In Vitro Evaluation of Vancomycin-Induced Toxicity in Human Primary Knee Chondrocytes.

Septic arthritis as a complication of orthopaedic joint surgery can have catastrophic outcomes for patients. To minimise infection risk associated with elective orthopaedics, topical vancomycin during surgery has become increasingly common. Evidence suggests that high concentrations of vancomycin, following direct application of the drug to the joint, are toxic towards various local cell types in the joint, including chondrocytes. However, the mechanism of this vancomycin tissue toxicity is yet to be determined. The aim of this study was to evaluate the toxicity of vancomycin on chondrocytes and the mechanisms of cell death involved. Human primary knee chondrocytes were exposed to vancomycin (1.25-10 mg/mL) for 24 h and their viability assessed using the resazurin reduction assay in vitro. Specific cell death mechanisms and their contributors, including reactive oxygen species (ROS) production and apoptosis, were measured. This study showed that high concentrations of vancomycin (5 and 10 mg/mL) were toxic towards human primary knee chondrocyte cells, while lower concentrations (1.25 and 2.5 mg/mL) were not. Cell death studies found that this occurred through an apoptotic pathway. This study provides additional support that vancomycin in high doses is toxic towards chondrocytes and preliminary evidence that this toxicity occurs via apoptotic cell death mechanisms.

Emergency department presentations during the COVID-19 pandemic in Queensland (to June 2021): interrupted time series analysis.

OBJECTIVES: To assess emergency department (ED) presentation numbers in Queensland during the coronavirus disease 2019 (COVID-19) pandemic to mid-2021, a period of relatively low COVID-19 case numbers. DESIGN: Interrupted time series analysis. SETTING: All 105 Queensland public hospital EDs. MAIN OUTCOME MEASURES: Numbers of ED presentations during the COVID-19 lockdown period (11 March 2020 - 30 June 2020) and the period of easing restrictions (1 July 2020 - 30 June 2021), compared with pre-pandemic period (1 January 2018 - 10 March 2020), overall (daily numbers) and by Australasian Triage Scale (ATS; daily numbers) and selected diagnostic categories (cardiac, respiratory, mental health, injury-related conditions) and conditions (stroke, sepsis) (weekly numbers). RESULTS: During the lockdown period, the mean number of ED presentations was 19.4% lower (95% confidence interval, -20.9% to -17.9%) than during the pre-pandemic period (predicted mean number: 5935; actual number: 4786 presentations). The magnitudes of the decline and the time to return to predicted levels varied by ATS category and diagnostic group; changes in presentation numbers were least marked for ATS 1 and 2 (most urgent) presentations, and for presentations with cardiac conditions or stroke. Numbers remained below predicted levels during the 12-month post-lockdown period for ATS 5 (least urgent) presentations and presentations with mental health problems, respiratory conditions, or sepsis. CONCLUSIONS: The COVID-19 pandemic and related public restrictions were associated with profound changes in health care use. Pandemic plans should include advice about continuing to seek care for serious health conditions and health emergencies, and support alternative sources of care for less urgent health care needs.

Amphiphilic Polyamine α-Synuclein Aggregation Inhibitors from the Sponge Aaptos lobata.

Bioassay-guided investigation of the sponge Aaptos lobata resulted in the isolation and identification of two new amphiphilic polyamines, aaptolobamines A (1) and B (2). Their structures were determined through analysis of NMR and MS data. MS analysis also indicated that A. lobata contained a complex mixture of aaptolobamine homologues. Both aaptolobamines A (1) and B (2) show broad bioactivity, including cytotoxicity against cancer cell lines, moderate antimicrobial activity against a methicillin-resistant strain of Staphylococcus aureus, and weak activity against a Pseudomonas aeruginosa strain. The mixtures of aaptolobamine homologues were shown to contain compounds that bind to the Parkinson's disease associated amyloid protein α-synuclein and inhibit its aggregation.

Involvement of indoleamine 2, 3-dioxygenase (IDO) and brain-derived neurotrophic factor (BDNF) in the neuroprotective mechanisms of ferulic acid against depressive-like behaviour.

OBJECTIVE: Ferulic acid (FA) is a common food ingredient that is abundantly present in various routinely consumed food and beverages. Like many cinnamic acid derivatives, FA produces wide-ranging effects in a dose-dependent manner and various studies link FA consumption with reduced risk of depressive disorders. The aim of this study was to exploit the neuroprotective mechanisms of FA including indoleamine 2,3-dioxygenase (IDO), brain-derived neurotrophic factor (BDNF), and other pro-inflammatory cytokines by employing lipopolysaccharide (LPS)-induced depressive-like behaviour model. METHODS: C57BL/6J male mice were divided into 4 groups consisting of saline (SAL), LPS, FA and Imipramine (IMI). Animals were pretreated orally with FA (10 mg/kg) and IMI (10 mg/kg) for 21 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 21. RESULTS: LPS administration produced a biphasic change in the behaviour of the animals where the animals lost a significant weight and express high immobility time at 24 h. Proinflammatory cytokines including, TNF-α, IL-6, IL-1ß, and IFN-γ were significantly increased along with increased lipid peroxidation and reduced BDNF. Furthermore, the increased kynurenine to tryptophan ratio was indicative of elevated IDO activity. CONCLUSION: The results of this study emphasise that low dose of FA is effective in attenuating depressive-like behaviour by modulating IDO, BDNF and reducing neuroinflammation.

A systematic review of methodology for the creation of virtual 3D models for use in dental education and a narrative review.

OBJECTIVES: Virtual Reality (VR) technologies can be used as a content-delivery system for the purposes of both entertainment and education. Remote and digital education has become ever so important in a world where global disruptive events such as pandemics and natural disasters can define access to a face-to-face learning environment. An important aspect of VR technologies for dentistry is the creation of digital 3D models. The primary of this review was to answer the focused research question, "What software techniques are used in the creation of digital 3D models for use in dental education." METHODS: This study systematically evaluates current software and techniques used for creating digital 3D models in dental education using the Preferred Reporting Items for Systematic Reviews (PRIMSA). RESULTS: The search strategies did not find any studies specific to the creation of dental-related 3D models. Therefore, this study for the first time provided an overview of common techniques of 3D model fabrication is discussed. Further some examples of methods of creating 3D models relevant to dentistry such armamentarium and anatomical oral structures have been discussed in considerable detail. CONCLUSION: The creation of 3D modelling is a rapidly evolving field with software updates and new programs being continually released. This work highlights fundamental lack of published work in the creation of 3D dental models for educational applications.

An education on pharmacologically active complementary and alternative medicine and its effects on cancer treatment: literature review.

PURPOSE: This literature review examines the provision of an education on pharmacologically active complementary and alternative medicines (CAMs), to people with cancer, their carers and oncology health professionals. METHODS: A search of the published literature between 2000 and 2020, in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, was conducted. The search retrieved 1121 studies, 1080 were excluded based on their title or abstract and 26 articles were excluded based on their text. One article was retrieved from the reference lists of the included articles and in total fifteen studies met the inclusion criteria. This review utilised Medical Education Research Quality Instrument (MERSQI) to evaluate the quality of the included studies. Four key outcomes were utilised for analysis and recommendations for future education and/or research were generated. The recommendations were graded according to the Strength of Recommendation Taxonomy (SORT). RESULTS: This review consistently found that people with cancer, their carers and oncology health professionals derived benefit from a pharmacologically active CAM education and recommends that this population receives one. Conversely, the review found many education formats utilised and no consensus on the most successful methods. CONCLUSION: Future research should examine who a CAM education should be delivered to, what type of delivery platform is most accessible and useful, and the features of the education that most increase CAM knowledge. The popularity of CAMs amongst people with cancer and the potential dangers associated with their use necessitates further research into how best to communicate CAMs to this population.

Remedial effects of caffeine against depressive-like behaviour in mice by modulation of neuroinflammation and BDNF.

Objective: Caffeine (CAF) is one of the most commonly consumed nutritional stimulant in beverages. Interestingly, CAF produces varied effects in a dose-dependent manner, and that makes it one of the most controversial nutritional ingredients. Various studies have linked CAF consumption and reduced risk of depressive disorders. The aim of this study was to investigate the effect of CAF on lipopolysaccharide (LPS)-induced neuroinflammation and depressive-like behaviour.Methods: C57BL/6J male mice were divided into four groups consisting of saline (SAL), LPS, CAF and Imipramine (IMI). Animals were pretreated orally with CAF (10 mg/kg) and IMI (10 mg/kg) for 14 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 14.Results: LPS produced a biphasic behavioural response with a significantly high immobility time and weight loss after 24 h. The brain cytokines (TNF-α, IL-6, IL-1ß, and IFN-γ) levels were remarkably high, along with increased lipid peroxidation and reduced Brain Derived Neurotrophic Factor (BDNF). These biochemical and behavioural changes were significantly alleviated by CAF and IMI chronic treatment.Conclusion: The results of this study implicate that mild-moderate consumption of CAF could impart anti-inflammatory properties under neuroinflammatory conditions by modulating the cytokine and neurotrophic mechanisms.

Putative involvement of sirtuin modulators in LPS-induced sickness behaviour in mice.

NAD+-dependent histone deacetylases (sirtuins 1-7) have been shown to be involved in various pathophysiological conditions including their involvement in cardiovascular, cancerous, neurodegenerative, immune dysregulation and inflammatory conditions. This study investigates the inflammomodulatory potential of resveratrol (RES), a sirtuin activator and sirtinol (SIR), a sirtuin inhibitor in lipopolysaccharide (LPS)-induced model of sickness behaviour in mice. Male Swiss albino mice were divided into five groups (n = 6) consisting of saline (SAL), LPS, RES, SIR, and fluoxetine (FLU) respectively, each group except LPS was prepared by intraperitoneally (i.p.) administration of SAL (10 mL/kg), RES (50 mg/kg), SIR (2 mg/kg) and FLU (10 mg/kg). Thirty minutes after the treatments, all the groups, except SAL were administered LPS (2 mg/kg, i.p.). The behavioural assays including, open field test, forced swim test, and tail suspension tests were conducted 1 h after LPS challenge. LPS administration significantly reduced the locomotor activity along with inducing a state of high immobility and that was prevented by pretreatment with RES and SIR. Further, various proinflammatory cytokines (TNF-α, IL-6, and IL-1ß), and oxidative stress markers (MDA and GSH) were found to be significantly elevated in the brain homogenates after LPS treatment. SIR pretreatment abrogated the LPS-induced neuroinflammatory and oxidative stress changes, whereas RES was only effective in reducing the oxidative stress and TNF-α levels. The results of this study speculate that the role of SIRT modulators in neuroinflammatory conditions could vary with their dose, regimen and chemical properties. Further studies with detailed molecular and pharmacokinetic profiling will be needed to explore their therapeutic potentials.

Evaluation of the vestibular/ocular motor screening assessment in active combat sport athletes: an exploratory study.

OBJECTIVE: The first aim of this study was to compare the results of the vestibular/ocular motor screening (VOMS) in combat sport athletes with a healthy control population. Second, to explore differences between athletes with and without a concussion history. Third, to examine the relationship between VOMS and the Post-Concussion Symptom Scale (PCSS) in combat sport athletes. PARTICIPANTS: Forty active male combat sport athletes and 40 healthy male control participants were recruited from 4 clubs and a University in Australia. METHODS: Participants completed the VOMS in a primary care physiotherapy clinic. Participants completed an injury questionnaire and the PCSS. RESULTS: An "abnormal" score in at least one subtest or near point convergence (NPC) was recorded in 45% of the combat group compared with 22.5% of the control group. All VOMS scores and NPC distance were greater in the combat group compared with control group (p < 0.05). The VOMS scores were found to be moderately positively correlated with the PCSS. There was no difference in VOMS between athletes with and without a history of concussion (p > 0.05). CONCLUSION: VOMS scores differed between combat sport athletes and control participants. The PCSS may aid clinicians in identifying athletes who have underlying vestibular/oculomotor impairment.

Design, synthesis and bioactivity evaluation of novel pyrazole linked phenylthiazole derivatives in context of antibacterial activity.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant burden both clinically and economically worldwide. Increasing resistance to current antibiotics requires an urgent investigation into novel classes of antimicrobial agents. This study presents a structure-activity relationship (SAR) rationale for pyrazole linked phenylthiazole analogues as new antibacterial agents. A library of 23 novel pyrazole linked phenylthiazole compounds were synthesised, followed by screening for antimicrobial activity against five bacterial species and two fungi. The most active compound 14b has shown promising antibacterial activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) strain (MIC 4 µg/mL). Furthermore, the active pyrazole linked phenylthiazole compound exhibited a better toxicity profile than standard antibiotics. In summary, these results demonstrate that a pyrazole linked phenylthiazole scaffold has potential as a lead for further investigation to afford novel antibacterial agents.

Epothilone D inhibits microglia-mediated spread of alpha-synuclein aggregates.

Multiple System Atrophy (MSA) is a progressive neurodegenerative disease characterized by chronic neuroinflammation and widespread α-synuclein (α-syn) cytoplasmic inclusions. Neuroinflammation associated with microglial cells is typically located in brain regions with α-syn deposits. The potential link between microglial cell migration and the transport of pathological α-syn protein in MSA was investigated. Qualitative analysis via immunofluorescence of MSA cases (n = 4) revealed microglial cells bearing α-syn inclusions distal from oligodendrocytes bearing α-syn cytoplasmic inclusions, as well as close interactions between microglia and oligodendrocytes bearing α-syn, suggestive of a potential transfer mechanism between microglia and α-syn bearing cells in MSA and the possibility of microglia acting as a mobile vehicle to spread α-syn between anatomically connected brain regions. Further In vitro experiments using microglial-like differentiated THP-1 cells were conducted to investigate if microglial cells could act as potential transporters of α-syn. Monomeric or aggregated α-syn was immobilized at the centre of glass coverslips and treated with either cell free medium, undifferentiated THP-1 cells or microglial-like phorbol-12-myristate-13-acetate differentiated THP-1 cells (48 h; n = 3). A significant difference in residual immobilized α-syn density was observed between cell free controls and differentiated (p = 0.016) as well as undifferentiated and differentiated THP-1 cells (p = 0.032) when analysed by quantitative immunofluorescence. Furthermore, a significantly greater proportion of differentiated cells were observed bearing α-syn aggregates distal from the immobilized protein than their non-differentiated counterparts (p = 0.025). Similar results were observed with Highly Aggressive Proliferating Immortalised (HAPI) microglial cells, with cells exposed to aggregated α-syn yielding lower residual immobilized α-syn (p = 0.004) and a higher proportion of α-syn positive distal cells (p = 0.001) than cells exposed to monomeric α-syn. Co-treatment of THP-1 groups with the tubulin depolymerisation inhibitor, Epothilone D (EpoD; 10 nM), was conducted to investigate if inhibition of microtubule activity had an effect on cell migration and residual immobilized α-syn density. There was a significant increase in both residual immobilized α-syn between EpoD treated and non-treated differentiated cells exposed to monomeric (p = 0.037) and aggregated (p = 0.018) α-syn, but not with undifferentiated cells. Differentiated THP-1 cells exposed to immobilized aggregated α-syn showed a significant difference in the proportion of distal aggregate bearing cells between EpoD treated and untreated (p = 0.027). The results suggest microglia could play a role in α-syn transport in MSA, a role which could potentially be inhibited therapeutically by EpoD.

Possible involvement of metformin in downregulation of neuroinflammation and associated behavioural changes in mice.

Metformin (MET), a biguanide oral hypoglycaemic agent, recently has been shown to be effective in various conditions other than type-2 diabetes including cancer, stroke, weight reduction, and polycystic ovarian syndrome, to name a few. MET has also possessed antioxidant and antiinflammatory properties by activation of AMPK . This study was aimed at evaluating the effects of MET on lipopolysaccharide (LPS)-induced systemic and neuroinflammation, oxidative stress, and behavioural changes. The study consisted of six groups, where three selected doses of MET (100, 200, and 300 mg/kg) were employed in male Swiss albino mice, with one group of imipramine (IMI), saline, and LPS each. Systemic inflammation was induced by injecting LPS (1.5 mg/kg) by intraperitoneal route. A battery of behavioural tests including open field, forced swim, and tail suspension tests were employed to assess the impact of systemic inflammation on exploratory behaviour and learned helplessness. LPS induced significant immobility with profound symptoms of sickness behaviour. Furthermore, LPS led to significant increase in serum and brain proinflammatory cytokines TNF-α and IL-6; and also increased lipid peroxidation with reduced glutathione levels. Pretreatment of the animals with 100 and 200 mg/kg of MET significantly reduced both systemic and central inflammatory markers along with protecting against LPS-induced oxidative stress. The higher dose, 300 mg/kg of MET was not effective against most of LPS-induced biochemical changes. Our preliminary results from this study suggest the antiinflammatory and neuroprotective effects of MET in LPS-induced model of sickness behaviour and neuroinflammation.

Scleroderma fibroblasts suppress angiogenesis via TGF-ß/caveolin-1 dependent secretion of pigment epithelium-derived factor.

OBJECTIVES: Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-ß) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, its role in defective angiogenesis is less clear. Pigment epithelium-derived factor (PEDF), a major antiangiogenic factor, is abundantly secreted by SSc fibroblasts. Here, we investigated the effect of TGF-ß and Cav-1 on PEDF expression and the role of PEDF in the ability of SSc fibroblasts to modulate angiogenesis. METHODS: PEDF and Cav-1 expression in fibroblasts and endothelial cells were evaluated by means of immunohistochemistry on human and mouse skin biopsies. PEDF and Cav-1 were silenced in cultured SSc and control fibroblasts using lentiviral short-hairpin RNAs. Organotypic fibroblast-endothelial cell co-cultures and matrigel assays were employed to assess angiogenesis. RESULTS: PEDF is highly expressed in myofibroblasts and reticular fibroblasts with low Cav-1 expression in SSc skin biopsies, and it is induced by TGF-ß in vitro. SSc fibroblasts suppress angiogenesis in an organotypic model. This model is reproduced by silencing Cav-1 in normal dermal fibroblasts. Conversely, silencing PEDF in SSc fibroblasts rescues their antiangiogenic phenotype. Consistently, transgenic mice with TGF-ß receptor hyperactivation show lower Cav-1 and higher PEDF expression levels in skin biopsies accompanied by reduced blood vessel density. CONCLUSIONS: Our data reveal a new pathway by which TGF-ß suppresses angiogenesis in SSc, through decreased fibroblast Cav-1 expression and subsequent PEDF secretion. This pathway may present a promising target for new therapeutic interventions in SSc.

Effect of 8-weeks prebiotics/probiotics supplementation on alcohol metabolism and blood biomarkers of healthy adults: a pilot study.

PURPOSE: Modulating gut bacteria via regular prebiotics/probiotics consumption may improve the metabolism of acute alcohol ingestion. This study investigated the impact of 8-weeks prebiotics/probiotics supplementation on microbiome changes and responses to acute alcohol consumption. METHODS: 38 participants (21 females, 23.6 ± 3.4 kg m-2, mean ± SD) attended the laboratory on two occasions separated by an 8-week intervention period. On each of these visits, a dose of alcohol (0.40 ± 0.04 g kg-1, Vodka + Soda-Water) was consumed over 10 min. Breath alcohol concentration was sampled over 5 h and alcohol pharmacokinetics was analysed using WinNonlin non-compartmental modelling (C max, t max, AUClast). For the intervention, participants were randomised to receive Placebo + Placebo (PLA), Placebo + Prebiotics (PRE), Probiotics + Placebo (PRO), or Probiotics + Prebiotics (SYN) in a double-blinded manner. Probiotics were a commercially available source of Lactobacillus acidophilus (NCFM®) and Bifidobacterium lactis (Bi-07). Prebiotics were a commercially available source of Larch Gum (from Larix occidentalis). Placebo was microcrystalline cellulose. Each visit, participants provided a stool sample, which was analysed to determine the presence of L. acidophilus and B. lactis. Differences between trials were analysed using paired samples t tests. RESULTS: Increased counts for at least one bacterial strain (L. acidophilus or B. lactis) were observed for all participants on SYN (n = 10) and PRO (n = 10) trials. No difference in C max or t max was observed between trials when analysed by treatment condition or microbiome outcome. A significant decrease in AUClast was observed between trials for PLA (p = 0.039) and PRE (p = 0.030) treatments, and when increases in at least one bacterial strain (p = 0.003) and no microbiome changes (p = 0.016) were observed. CONCLUSION: Consumption of probiotics appears to alter faecal counts of supplemental bacterial strains in otherwise healthy individuals. However, translation to any possible beneficial impact on alcohol metabolism remains to be elucidated.

Interplay between adenosine receptor antagonist and cyclooxygenase inhibitor in haloperidol-induced extrapyramidal effects in mice.

Antipsychotic drugs are the mainstay of psychotic disorders. The 'typical' antipsychotic agents are commonly employed for the positive symptoms of schizophrenia, though at an expense of extrapyramidal side effects (EPS). In the present study, we employed haloperidol (HP)-induced catalepsy model in mice to evaluate the role of adenosine receptor antagonist and cyclooxygenase (COX) enzyme inhibitor in the amelioration of EPS. HP produced a full blown catalepsy, akinesia and a significant impairment in locomotion and antioxidant status. Pre-treatment with COX inhibitor; naproxen (NPx) and adenosine receptor antagonist; caffeine (CAF), showed a significant impact on HP-induced cataleptic symptoms. Adenosine exerts pivotal control on dopaminergic receptors and is also involved in receptor internalization and recycling. On the other hand, prostaglandins (PGs) are implicated as neuro-inflammatory molecules released due to microglial activation in both Parkinson's disease (PD) and antipsychotics-induced EPS. The involvement of these neuroeffector molecules has led to the possibility of use of CAF and COX inhibitors as therapeutic approaches to reduce the EPS burden of antipsychotic drugs. Both these pathways seem to be interlinked to each other, where adenosine modulates the formation of PGs through transcriptional modulation of COXs. We observed an additive effect with combined treatment of NPx and CAF against HP-induced movement disorder. These effects lead us to propose that neuromodulatory pathways of dopaminergic circuitry need to be explored for further understanding and utilizing the full therapeutic potential of antipsychotic agents.

Pyocyanin induces systemic oxidative stress, inflammation and behavioral changes in vivo.

Pyocyanin (PCN) is a virulence factor secreted by Pseudomonas aeruginosa (P. aeruginosa) that has been shown to have numerous toxic effects in both in vitro and in vivo studies. Such toxicities include pro-inflammatory and pro-oxidant mediated responses. It is hypothesized that PCN can cross biological membranes and reach the systemic circulation, but no previous studies have investigated this. The aim of this study was, therefore, to quantify PCN in plasma and assess if systemic responses were occurring after localized intranasal administration in C57BL/6 J mice. This was achieved through the plasma quantification of PCN and assessment of changes to behavior using two commonly used tests, the forced swimming test and the open field test. Furthermore, evidence of systemic oxidative stress and inflammation was measured using malondialdehyde (MDA) and TNF-α post PCN exposure. PCN was found to cross into systemic circulation but in a variable manner. Furthermore, significant increases in plasma TNF-α and MDA (both p < 0.001) were observed along with changes in behavior indicative of systemic inflammatory responses.

Modulation of chemotherapy-induced cytotoxicity in SH-SY5Y neuroblastoma cells by caffeine and chlorogenic acid.

Chemotherapy is an important treatment modality for malignancy but is limited by significant toxicity and it susceptibility to numerous drug interactions. While the interacting effects with medications are well known, there is limited evidence on the interaction with commonly consumed food and natural products. The aim of this study was to evaluate the bioactive constituents of coffee (caffeine and chlorogenic acid) on the cytotoxicity of doxorubicin, gemcitabine, and paclitaxel in vitro. Pretreatment with caffeine (100 nM and 10 µM) sensitized SH-SY5Y cells to doxorubicin-induced toxicity and increased apoptosis and sensitized PC3 cells to gemcitabine-induced toxicity. Pretreatment with 10 µM caffeine decreased total cell reactive oxygen species (ROS) production but increased mitochondrial ROS production. In contrast, caffeine (10 nM and 10 µM) protected cells against gemcitabine-induced toxicity and apoptosis. Similarly, 1 µM and 10 µM caffeine protected cells against paclitaxel-induced toxicity and mitochondrial ROS production. Chlorogenic acid had no effect on chemotherapy-induced toxicity in SH-SY5Y cells. In conclusion, this study provides preliminary evidence that caffeine, not chlorogenic acid, modulates the cytotoxicity of doxorubicin, gemcitabine, and paclitaxel in SH-SY5Y cells via different mechanisms.

Pyocyanin inhibits both nitric oxide-dependent and -independent relaxation in porcine coronary arteries.

The effects of the Pseudomonas aeruginosa virulence factor pyocyanin (PCN) on the contractile function of porcine coronary arteries was investigated in vitro. Artery rings (5 mm) were suspended in organ baths containing Krebs' solution for the measurement of isometric tension. The effect of PCN on resting and precontracted coronary arteries was initially investigated with various agents. Arteries were precontracted with prostaglandin (PG) F2α or potassium chloride and endothelium-dependent relaxations were induced by various agents in the presence of PCN. Pyocyanin (0.1-10 µmol/L) evoked small-amplitude, dose-dependent contractions in resting porcine coronary arteries. In addition, PCN amplified the contractile response to PGF2α , but did not alter responses to carbachol. Pyocyanin (0.1-10 µmol/L) significantly inhibited endothelium-dependent relaxations evoked by neurokinin A. Pyocyanin also inhibited relaxations evoked by diethylamine nitric oxide (a nitric oxide donor), forskolin (an adenylate cyclase activator), dibuytyryl-cAMP (a cAMP analogue), 8-bromo-cGMP (a cGMP analogue) and P1075 (a KATP channel activator), but not isoprenaline (ß-adrenoceceptor agonist). These results indicate that physiological concentrations of PCN interfere with multiple intracellular processes involved in vascular smooth muscle relaxation, in particular pathways downstream of nitric oxide release. Thus, PCN may alter normal vascular function in patients infected with P. aeruginosa.

Manipulations to the Alcohol and Sodium Content of Beer for Postexercise Rehydration.

The addition of 25 mmol·L(-1) sodium to low alcohol (2.3% ABV) beer has been shown to enhance post exercise fluid retention compared with full strength (4.8% ABV) beer with and without electrolyte modification. This investigation explored the effect of further manipulations to the alcohol and sodium content of beer on fluid restoration following exercise. Twelve male volunteers lost 2.03 ± 0.19% body mass (mean ± SD) using cycling-based exercise. Participants were then randomly allocated a different beer to consume on four separate occasions. Drinks included low alcohol beer with 25 mmol·L-1 of added sodium [LightBeer+25], low alcohol beer with 50 mmol·L(-1) of added sodium [LightBeer+50], midstrength beer (3.5% ABV) [Mid] or midstrength beer with 25 mmol·L(-1) of added sodium [Mid+25]. Total drink volumes in each trial were equivalent to 150% of body mass loss during exercise, consumed over a 1h period. Body mass, urine samples and regulatory hormones were obtained before and 4 hr after beverage consumption. Total urine output was significantly lower in the LightBeer+50 trial (1450 ± 183 ml) compared with the LightBeer+25 (1796 ± 284 ml), Mid+25 (1786 ± 373 ml) and Mid (1986 ± 304 ml) trials (all p < .05). This resulted in significantly higher net body mass following the LightBeer+50 trial (-0.97 ± 0.17 kg) compared with all other beverages (LightBeer+25 (-1.30 ± 0.24 kg), Mid+25 (-1.38 ±0.33 kg) and Mid (-1.58 ±0.29 kg), all p < .05). No significant changes to aldosterone or vasopressin were associated with different drink treatments. The electrolyte concentration of low alcohol beer appears to have more significant impact on post exercise fluid retention than small changes in alcohol content.