A study was carried out to investigate the combined effect of exogenous enzymes and probiotic supplementation on tilapia growth, intestinal morphology and microbiome composition. Tilapia ...(34.56±0.05g) were fed one of four diets (35% protein, 5% lipid); one of which was a control and the remaining three diets were supplemented with either enzymes (containing phytase, protease and xylanase), probiotic (containing Bacillus subtilis, Bacillus licheniformis and Bacillus pumilus) or enz-pro (the combination of the enzymes and probiotic). Tilapia fed diet supplemented with enz-pro performed better (P<0.05) than tilapia fed the control and probiotic supplemented diets in terms of final body weight (FBW), specific growth rate (SGR), feed conversion ratio (FCR) and protein efficiency ratio (PER). The dietary treatments did not affect somatic indices. The serum lysozyme activity was significantly higher (P<0.05) in tilapia fed the probiotic supplemented diet than of those fed the remaining experimental diets. The intestinal perimeter ratio was higher (P<0.05) in tilapia fed enz-pro supplemented diet when compared to those fed with the control and probiotic supplemented diets. Goblet cells abundance, microvilli diameter and total enterocyte absorptive surface was higher (P<0.05) in tilapia fed diet supplemented with enz-pro than those fed the control diet. High-throughput sequencing revealed that majority of reads derived from the tilapia digesta belonged to members of Fusobacteria (predominantly Cetobacterium) distantly followed by Proteobacteria and Firmicutes. The alpha and beta diversities did not differ among dietary treatments indicating that the overall microbial community was not modified to a large extent by dietary treatment. In conclusion, supplementation of the diet with a combination of enzymes and probiotic is capable of improving tilapia growth and intestinal morphology without deleterious effect on the intestinal microbial composition.
1.Intensive operations in aquaculture are often accompanied by sub-optimum environmental conditions which may be stressful for fish.2.The production of high quality aquafeed with optimal growth and immune boosting effects could benefit intensive aquaculture operations.3.Dietary supplementation of exogenous digestive enzymes and probiotic as a cocktail may result in complimentary mode of action.4.Previous studies did not investigate the combined effects of exogenous digestive enzymes and probiotic on Nile tilapia.
•A combination of exogenous enzymes and probiotic increases the growth performance of tilapia, Oreochromis niloticus.•A combination of exogenous enzymes and probiotic improves the intestinal morphology of tilapia.•Dietary supplementation of diet with probiotic has stimulating effect on serum lysozyme activity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Major depressive disorder (MDD), or depression, is a syndrome characterised by a number of behavioural, cognitive and emotional features. It is most commonly associated with a sad or ...depressed mood, a reduced capacity to feel pleasure, feelings of hopelessness, loss of energy, altered sleep patterns, weight fluctuations, difficulty in concentrating and suicidal ideation. There is a need for more effective and better tolerated antidepressants to combat this condition. Agomelatine was recently added to the list of available antidepressant drugs; it is a novel antidepressant that works on melatonergic (MT1 and MT2), 5‐HT 2B and 5‐HT2C receptors. Because the mechanism of action is claimed to be novel, it may provide a useful, alternative pharmacological strategy to existing antidepressant drugs.
Objectives
The objective of this review was 1) to determine the efficacy of agomelatine in alleviating acute symptoms of major depressive disorder in comparison with other antidepressants, 2) to review the acceptability of agomelatine in comparison with other antidepressant drugs, and, 3) to investigate the adverse effects of agomelatine, including the general prevalence of side effects in adults.
Search methods
We searched the Cochrane Collaboration's Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) to 31 July 2013. The CCDANCTR includes relevant randomised controlled trials from the following bibliographic databases: CENTRAL (the Cochrane Central Register of Controlled Trials) (all years), EMBASE (1974 onwards), MEDLINE (1950 onwards) and PsycINFO (1967 onwards). We checked reference lists of relevant studies together with reviews and regulatory agency reports. No restrictions on date, language or publication status were applied to the search. Servier Laboratories (developers of agomelatine) and other experts in the field were contacted for supplemental data.
Selection criteria
Randomised controlled trials allocating adult participants with major depression to agomelatine versus any other antidepressive agent.
Data collection and analysis
Two review authors independently extracted data and a double‐entry procedure was employed. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability.
Main results
A total of 13 studies (4495 participants) were included in this review. Agomelatine was compared to selective serotonin reuptake inhibitors (SSRIs), namely paroxetine, fluoxetine, sertraline, escitalopram, and to the serotonin–norepinephrine reuptake inhibitor (SNRI), venlafaxine. Participants were followed up for six to 12 weeks. Agomelatine did not show any advantage or disadvantage over the other antidepressants for our primary outcome, response to treatment (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.95 to 1.08, P value 0.75 compared to SSRIs, and RR 1.06; 95% CI 0.98 to 1.16, P value 0.16 compared to venlafaxine). Also, agomelatine showed no advantage or disadvantage over other antidepressants for remission (RR 0.83; 95% CI 0.68 to 1.01, P value 0.07 compared to SSRIs, and RR 1.08; 95% CI 0.94 to 1.24, P value 0.73 compared to venlafaxine). Overall, agomelatine appeared to be better tolerated than venlafaxine in terms of lower rates of drop outs (RR 0.40; 95% CI 0.24 to 0.67, P value 0.0005), and showed the same level of tolerability as SSRIs (RR 0.95; 95% CI 0.83 to 1.09, P value 0.44). Agomelatine induced a lower rate of dizziness than venlafaxine (RR 0.19, 95% CI 0.06 to 0.64, P value 0.007).
With regard to the quality of the body of evidence, there was a moderate risk of bias for all outcomes, due to the number of included unpublished studies. There was some heterogeneity, particularly between published and unpublished studies. The included studies were conducted in inpatient and outpatient settings, thus limiting the generalisability of the results to primary care settings. With regard to precision, the efficacy outcomes were precise, but the tolerability outcomes were mostly imprecise. Publication bias was variable and depended on the outcome of the trial. Our review included unpublished studies, and we think that this reduced the impact of publication bias. The overall methodological quality of the studies was not very good. Almost all of the studies were sponsored by the pharmaceutical company that manufactures agomelatine (Servier), and some of these were unpublished. Attempts to contact the pharmaceutical company Servier for additional information on all unpublished studies were unsuccessful.
Authors' conclusions
Agomelatine did not seem to provide a significant advantage in efficacy over other antidepressive agents for the acute‐phase treatment of major depression. Agomelatine was better tolerated than paroxetine and venlafaxine in terms of overall side effects, and fewer participants treated with agomelatine dropped out of the trials due to side effects compared to sertraline and venlafaxine, but data were limited because the number of included studies was small. We found evidence that compared agomelatine with only a small number of other active antidepressive agents, and there were only a few trials for each comparison, which limits the generalisability of the results. Moreover, the overall methodological quality of the studies was low, and, therefore, no firm conclusions can be drawn concerning the efficacy and tolerability of agomelatine.
The interactions between the endogenous gut microbiota and the fish host are integral in mediating the development, maintenance and effective functionality of the intestinal mucosa and gut associated ...lymphoid tissues (GALTs). These microbial populations also provide a level of protection against pathogenic visitors to the gastrointestinal (GI) tract and aid host digestive function via the production of exogenous digestive enzymes and vitamins. Manipulation of these endogenous populations may provide an alternative method to antibiotics to control disease and promote health management. Applications of probiotics for Mediterranean teleosts can stimulate immune responses, enhance growth performance, feed utilisation, digestive enzyme activities, antioxidant enzyme activities, gene expression, disease resistance, larval survival, gut morphology, modulate GI microbiota and mediate stress responses. Although considerably less information is available regarding prebiotic applications for Mediterranean teleosts, prebiotics also offer benefits with regards to improving immune status and fish production.
Despite the promising potential benefits demonstrated in current literature, obtaining consistent and reliable results is often difficult due to our incomplete understanding of indigenous fish GI microbiota and their subsequent host interactions which mediate and drive both localised and systemic host immunological responses. Additionally, the probiotic and prebiotic (biotics) mechanisms which mediate host benefits at the mucosal interface are poorly understood. Future studies focused on these interactions utilising gnotobiotic techniques should provide a better understanding of how to extract the full potential of biotic applications to promote immune function of Mediterranean teleosts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Introduction:
Behavioural and psychological symptoms of dementia (BPSD) include agitation and aggression in people with dementia. BPSD is common on inpatient psychogeriatric units and may prevent ...individuals from living at home or in residential/nursing home settings. Several drugs and non-pharmacological treatments have been shown to be effective in reducing behavioural and psychological symptoms of dementia. Algorithmic treatment may address the challenge of synthesizing this evidence-based knowledge.
Methods:
A multidisciplinary team created evidence-based algorithms for the treatment of behavioural and psychological symptoms of dementia. We present drug treatment algorithms for agitation and aggression associated with Alzheimer’s and mixed Alzheimer’s/vascular dementia. Drugs were appraised by psychiatrists based on strength of evidence of efficacy, time to onset of clinical effect, tolerability, ease of use, and efficacy for indications other than behavioural and psychological symptoms of dementia.
Results:
After baseline assessment and discontinuation of potentially exacerbating medications, sequential trials are recommended with risperidone, aripiprazole or quetiapine, carbamazepine, citalopram, gabapentin, and prazosin. Titration schedules are proposed, with adjustments for frailty. Additional guidance is given on use of electroconvulsive therapy, optimization of existing cholinesterase inhibitors/memantine, and use of pro re nata medications.
Conclusion:
This algorithm-based approach for drug treatment of agitation/aggression in Alzheimer’s/mixed dementia has been implemented in several Canadian Hospital Inpatient Units. Impact should be assessed in future research.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Systemic inflammation, as evidenced by elevated inflammatory cytokines, is a feature of advanced renal failure and predicts worse survival. Dialysate IL-6 concentrations associate with variability in ...peritoneal small solute transport rate (PSTR), which has also been linked to patient survival. Here, we determined the link between systemic and intraperitoneal inflammation with regards to peritoneal membrane function and patient survival as part of the Global Fluid Study, a multinational, multicenter, prospective, combined incident and prevalent cohort study (n=959 patients) with up to 8 years of follow-up. Data collected included patient demographic characteristics, comorbidity, modality, dialysis prescription, and peritoneal membrane function. Dialysate and plasma cytokines were measured by electrochemiluminescence. A total of 426 survival endpoints occurred in 559 incident and 358 prevalent patients from 10 centers in Korea, Canada, and the United Kingdom. On patient entry to the study, systemic and intraperitoneal cytokine networks were dissociated, with evidence of local cytokine production within the peritoneum. After adjustment for multiple covariates, systemic inflammation was associated with age and comorbidity and independently predicted patient survival in both incident and prevalent cohorts. In contrast, intraperitoneal inflammation was the most important determinant of PSTR but did not affect survival. In prevalent patients, the relationship between local inflammation and membrane function persisted but did not account for an increased mortality associated with faster PSTR. These data suggest that systemic and local intraperitoneal inflammation reflect distinct processes and consequences in patients treated with peritoneal dialysis, so their prevention may require different therapeutic approaches; the significance of intraperitoneal inflammation requires further elucidation.
To estimate the benefits of screening and early treatment of type 2 diabetes compared with no screening and late treatment using a simulation model with data from the ADDITION-Europe study.
We used ...the Michigan Model, a validated computer simulation model, and data from the ADDITION-Europe study to estimate the absolute risk of cardiovascular outcomes and the relative risk reduction associated with screening and intensive treatment, screening and routine treatment, and no screening with a 3- or 6-year delay in the diagnosis and routine treatment of diabetes and cardiovascular risk factors.
When the computer simulation model was programmed with the baseline demographic and clinical characteristics of the ADDITION-Europe population, it accurately predicted the empiric results of the trial. The simulated absolute risk reduction and relative risk reduction were substantially greater at 5 years with screening, early diagnosis, and routine treatment compared with scenarios in which there was a 3-year (3.3% absolute risk reduction ARR, 29% relative risk reduction RRR) or a 6-year (4.9% ARR, 38% RRR) delay in diagnosis and routine treatment of diabetes and cardiovascular risk factors.
Major benefits are likely to accrue from the early diagnosis and treatment of glycemia and cardiovascular risk factors in type 2 diabetes. The intensity of glucose, blood pressure, and cholesterol treatment after diagnosis is less important than the time of its initiation. Screening for type 2 diabetes to reduce the lead time between diabetes onset and clinical diagnosis and to allow for prompt multifactorial treatment is warranted.
Aquaculture is central in meeting expanding global demands for shrimp consumption. Consequently, increasing feed use is mainly responsible for the overall environmental impact of aquaculture ...production. Significant amounts of fishmeal are included in shrimp diets, causing dependency on finite marine resources. Driven by economic incentives, terrestrial plant ingredients are widely viewed as sustainable alternatives. Incremental fishmeal substitution by plant ingredients in shrimp feed was modeled and effects on marine and terrestrial resources such as fish, land, freshwater, nitrogen, and phosphorus were assessed. We find that complete substitution of 20–30% fishmeal totals could lead to increasing demand for freshwater (up to 63%), land (up to 81%), and phosphorus (up to 83%), while other substitution rates lead to proportionally lower impacts. These findings suggest additional pressures on essential agricultural resources with associated socio-economic and environmental effects as a trade-off to pressures on finite marine resources. Even though the production of shrimp feed (or aquafeed in general) utilizes only a small percentage of the global crop production, the findings indicate that the sustainability of substituting fishmeal by plant ingredients should not be taken for granted, especially since aquaculture has been one of the fastest growing food sectors. Therefore, the importance of utilizing by-products and novel ingredients such as microbial biomass, algae, and insect meals in mitigating the use of marine and terrestrial resources is discussed.
BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly ...cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-X
expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-X
inhibitors is stronger in CRC, correlating with a low MCL1:BCL-X
ratio; indeed the MCL1:BCL-X
ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-X
inhibitors. Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance. Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.
Spatial variation in growth is a common feature of demersal fish populations which often exist as discrete adult sub-populations linked by a pelagic larval stage. However, it remains unclear whether ...variation in growth occurs at similar spatial scales for populations of highly migratory pelagic species, such as tuna. We examined spatial variation in growth of albacore Thunnus alalunga across 90° of longitude in the South Pacific Ocean from the east coast of Australia to the Pitcairn Islands. Using length-at-age data from a validated ageing method we found evidence for significant variation in length-at-age and growth parameters (L(∞) and k) between sexes and across longitudes. Growth trajectories were similar between sexes up until four years of age, after which the length-at-age for males was, on average, greater than that for females. Males reached an average maximum size more than 8 cm larger than females. Length-at-age and growth parameters were consistently greater at more easterly longitudes than at westerly longitudes for both females and males. Our results provide strong evidence that finer spatial structure exists within the South Pacific albacore stock and raises the question of whether the scale of their "highly migratory" nature should be re-assessed. Future stock assessment models for South Pacific albacore should consider sex-specific growth curves and spatial variation in growth within the stock.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neuronal loss in numerous neurodegenerative disorders has been linked to protein aggregation and oxidative stress. Emerging data regarding overlapping proteinopathy in traditionally distinct ...neurodegenerative diseases suggest that disease-modifying treatments targeting these pathological features may exhibit efficacy across multiple disorders. Here, we describe proteinopathy distinct from classic synucleinopathy, predominantly comprised of the anti-oxidant enzyme superoxide dismutase-1 (SOD1), in the Parkinson’s disease brain. Significant expression of this pathology closely reflected the regional pattern of neuronal loss. The protein composition and non-amyloid macrostructure of these novel aggregates closely resembles that of neurotoxic SOD1 deposits in SOD1-associated familial amyotrophic lateral sclerosis (fALS). Consistent with the hypothesis that deposition of protein aggregates in neurodegenerative disorders reflects upstream dysfunction, we demonstrated that SOD1 in the Parkinson’s disease brain exhibits evidence of misfolding and metal deficiency, similar to that seen in mutant SOD1 in fALS. Our data suggest common mechanisms of toxic SOD1 aggregation in both disorders and a potential role for SOD1 dysfunction in neuronal loss in the Parkinson’s disease brain. This shared restricted proteinopathy highlights the potential translation of therapeutic approaches targeting SOD1 toxicity, already in clinical trials for ALS, into disease-modifying treatments for Parkinson’s disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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