers with neurochemistry, psychopathology, and extrapyramidal symptoms. Antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and concentrations of malondialdehyde, protein carbonyls, nitrite, nitrate, glutathione, dopamine, noradrenaline, adrenaline, and serotonin were measured in 52 outpatients with DSM-IV diagnosis of schizophrenia treated with haloperidol decanoate. Psychopathology and extrapyramidal symptoms were assessed by positive and negative syndrome scale, global assessment of functioning, abnormal involuntary movement scale, Simpson Angus scale, and Barnes akathisia rating scale. Haloperidol dose was positively correlated with plasma protein carbonyls. Longer duration of illness was associated with decreased levels of glutathione peroxidase. Increased activity of superoxide dismutase was associated with increased levels of catalase, glutathione peroxidase, glutathione reductase and reduced glutathione, and decreased concentration of malondialdehyde, indicating joint action of various antioxidative systems. Increased levels of nitrite and noradrenaline were associated with decreased level of malondialdehyde. Akathisia was greater in patients with decreased catalase activity, indicating involvement of impaired antioxidant defense in developing extrapyramidal symptoms. These results confirm the hypothesis that oxidative stress is involved in pathophysiology of schizophrenia and severity of extrapyramidal symptoms.     

Circular and linear: a tale of aptamer selection for the activation of SIRT1 to induce death in cancer cells

It is a challenge to select the right target to treat conditions without affecting non-diseased cells. Cancer belongs to the top 10 causes of death in the world and it remains difficult to treat. Amongst cancer emerging targets, silent information regulator 1 (SIRT1) – a histone deacetylase – has shown many roles in cancer, ageing and metabolism. Here we report novel SIRT1 ligands that bind and modulate the activity of SIRT1 within cells and enhance its enzymatic activity. We developed a modified aptamer capable of binding to and forming a complex with SIRT1. Our ligands are aptamers, they can be made of DNA or RNA oligonucleotides, their binding domain can recognise a target with very high affinity and specificity. We used the systematic evolution of ligands by exponential enrichment (SELEX) technique to develop circular and linear aptamers selectively binding to SIRT1. Cellular consequences of the interaction were monitored by fluorescence microscopy, cell viability assay, stability and enzymatic assays. Our results indicate that from our pool of aptamers, circular AC3 penetrates cancerous cells and is recruited to modulate the SIRT1 activity. This modulation of SIRT1 resulted in anticancer activity on different cancer cell lines. Furthermore, this modified aptamer showed no toxicity on one non-cancerous cell line and was stable in human plasma. We have demonstrated that aptamers are efficient tools for localisation of internal cell targets, and in this particular case, anticancer activity through modulation of SIRT1.

We report novel SIRT1 ligands that bind and modulate the activity of SIRT1 within cells and enhance its enzymatic activity. From a pool of aptamers we identify circular AC3 as having anticancer activity.     

Validation of flavonoids as potential dipeptidyl peptidase III inhibitors: Experimental and computational approach

Fifteen flavonoids were studied for their inhibitory activity against human dipeptidyl peptidase III (hDPP III) combining an in vitro assay with an in silico molecular modeling study. All analyzed flavonoids showed inhibitory effects against hDPP III with the IC₅₀ values ranging from 22.0 to 437.2 μm . Our 3D QSAR studies indicate that the presence of hydrophilic regions at a flavonoid molecule increases its inhibitory activity, while the higher percentage of hydrophobic surfaces has negative impact on enzyme inhibition. Furthermore, molecular dynamics (MD) simulations of the complex of hDPP III with one of the most potent inhibitors, luteolin, were performed, and binding mode analysis revealed that the 3′ and 4′ hydroxyl group on B‐ring as well as 5 and 7 hydroxyl group on A‐ring helps luteolin to interact with the Asn391, Asn406, Tyr417, His450, Glu451, Val447, Glu512, Asn545, Gln566, and Arg572 residues. The MD results clearly provide valuable information explaining the importance of flavonoid hydroxyl groups in the mechanism for the binding pattern at the active site of hDPP III.     

Prevalence and Factors Associated with Depression,Anxiety and Stress in IBD Patients Undergoing Intravenous Biological Therapy during the COVID-19 Pandemic-Montenegro Experience

Throughout its duration, the coronavirus disease 2019 (COVID-19) pandemic has been affecting lives worldwide and has had a sizeable impact on mental health, particularly for those who already suffer from a chronic illnesses. Depression, Anxiety and Stress (DAS) are common psychiatric comorbidities in inflammatory bowel disease (IBD) patients. This study aims to determine the prevalence and risk factors for moderate and severe symptoms of DAS in IBD patients have been undergoing intravenous biological therapy (IvBTh) during the COVID-19 pandemic. The study was conducted between September 1^st and November 30^th, 2020 at the Clinical Center of Montenegro-IBD unit, where all patients from Montenegro received the registered IvBTh. This case control study consists of 94 IBD patients that completed a validated questionnaire Depression, Anxiety and Stress Score-21 (DASS-21). A total of 59 patients received tumor necrosis factor alpha inhibitors (anti-TNF therapy), while 35 received anti-integrin therapy. After we calculated the DASS-21 score, we divided the patients into two groups: those who had moderate and severe symptoms (if they had any of the mentioned DASS-21 subscale score above limit for moderate or more severe symptoms: DASS-21 Depression, higher than 14; DASS-21 Anxiety, higher than 10 and DASS-21 Stress, higher than 19) and those who did not have significant symptoms (DASS-21 subscale score did not exceed the limit). We also examined demographic data, data on IBD characteristics and COVID-19 data and their impact on mental disorders. Standard statistical processing tests were used to identify risk factors for examined mental disorders. Following the DASS-21 criteria, we diagnosed the least moderate depression in 19.1%, anxiety in 14.9% and stress in 20.2% patients. The multivariate analysis indicated there to be a statistically significant relation of being higher at risk of developing depression, anxiety and stress when suffering from an active form of IBD (OR 6.487; 95% Cl 1.220–34.500, P = 0.028). Almost one third (30.9%) of patients have at least one of the examined mental disorders during the COVID-19 pandemic. Particular attention and efforts must be better focused on patients who suffer from an active form of IBD during the ongoing COVID-19 pandemic.     

Toxicity of pamam‐coated gold nanoparticles in different unicellular models

Polyamidoamine (PAMAM) dendrimers are used for many pharmaceutical and biomedical applications. However, the toxicological risks of several PAMAM‐based compounds are still not fully evaluated, despite evidences of PAMAM deleterious effects on biological membranes, leading to toxicity. In this report, we investigated the toxicity of generation 0 PAMAM‐coated gold nanoparticles (AuG0 NPs) in four different models to determine how different cellular systems are affected by PAMAM‐coated NPs. Toxicity was evaluated in two mammalian cell lines, Neuro 2A and Vero, in the green alga Chlamydomonas reinhardtii and the bacteria Vibrio fischeri. AuG0 NP treatments reduced cell metabolic activity in algal and bacterial cells, measured by esterase enzymatic activity (C. reinhardtii) and luminescence emission (V. fischeri). EC50 value after 30 min of treatment was similar in both organisms, with 0.114 and 0.167 mg mL^?1 for C. reinhardtii and V. fischeri, respectively. On the other hand, AuG0 NPs induced no change of mitochondrial activity in mammalian cells after 24 h of treatment to up to 0.4 mg mL^?1 AuG0 NPs. Change in the absorption spectra of AuG0 NP in the mammalian cell culture media may indicate an alteration of NP properties that contributed to the low toxicity of AuG0 NPs in mammalian cells. For a safe development of PAMAM‐based nanomaterials, the difference of sensitivity between mammalian and microbial cells, as well as the modulation of NPs toxicity by medium properties, should be taken into account when designing PAMAM NPs for applications that may lead to their introduction in the environment. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 328–336, 2014.     

Clinical characteristics and functional outcome of patients with West Nile neuroinvasive disease in Serbia

Neurologic manifestations are prominent characteristic of West Nile virus (WNV) infection. The aim of this article was to describe neurological manifestations in patients with WNV neuroinvasive disease and their functional outcome at discharge in the first human outbreak of WNV infection in Serbia. The study enrolled patients treated in the Clinic for Infectious and Tropical Diseases, Clinical Center Serbia in Belgrade, with serological evidence of acute WNV infection who presented with meningitis, encephalitis and/or acute flaccid paralyses (AFP). Functional outcome at discharge was assessed using modified Rankin Scale (mRS) and Barthel index. Fifty-two patients were analysed. Forty-four (84.6 %) patients had encephalitis, eight (15.4 %) had meningitis, and 13 (25 %) had AFP. Among patients with AFP, 12 resembled poliomyelitis and one had clinical and electrodiagnostic findings consistent with polyradiculoneuritis. Among patients with encephalitis, 17 (32.7 %) had clinical signs of rhombencephalitis, and eight (15.4 %) presented with cerebellitis. Respiratory failure with subsequent mechanical ventilation developed in 13 patients with WNE (29.5 %). Nine (17.3 %) patients died, five (9.6 %) were functionally dependent (mRS 3–5), and 38 (73.1 %) were functionally independent at discharge (mRS 0–2). In univariate analysis, the presence of AFP, respiratory failure and consciousness impairment were found to be predictors of fatal outcome in patients with WNV neuroinvasive disease (p < 0.001, p < 0.001, p = 0.018, respectively). The outbreak of human WNV infection in Serbia caused a notable case fatality ratio, especially in patients with AFP, respiratory failure and consciousness impairment. Rhombencephalitis and cerebellitis could be underestimated presentations of WNV neuroinvasive disease.     

An early shoulder repositioning program in birth-related brachial plexus injury: a pilot study of the Sup-ER protocol

Background

Birth-related brachial plexus injury (BRBPI) occurs in 1.2/1,000 births in British Columbia. Even in children with “good” recovery, external rotation (ER) and supination (Sup) are often weaker, and permanent skeletal imbalance ensues. A preventive early infant shoulder passive repositioning program was created using primarily a novel custom splint holding the affected arm in full ER and Sup: the Sup-ER splint. The details of the splint and the shoulder repositioning program evolved with experience over several years. This study reviews the first 4 years.

Methods

A retrospective review of BCCH patients managed with the Sup-ER protocol from 2008 to 2011 compared their recovery scores to matched historical controls selected from our database by two independent reviewers.

Results

The protocol was initiated in 18 children during the study period. Six were excluded due to the following: insufficient data points, non-compliance, late splint initiation, and loss to follow-up. Of the 12 matches, the Sup-ER group final score at 2 years was better than controls by 1.18 active movement scale (AMS) points (p = 0.036) in Sup and 0.96 AMS points in ER (but not statistically significant (p = 0.13)). Unexpectedly, but importantly, during the study period, zero subjects were assessed to have the active functional criteria to indicate brachial plexus reconstruction, where previously we operated on 13 %.

Conclusions

Early application of passive shoulder repositioning into Sup and ER may improve outcomes in function of the arm in infants with BRBPI. A North American multi-site randomized control trial has been approved and has started recruitment.     

Potential of Using Wood Biomass Ash in Low-Strength Composites

Reducing greenhouse gas emissions and dependence on fossil fuels is the cornerstone of all European climate and energy strategies. Consequently, renewable energy sources are becoming more competitive with fossil fuels. The largest source of bioenergy in the European Union is biomass-fired power plants. Therefore, the European coal phase-out strategy led to an increased use of wood biomass as a sustainable fuel, generating large amounts of wood biomass ash (WBA). In the research studies reported so far, WBA has been mainly used in cementitious composites. However, given the similarities between the chemical composition of WBA and hydraulic lime (HL), this research focused on its potential classification as a building lime. Overall, three different sources of fly WBA were considered for the preparation of binders as mixtures of WBA and coal fly ash (CFA) in different ratios. The contribution of each binder mixture on the paste and mortar properties was analyzed based on the chemical composition, setting time, volume stability, and contribution to the mortar strength (compressive and flexural). In general, it can be concluded that the studied binders can meet the criteria of EN 459-1. However, special attention should be paid to the volume deformations and the setting time.