Role of Alginates Combined with Natural Extracts to Prevent the Gastric Acid-Related Damage

The human stomach is extremely vulnerable to various attacks able to cause erosion and mucosal epithelium damage which lead to gastrointestinal tract bleeding and/or ulcer perforations and finally worsen the original disease. A prolonged exposition to strong acidic environment causes coagulation necrosis resulting from the desiccating action of the acid on proteins in exposed tissues with inflammation and accumulation of intracellular radical oxygen species. Therapeutic strategies aim to treat both symptoms and epithelial damage with chemical or mechanical approaches. In this context, alginates seem to have great importance, especially if combined with other molecules known to have some properties on gastric epithelial cells, for example, vitamin D3, extract of prickly pear and olive leaves, and a tyndalized probiotic. This natural composition is able to exert a gastroprotective effect to maintain or restore the integrity of gastric epithelium through an antioxidant pathway, inhibiting apoptosis and activating survival kinases better than other pharmacological or natural active principles

Effect of Mixed Lipoic Acid, Vitamin D, Phosphatidylserine and Homotaurine to Obtain a New Formulation for Brain Ageing Prevention

By 2050, it is estimated that there will be two billion people aged 60 or over, of which 131 million are expected to be affected by dementia, while depression is expected to be the second-largest cause of disability worldwide in 2020. Preventing or delaying the onset of these disorders should therefore be a priority for public health systems. There is some evidence linking certain substances present in most common food supplements with a reduced risk of neuronal degeneration improving brain health. Recently, many compounds or extracts from natural products slowing aging and extending lifespan have been reported. The main goal of this study is to develop a new formulation that delay age-related diseases in human. For this reason, the effects of selected agents (such as lipoic acid, vitamin D3, phosphatidylserine and homotaurine) were assessed in order to find a new formulation able to slow down the physiological decay linked to brain ageing. Cell viability, radical oxygen species production, inflammatory marker along with some intracellular pathways have been evaluated. The results show that the new combination is highly effective to counteract the negative effects of oxidative stress and inflammation acting through some important brain markers involved in cell survival, enhancing viability of astrocyte

Role of Vitamin D3 and Alginates in Prevention of NSAID-Dependent Cellular Injury

About 30 million people use nonsteroidal anti-inflammatory drugs. Therefore, they have a high risk of developing gastropathic and enteropathic damages. These patients receive anti-acid treatment, but a number of clinical studies provided evidence of the ineffectiveness of proton-pump inhibitors. Vitamin D, on the other hand, appears to have high preventive and therapeutic potential. Recently, it has been introduced a product that, in addition to anti-acid properties of alginates, claims to possess gastroprotective properties deriving from vitamin D3 and from plant extractsThis study was planned to verify the effectiveness of vitamin D3 combined with alginates to prevent the damage induced in cul-tured gastric cells by diclofenac during acidic or hyperacidic exposition measuring cell viability, radical oxygen species production along with apoptotic and survival pathways.Around 30 million people consume nonsteroidal anti-inflammatory drugs (NSAID) globally every day [1] since they are widely pre-scribed because of their efficacy in the management of pain, inflammation, and fever [2]. Generally, the action mechanism of these drugs consists in the inhibition of the biosynthesis of prostaglandins, the inactivation of cyclooxygenase, and an increase in leukotrienes produc-tion [3]. Adverse events associated with NSAID, such as alterations in renal function, effects on blood pressure, hepatic injury, and plate-let inhibition, are a challenge in clinical treatment optimization [4]. However, severe gastrointestinal disorder accompanied by gastric mucosal perforation and bleeding is a major concern as well as the worst outcome of prolonged NSAID-therapy [5]: indeed, they induce gastric mucosal lesions because of their acidic properties [3]. Gastric mucosal erosions, ulceration, bleeding, and perforation, as well as an increased risk of bleeding from pre-existing peptic ulcers are major causes of gastrointestinal iatrogenic diseases [6]. The mechanism behind gastric damage involves a highly acidic gastric environment that favours the migration of nonionized lipophilic NSAID into the Findings show that this combination is more potent to counteract the negative effects of diclofenac and hyperacidic conditions than some other gastroprotective agents on epithelial gastric cells. This was confirmed by the maintenance of p53 expression at physiological level. In addition, when added before diclofenac, it can exert beneficial effects counteracting the negative effect of diclof-enac alone. These data were similar to the sample treated with pantoprazole, supporting the hypothesis that the combination could act as a gastroprotector to prevent cell loss. These results have pointed out the gastroprotective effect of the combination when compared to other commercial natural ex-tracts, this effect is obtained via antioxidant pathway, inhibiting apoptosis, enhancing cell viability and activating survival kinase

The LiberAction Project: Implementation of a Pediatric Liberation Bundle to Screen Delirium, Reduce Benzodiazepine Sedation, and Provide Early Mobilization in a Human Resource-Limited Pediatric Intensive Care Unit

Background: Delirium, bed immobilization, and heavy sedation are among the major contributors of pediatric post-intensive care syndrome. Recently, the Society of Critical Care Medicine has proposed the implementation of daily interventions to minimize the incidence of these morbidities and optimize children functional outcomes and quality of life. Unfortunately, these interventions require important clinical and economical efforts which prevent their use in many pediatric intensive care units (PICU). Aim: First, to evaluate the feasibility and safety of a PICU bundle implementation prioritizing delirium screening and treatment, early mobilization (<72 h from PICU admission) and benzodiazepine-limited sedation in a human resource-limited PICU. Second, to evaluate the incidence of delirium and describe the early mobilization practices and sedative drugs used during the pre- and post-implementation periods. Third, to describe the barriers and adverse events encountered during early mobilization. Methods: This observational study was structured in a pre- (15th November 2019-30th June 2020) and post-implementation period (1st July 2020-31st December 2020). All patients admitted in PICU for more than 72 h during the pre and post-implementation period were included in the study. Patients were excluded if early mobilization was contraindicated. During the pre-implementation period, a rehabilitation program including delirium screening and treatment, early mobilization and benzodiazepine-sparing sedation guidelines was developed and all PICU staff trained. During the post-implementation period, delirium screening with the Connell Assessment of Pediatric Delirium scale was implemented at bedside. Early mobilization was performed using a structured tiered protocol and a new sedation protocol, limiting the use of benzodiazepine, was adopted. Results: Two hundred and twenty-five children were enrolled in the study, 137 in the pre-implementation period and 88 in the post-implementation period. Adherence to delirium screening, benzodiazepine-limited sedation and early mobilization was 90.9, 81.1, and 70.4%, respectively. Incidence of delirium was 23% in the post-implementation period. The median cumulative dose of benzodiazepines corrected for the total number of sedation days (mg/kg/sedation days) was significantly lower in the post-implementation period compared with the pre-implementation period: [0.83 (IQR: 0.53-1.31) vs. 0.74 (IQR: 0.55-1.16), p = 0.0001]. The median cumulative doses of fentanyl, remifentanil, and morphine corrected for the total number of sedation days were lower in the post-implementation period, but these differences were not significant. The median number of mobilizations per patient and the duration of each mobilization significantly increased in the post-implementation period [3.00 (IQR: 2.0-4.0) vs. 7.00 (IQR: 3.0-12.0); p = 0.004 and 4 min (IQR: 3.50-4.50) vs. 5.50 min (IQR: 5.25-6.5); p < 0.0001, respectively]. Barriers to early mobilization were: disease severity and bed rest orders (55%), lack of physicians' order (20%), lack of human resources (20%), and lack of adequate devices for patient mobilization (5%). No adverse events related to early mobilization were reported in both periods. Duration of mechanical ventilation and PICU length of stay was significantly lower in the post-implementation period as well as the occurrence of iatrogenic withdrawal syndrome. Conclusion: This study showed that the implementation of a PICU liberation bundle prioritizing delirium screening and treatment, benzodiazepine-limited sedation and early mobilization was feasible and safe even in a human resource-limited PICU. Further pediatric studies are needed to evaluate the clinical impact of delirium, benzodiazepine-limited sedation and early mobilization protocols on patients' long-term functional outcomes and on hospital finances

Independent lung ventilation in a newborn with asymmetric acute lung injury due to respiratory syncytial virus: a case report

<p>Abstract</p> <p>Introduction</p> <p>Independent lung ventilation is a form of protective ventilation strategy used in adult asymmetric acute lung injury, where the application of conventional mechanical ventilation can produce ventilator-induced lung injury and ventilation-perfusion mismatch. Only a few experiences have been published on the use of independent lung ventilation in newborn patients.</p> <p>Case presentation</p> <p>We present a case of independent lung ventilation in a 16-day-old infant of 3.5 kg body weight who had an asymmetric lung injury due to respiratory syncytial virus bronchiolitis. We used independent lung ventilation applying conventional protective pressure controlled ventilation to the less-compromised lung, with a respiratory frequency proportional to the age of the patient, and a pressure controlled high-frequency ventilation to the atelectatic lung. This was done because a single tube conventional ventilation protective strategy would have exposed the less-compromised lung to a high mean airways pressure. The target of independent lung ventilation is to provide adequate gas exchange at a safe mean airways pressure level and to expand the atelectatic lung. Independent lung ventilation was accomplished for 24 hours. Daily chest radiograph and gas exchange were used to evaluate the efficacy of independent lung ventilation. Extubation was performed after 48 hours of conventional single-tube mechanical ventilation following independent lung ventilation.</p> <p>Conclusion</p> <p>This case report demonstrates the feasibility of independent lung ventilation with two separate tubes in neonates as a treatment of an asymmetric acute lung injury.</p

Efficacy of ketamine in refractory convulsive status epilepticus in children: A protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01)

Introduction: Status epilepticus (SE) is a lifethreatening neurological emergency. SE lasting longer than 120 min and not responding to first-line and second-line antiepileptic drugs is defined as 'refractory' (RCSE) and requires intensive care unit treatment. There is currently neither evidence nor consensus to guide either the optimal choice of therapy or treatment goals for RCSE, which is generally treated with coma induction using conventional anaesthetics (high dose midazolam, thiopental and/or propofol). Increasing evidence indicates that ketamine (KE), a strong N-methyl-D-aspartate glutamate receptor antagonist, may be effective in treating RCSE. We hypothesised that intravenous KE is more efficacious and safer than conventional anaesthetics in treating RCSE. Methods and analysis: A multicentre, randomised, controlled, open-label, non-profit, sequentially designed study will be conducted to assess the efficacy of KE compared with conventional anaesthetics in the treatment of RCSE in children. 10 Italian centres/ hospitals are involved in enrolling 57 patients aged 1 month to 18 years with RCSE. Primary outcome is the resolution of SE up to 24 hours after withdrawal of therapy and is updated for each patient treated according to the sequential method. Ethics and dissemination: The study received ethical approval from the Tuscan Paediatric Ethics Committee (12/2015). The results of this study will be published in peer-reviewed journals and presented at international conferences

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2–4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer