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Objectives Evidence suggests that ketamine’s influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). Methods Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. Results There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. Conclusion There was no significant treatment impact on BDNF serum levels – neither with ketamine nor esketamine – despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion. This clinical trial is registered on the Japan Primary Registries Network: UMIN000032355.

Dissociative symptoms are common, possibly severe, side effects associated with the use of ketamine and esketamine in depression. We investigated the relationship between trait dissociation and dissociation induced by ketamine and esketamine used as augmentation therapy in treatment-resistant depression (TRD). Adults with TRD were randomly assigned to receive a single intravenous infusion, with a duration of 40 min, of either esketamine 0.25 mg/kg or ketamine 0.5 mg/kg. We assessed trait dissociation with the Dissociative Experience Scale (DES) and, to evaluate induced dissociation, the Clinician-Administered Dissociative States Scale (CADSS) was used. Thirty-two subjects received esketamine and 29 received ketamine. The groups had similar median DES scores (p = 0.26). More than 30% of the patients in both groups had DES scores ≥30 points. The median CADSS score in the esketamine group was equivalent to that in the ketamine group (p = 0.40). Every 5 points increment in the DES was associated with a 10.9% (95% CI 4.5–17.8%) increase in the CADSS, in an exponential fashion when the two groups were pooled together. Subjects with high trait dissociation had a higher risk of induced dissociation state (relative risk [RR] 1.41, 95% CI 1.11–1.78) and very high induced dissociation (RR 3.05, 95% CI 1.14–8.15). Induced dissociation was not a serious adverse effect. The findings suggest that trait dissociation is a predictor of induced dissociation by Ketamine or Esketamine in TRD subjects. Screening for trait dissociation and counseling patients with high trait dissociation on the risks of dissociation by these drugs are recommended.

This study sought to evaluate in vitro the effect of a dentifrice containing sodium trimetaphosphate (TMP) combined or not with low fluoride (500 ppm NaF) on dentine erosion of intrinsic origin. Human root dentine blocks were selected based on surface microhardness and randomly allocated into five groups (n = 12): negative control (0 ppm F; no TMP); F500 (500 ppm NaF); F1500 (1500 ppm NaF—positive control); TMP (1% TMP); and F + TMP (500 ppm NaF + 1% TMP). The blocks were submitted to erosion cycles (3 ×/day) for 3 days (0.01 M HCl, pH 1.5–30 s), treatment (1 min—1:3 p/p dentifrice/distilled water) and remineralization (artificial saliva/120 min). Dentine alterations were determined according to the percentage of microhardness loss (%HL), surface loss (SL) and surface analysis by scanning electron microscopy. The data were analyzed using one-way ANOVA (p

AIM To assess the effect of aesthetic crown lengthening (ACL) and lip repositioning surgery (LRS) on perception of smile attractiveness. MATERIALS AND METHODS Preoperative and 6-month postoperative smile photographs of ACL- or LRS-treated patients were evaluated by 100 raters (five gender-balanced groups of ten per procedure) of diverse background (dental students, general dentists, periodontists and laypersons with and without any aesthetic concerns about their own smile). Smile attractiveness was rated by visual analogue scale (VAS). Multivariate mixed-effect models were applied to determine the effect of procedure, rater (age, gender and group) and case (gingival display and GD) on smile attractiveness rating. RESULTS Average preoperative and postoperative VAS scores for ACL patients were 3.8 ± 2.0 and 6.2 ± 1.9, respectively. Corresponding LRS patient values were 4.8 ± 2.0 and 6.4 ± 1.9. Treatment, baseline GD and rater age were significant determinants (p

Bovine lactoferricin (LFcinB) has antimicrobial and immunomodulatory properties; however, the effects on diabetic wound healing remain poorly understood. The wound healing potential of LFcinB was investigated with in vitro, ex vivo, and in vivo models. Cell migration and proliferation were tested on keratinocytes and on porcine ears. A type 1 diabetic mouse model was also used to evaluate wound healing kinetics, bacterial diversity patterns, and the effect of LFcinB on oxidative stress, macrophage phenotype, angiogenesis, and collagen deposition. LFcinB increased keratinocyte migration in vitro (p < 0.05) and ex vivo (p < 0.001) and improved wound healing in diabetic mice (p < 0.05), though not in normoglycemic control mice. In diabetic mouse wounds, LFcinB treatment led to the eradication of Bacillus pumilus, a decrease in Staphylococcus aureus, and an increase in the Staphylococcus xylosus prevalence. LFcinB increased angiogenesis in diabetic mice (p < 0.01), but this was decreased in control mice (p < 0.05). LFcinB improved collagen deposition in both diabetic and control mice (p < 0.05). Both oxidative stress and the M1-to-M2 macrophage ratios were decreased in LFcinB-treated wounds of diabetic animals (p < 0.001 and p < 0.05, respectively) compared with saline, suggesting a downregulation of inflammation in diabetic wounds. In conclusion, LFcinB treatment demonstrated noticeable positive effects on diabetic wound healing., Graphical Abstract, Topical delivery of bovine lactoferricin (LFcinB) has antimicrobial and immunomodulatory actions and improves wound closure and changes the bacterial diversity of diabetic wounds. Hallmarks of diabetic wound healing impairments like inflammation, oxidative stress, disrupted angiogenesis, and collagen deposition improved by LFcinB indicate its therapeutic potential.

To evaluate the heart rate (HR) and behaviour of children and teenagers with Cerebral Palsy (CP) when having a dental appointment. A comparative cross-sectional study was carried out with 60 participants with CP, between 2 and 14 years old (study group—SG), and 60 normotypical individuals (CG). The sample was paired according to age, gender and socioeconomic status. Behaviour was evaluated during dental prophylaxis using the Frankl Scale, and HR was measured at five moments: before the appointment, when sitting in the dental chair, during the clinical examination, during prophylaxis and immediately after prophylaxis. Mann–Whitney, Friedman and Chi-square tests were applied at a significance level of 5%. SG presented significantly higher HR (p

The fact that opioids are valuable tools for the management of pain has been known and used for thousands of years. Currently, millions of Americans are treated annually with opioids, and many of these patients are elderly. Opioids present risks to geriatric patients, some of which are unique to the population, and providers should have a good grasp of those risks. An understanding of how to select appropriate medications for the management of pain and of the myriad of alternatives available for pain management is vital to the care of older patients. This article presents a review, for primary care providers, of issues unique to opioid management in older adults.

Background Ketamine and its enantiomers have recently been highlighted as one of the most effective therapeutic options in refractory depression. However, racemic ketamine and esketamine have not been directly compared. The aim of this study is to assess the efficacy and safety of esketamine compared to ketamine in patients with treatment-resistant depression (TRD). Methods This is a randomized, double-blind, active-controlled, bicentre, non-inferiority clinical trial, with two parallel groups. Participants were randomly assigned to a 40-min single intravenous infusion of ketamine 0.5 mg/kg or esketamine 0.25 mg/kg. The primary outcome was the difference in remission rates for depression 24 h following intervention using the Montgomery-Asberg Depression Rating Scale (MADRS), with a non-inferiority margin of 20%. Results 63 subjects were included and randomly assigned (29 to receive ketamine and 34 to receive esketamine). At 24 h, 24.1% of participants in the ketamine group and 29.4% of participants in the esketamine group showed remission, with a difference of 5.3% (95% CILB -13.6%), confirming non-inferiority. MADRS scores improved from 33 (SD 9.3) to 16.2 (SD 10.7) in the ketamine group and from 33 (SD 5.3) to 17.5 (SD 12.2) in the esketamine one, with a difference of -5.27% (95% CILB, -13.6). Both groups presented similar mild side effects. Conclusions Esketamine was non-inferior to ketamine for TRD 24 h following infusion. Both treatments were effective, safe, and well tolerated. Trial Registration Registered in Japan Primary Registries Network: UMIN000032355.

Skeletal muscle provides a compact solution for performing multiple tasks under diverse operational conditions, a capability lacking in many current engineered systems. Here, we evaluate if shape memory alloy (SMA) components can serve as artificial muscles with tunable mechanical performance. We experimentally impose cyclic stimuli, electric and mechanical, to an SMA wire and demonstrate that this material can mimic the response of the avian humerotriceps, a skeletal muscle that acts in the dynamic control of wing shapes. We next numerically evaluate the feasibility of using SMA springs as artificial leg muscles for a bipedal walking robot. Altering the phase offset between mechanical and electrical stimuli was sufficient for both synthetic and natural muscle to shift between actuation, braking and spring-like behaviour.

Neurodegenerative diseases are characterized by a progressive loss of neuronal structures and functions. Although all biochemical and/or physiological processes are not completely understood, it is known that the main neurodegenerative diseases, like Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases, and also amyotrophic lateral sclerosis (ALS) present certain obvious similarities. Biometal microelements, such as copper, iron, manganese, and zinc, are crucial for many physiological functions, especially in the CNS. Shifts in the amounts of these metals are essential for the development and maintenance of numerous enzymatic activities, mitochondrial functions, neurotransmission, and also for memorization and learning. However, with deregulations in their homeostasis, particularly in those connected with redox activity, there are consequent changes in the ion and microelement balance. This redox activity may contribute to the production of free radicals that can react with various organic substrates, thus generating increased levels of oxidative stress. There is growing evidence that metal microelements play significant roles in the pathogenesis of neurodegenerative diseases. The interaction between metals and CNS proteins is crucial in the development or absence of neurodegeneration. In this way, homeostasis of metal microelements represents a mechanism of extreme importance. Our paper aims at an updated and critical review of the role of the respective metals in neurodegenerative diseases and the main related pathogenic mechanisms.

Small extracellular vesicles (SEVs) offer a promising strategy for tissue regeneration, yet their short lifetime at the injured tissue limits their efficacy. Here, we show that kinetics of SEV delivery impacts tissue regeneration at tissue, cellular, and molecular levels. We show that multiple carefully timed applications of SEVs had superior regeneration than a single dose of the same total concentration of SEVs. Importantly, diabetic and non-diabetic wounds treated with a single time point dose of an injectable light-triggerable hydrogel containing SEVs demonstrated a robust increase in closure kinetics relative to wounds treated with a single or multiple doses of SEVs or platelet-derived growth factor BB, an FDA-approved wound regenerative therapy. The pro-healing activity of released SEVs was mediated at the tissue/cell level by an increase in skin neovascularization and re-epithelization and at the molecular level by an alteration in the expression of 7 miRNAs at different times during wound healing. This includes an alteration of has-miR-150-5p, identified here to be important for skin regeneration.

The immunomodulatory properties of β-glucans are well documented for several animal species. However, little is known on their use as enhancers of non-specific and specific responses against Moritella viscosa and infectious salmon anemia (ISA) virus, which are two major pathogens affecting the Atlantic salmon aquaculture industry. The present study assessed the effects of dietary β-1,3/1,6-glucans (MacroGard®) and vaccination on the survival of Atlantic salmon (Salmo salar) post-smolts challenged with M. viscosa or ISA virus. Dietary supplementation decreased mortality in both unvaccinated (55.4%; RPSend 19.9) and vaccinated (9.3%; RPSend 86.6) M. viscosa-challenged fish compared to the non-supplemented groups (69.1% and 28.3% mortality in unvaccinated and vaccinated fish, respectively; RPSend 59 for vaccinate non-supplemented fish). Similarly, mortality of ISA virus-challenged fish decreased from 87.5% in vaccinated fish without supplementation (RPSend 9.2) to 70.9% in the supplemented and vaccinated group (RPSend 26.4). In summary, these findings show that dietary β-glucans increase Atlantic salmon resistance and improve the protective effect of vaccines against the tested pathogens.

The ionic liquids 1-n-butyl-3-methylimidazolium chloride (C4MImCl), 1-n-butyl-3-methylimidazolium hexafluorophosphate (C4MImPF6), 1-n-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (C4MImNTf2), 1-n-butyl-2,3-dimethylimidazolium chloride (C4MMImCl) and 1-n-butyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)imide (C4MMImNTf2) were degraded under UV and visible radiation in the presence of a silica-supported photocatalyst (SiTi), which was derived from a petrochemical residual catalyst slurry rich in titanium and magnesium. These ionic liquid advanced oxidation processes were studied by UV spectroscopy and electrospray ionization mass spectrometry. After 120 min of irradiation, 50.2, 48.7, 45.3, 40.7 and 35.3% of C4MImCl, C4MImPF6, C4MImNTf2, C4MMImCl and C4MMImNTf2 were degraded under UV and 45.4, 43.6, 40.2, 36.8 and 32.7% of C4MImCl, C4MImPF6, C4MImNTf2, C4MMImCl and C4MMImNTf2 were degraded under visible light, respectively. The commercial titania P25 catalyst degraded 66.3 and 50.2% of C4MImCl under UV and visible radiation, respectively. Regarding the stability of photocatalyst SiTi, it was reused five times with only minor loss of catalytic activity. Doping of SiTi with 25 wt% Mg2+/SiO2 resulted in improved degradation values of 64.6% (UV irradiation) and 65.3% (visible irradiation) of C4MImCl. Cytotoxicity assays (MTT reduction and Neutral Red incorporation) on NIH/3T3 cells after 24 h of irradiation of C4MImCl indicated the absence of in vitro cytotoxicity. Altogether, this study opens new opportunities for the management of petrochemical waste, providing access to effective and stable heterogeneous photocatalysts for the degradation of imidazolium ionic liquids.

Background The cannabinoid receptor type-1 (CB1R) is a major regulator of metabolism, growth and inflammation. Yet, its potential role in the skin is not well understood. Our aim was to evaluate the role of CB1R in aging-like diabetic skin changes by using a CB1R knockout mouse model. Methods We evaluated several signals of skin aging in wild-type control (WT), WT streptozotocin-induced type 1 diabetic mice (WT DM), CB1R knockout (CB1RKO) and CB1RKO DM mice. We quantified markers of inflammation, angiogenesis, antioxidant enzymes and collagen content. Moreover, we evaluate reactive oxygen species (ROS) levels and macrophage phenotype, M1 and M2. Results CB1R expression is decreased in the skin of WT DM mice and collagen levels are decreased in the skin of WT DM, CB1RKO and CB1RKO DM mice. Additionally, the absence of CB1R correlated with higher expression of pro-inflammatory markers, also evident in WT DM or CB1RKO DM mice. Moreover, the M1/M2 macrophage ratio and ROS levels were significantly elevated but in the diabetic WT and the CB1RKO mice, consistent with a significant decrease in the antioxidant capacity of the skin. Conclusions Our results indicate that CB1R deficiency in the skin may lead to accelerated skin aging due to the increased production of ROS, a decrease in the antioxidant defenses and a higher pro-inflammatory environment. A significant decrease in the CB1R expression may be a significant contributing factor to the early aging-like changes in diabetes.

This cohort profile aims to describe the ongoing follow-up of children in the Microcephaly Epidemic Research Group Paediatric Cohort (MERG–PC). The profile details the context and aims of the study, study population, methodology including assessments, and key results and publications to date. The children that make up MERG–PC were born in Recife or within 120 km of the city, in Pernambuco/Brazil, the epicentre of the microcephaly epidemic. MERG–PC includes children from four groups recruited at different stages of the ZIKV microcephaly epidemic in Pernambuco, i.e., the Outpatient Group (OG/n = 195), the Microcephaly Case–Control Study (MCCS/n = 80), the MERG Pregnant Women Cohort (MERG-PWC/n = 336), and the Control Group (CG/n = 100). We developed a comprehensive array of clinical, laboratory, and imaging assessments that were undertaken by a ‘task force’ of clinical specialists in a single day at 3, 6, 12, 18 months of age, and annually from 24 months. Children from MCCS and CG had their baseline assessment at birth and children from the other groups, at the first evaluation by the task force. The baseline cohort includes 711 children born between February 2015 and February 2019. Children’s characteristics at baseline, excluding CG, were as follows: 32.6% (184/565) had microcephaly, 47% (263/559) had at least one physical abnormality, 29.5% (160/543) had at least one neurological abnormality, and 46.2% (257/556) had at least one ophthalmological abnormality. This ongoing cohort has contributed to the understanding of the congenital Zika syndrome (CZS) spectrum. The cohort has provided descriptions of paediatric neurodevelopment and early epilepsy, including EEG patterns and treatment response, and information on the frequency and characteristics of oropharyngeal dysphagia, cryptorchidism and its surgical findings, endocrine dysfunction, and adenoid hypertrophy in children with Zika-related microcephaly. The study protocols and questionnaires were shared across Brazilian states to enable harmonization across the different studies investigating microcephaly and CZS, providing the opportunity for the Zika Brazilian Cohorts Consortium to be formed, uniting all the ZIKV clinical cohorts in Brazil.

Silver diamine fluoride (SDF) was developed in Japan in the 1960s. It is a clear solution containing silver and fluoride ions. Because of its anti-bacterial and remineralizing effect, silver diamine fluoride has been used in managing dental caries for decades worldwide. This paper aims to summarize and discuss the global policies, guidelines, and relevant information on utilizing SDF for caries management. SDF can be used for treating dental caries in most countries. However, it is not permitted to be used in mainland China. Several manufacturers, mainly in Australia, Brazil, India, Japan, and the United States, produce SDF at different concentrations that are commercially available around the world. The prices differ between contents and brands. Different government organizations and dental associations have developed guidelines for clinical use of SDF. Dental professionals can refer to the specific guidelines in their own countries or territories. Training for using SDF is part of undergraduate and/or postgraduate curriculums in almost all countries. However, real utilization of SDF of dentists, especially in the private sector, remains unclear in most places because little research has been conducted. There are at least two ongoing regional-wide large-scale oral health programs, using SDF as one of the components to manage dental caries in young children (one in Hong Kong and one in Mongolia). Because SDF treatment does not require caries removal, and it is simple, non-invasive, and inexpensive, SDF is a valuable strategy for caries management in young children, elderly people, and patients with special needs. In addition, to reduce the risk of bacteria or virus transmission in dental settings, using SDF as a non-aerosol producing procedure should be emphasized under the COVID-19 outbreak.

Monitoring the training load in football is an important strategy to improve athletic performance and an effective training periodization. The aim of this study was two-fold: (1) to quantify the weekly training load and recovery status variations performed by under-15, under-17 and under-19 sub-elite young football players, and (2) to analyze the influence of age, training day, weekly microcycle, training and playing position on the training load and recovery status. Twenty under-15, twenty under-17 and twenty under-19 players were monitored over a 2-week period during the first month of the 2019–2020 competitive season. Global positioning system technology (GPS) was used to collect external training loads: total distance covered, average speed, maximal running speed, relative high-speed running distance, high metabolic load distance, sprinting distance, dynamic stress load, accelerations and decelerations. Internal training load was monitored using ratings of perceived exertion (RPE) and session rating of perceived exertion (sRPE). Recovery status was obtained using the total quality recovery (TQR) scale. The results show an age-related influence for external training load (p ≤ 0.001, d = 0.29–0.86, moderate to strong effect), internal training load (p ≤ 0.001, d = 0.12–0.69, minimum to strong effect) and recovery status (p ≤ 0.001, d = 0.59, strong effect). The external training load presented differences between training days (p &lt, 0.05, d = 0.26–0.95, moderate to strong effect). The playing position had a minimum effect on the weekly training load (p &lt, 0.05, d = 0.06–0.18). The weekly microcycle had a moderate effect in the TD (p &lt, 0.05, d = 0.39), RPE (p &lt, d = 0.35) and sRPE (p &lt, 0.05, d = 0.35). Interaction effects were found between the four factors analyzed for deceleration (F = 2.819, p = 0.017) and between inter-day, inter-week and age for total covered distance (F = 8.342, p = 0.008). This study provided specific insights about sub-elite youth football training load and recovery status to monitor training environments and load variations. Future research should include a longer monitoring period to assess training load and recovery variations across different season phases.

Aim In patients (pts) with suspected coronary artery disease (CAD), computed tomographic angiography (CTA) may improve pt selection for invasive coronary angiography (ICA) as alternative to functional testing. However. the role of CTA in symptomatic pts after abnormal functional test (FT) is incompletely defined. Methods and results This randomized clinical trial conducted in single academic tertiary center selected 218 symptomatic pts with mild to moderately abnormal FT referred to ICA to receive either the originally intended ICA (n=103) or CTA (n=115). CTA interpretation and subsequent care decisions were made by the clinical team. Pts with high risk features on FT, previous acute coronary syndrome, previously documented CAD, chronic kidney disease (GFR (UP) and symptomatic status (SS) were also evaluated. Pts averaged 68±9 years of age, 60% were male, 29% were diabetic. Nuclear perfusion stress test was used in 33.9% in CTA group and 31.1% in control group (p=0.655). Mean post (functional) test probability of obstructive CAD was 34%. Overall prevalence of obstructive CAD was 32.1%. In the CTA group, ICA was cancelled by referring physicians in 83 of the pts (72.2%) after receiving CTA results. For those undergoing ICA, non-obstructive CAD was found in 5 pts (15.6%) in the CTA-guided arm and 60 (58.3%) in the usual care arm (p Conclusions In pts with suspected CAD and mild to moderately abnormal ischemia test, a diagnostic strategy including CTA as gatekeeper is safe, effective and significantly improves diagnostic and revascularization yields of ICA. Funding Acknowledgement Type of funding source: None

Wound healing is a complex biological process that is impaired under diabetes conditions. Chronic non-healing wounds in diabetes are some of the most expensive healthcare expenditures worldwide. Early diagnosis and efficacious treatment strategies are needed. microRNAs (miRNAs), a class of 18–25 nucleotide long RNAs, are important regulatory molecules involved in gene expression regulation and in the repression of translation, controlling protein expression in health and disease. Recently, miRNAs have emerged as critical players in impaired wound healing and could be targets for potential therapies for non-healing wounds. Here, we review and discuss the mechanistic background of miRNA actions in chronic wounds that can shed the light on their utilization as specific wound healing biomarkers.

Systemic Lupus Erythematosus affects several people around the world and because it is characterized as a chronic inflammatory disease of multifactorial origin, and with systemic impairment, great attention must be paid from diagnosis to treatment in order to optimize the entire follow-up of the patient. The dental doctor plays an important role in the diagnosis of the condition and must be attentive to the early signs that can appear in the oral cavity with a frequency of up to 21%. In this way, through this bibliographic review, which has as main goal to correlate Systemic Lupus Erythematosus with its direct consequences in the oral cavity, it will be possible to help dentists in the diagnosis, to understand in detail the development of the disease and what attitude should be taken in its presence.

Hypothyroidism is a common condition in the general population. While myxedema is a known complication, we present a case highlighting a late-onset presentation of psychosis with confounding cognitive impairment in a patient who believed she no longer needed thyroid replacement medication because of her advanced age.

The objective of this study is to evaluate cognition in patients using either ketamine or esketamine to treat TRD. We also evaluate if both ketamine and esketamine as one group influence cognition in patients with TRD. Fifty-four patients with TRD were infused with either ketamine or esketamine and were assessed at three time points: baseline, 24 h, and 7 days after infusion. We applied neuropsychological tests to evaluate executive functions, processing speed, short term memory, and auditory-verbal episodic memory. There is no cognitive difference between ketamine and esketamine, with the exception of one variable. When considered as one group, ketamine and esketamine do not impair cognition; on the contrary, they improve some neuropsychological functions such as visuospatial short-term memory, executive functions, processing speed, and several measures related to episodic verbal memory. Ketamine and esketamine do not present differing cognitive effects when used in antidepressant doses to treat TRD. Furthermore, they rapidly improve many cognitive aspects of patients with TRD at 24 h after the infusion and maintain these effects for at least 7 days.

This study investigated the role of CDK4 in the oxidative metabolism of brown adipose tissue (BAT). BAT from Cdk4 −/− mice exhibited fewer lipids and increased mitochondrial volume and expression of canonical thermogenic genes, rendering these mice more resistant to cold exposure. Interestingly, these effects were not BAT cell‐autonomous but rather driven by increased sympathetic innervation. In particular, the ventromedial hypothalamus (VMH) is known to modulate BAT activation via the sympathetic nervous system. We thus examined the effects of VMH neuron‐specific Cdk4 deletion. These mice display increased sympathetic innervation and enhanced cold tolerance, similar to Cdk4 −/− mice, in addition to browning of scWAT. Overall, we provide evidence showing that CDK4 modulates thermogenesis by regulating sympathetic innervation of adipose tissue depots through hypothalamic nuclei, including the VMH. This demonstrates that CDK4 not only negatively regulates oxidative pathways, but also modulates the central regulation of metabolism through its action in the brain., CDK4 negatively regulates thermogenesis by suppressing oxidative pathways. This study reveals that CDK4 also modulates the systemic regulation of metabolism through its action in the hypothalamus.

Among the most common malformations observed in the oral cavity are cleft lip/palate and malocclusions, being this last one considered by the World Health Organization, the third public health problem.Malocclusions include the anterior open bite, a change in the vertical plane, that can be of two types: dental anterior open bite and skeletal anterior open bite. Cleft lip and cleft palate are the most common congenital malformations at birth. These malformations result from a failure in the normal craniofacial development process, which requires the coordination of a complex series of events. From the embryological point of view, the cleft lip/palate is a consequence of the failure of the first superior branchial arch to complete fusion with the frontonasal process during pregnancy.All these malformations result from the interaction of both genetic and environmental factors. Among the environmental factors involved in the development of malocclusions are deleterious habits, mouth breathing and trauma. Several genes involved in the development of facial bones, muscles and teeth are also responsible for the development of malocclusions. In the same way, clefts development is a multifactorial trait where multiple genes are involved as well as environmental factor like alcohol consumption, tobacco, exposure to pesticides or toxic solvents, in a complex interaction.All these factors may jeopardize the normal functioning of the stomatognathic system and the consequent quality of life of the patient. The purpose of this study was to review the literature concerning the genetic and environmental aspects involved in the development of these malformations.

Peripheral neuropathy plays a role in chronic diabetic foot ulcers (DFUs), also leading to an imbalance in inflammation, as pro-inflammatory macrophages (M1) have difficulty switching to an anti-inflammatory phenotype (M2) contributing to a chronic inflammatory phase and healing impairment. Protein tyrosine phosphatase 1B (PTP1B), in the skin, is over expressed in diabetes and DFUs. We aimed to evaluate the role of PTP1B inhibition in macrophage under high glucose conditions. THP-1 monocytic cells were differentiated into macrophages, treated with the PTP1B inhibitor MSI-1436 (1 µM) and stimulated with LPS for 24h, under high glucose (25 mM) or normoglycemic conditions (5.5 mM). Cell viability was measured by MTT assay. The numbers of M1 and M2 macrophages were evaluated by immunocytochemistry by double staining with CD68 and TNF-α for M1 macrophages, and CD68 and CD163 for M2 macrophages. In addition, pro-inflammatory cytokine expression was analyzed by qRT-PCR. Oxidative stress was assessed by the DCFH-DA assay, heme oxygenase-1 (HO-1) enzyme levels were also measured by immunocytochemistry and Western blot. The treatment with MSI-1436 did not alter THP-1 cell viability. In inflammatory conditions (LPS), THP-1 cells grown under HG and treated with MSI-1436 showed an increase in M2 macrophages and a reduction in M1 macrophages (246 ± 26% and 102 ± 9%, p Disclosure A. Figueiredo: None. E.C. Leal: None. D. Santos: None. G. Gasiunaite: None. M. Delibegovic: None. E. Carvalho: None. Funding Diabetes UK; Portuguese Foundation for Science and Technology; European Foundation for the Study of Diabetes; Portuguese Society of Diabetology

Diabetic neuropathy plays an important role in the development of chronic wounds. Endothelial progenitor cells (EPCs) are known important regulators of wound angiogenesis. However, the role of neuropeptides in EPC function, and particularly Neurotensin (NT), is unknown in diabetic wound healing. EPCs isolated from normal mice were cultured in high glucose (25 mM) or normoglicemia (5.5 mM) and treated with NT (25-400 nM) for 3 days. Moreover, EPCs isolated from streptozotocin (STZ)-induced diabetic mice were treated with NT (100 nM) for 3 days. Subsequently, EPC viability, cell adhesion and reactive oxygen species (ROS) levels were evaluated. To the in vivo wound healing model, 6 mm wounds were created in the dorsum of diabetic mice and wound progression was followed up to day 10. The wound edges were injected with ex-vivo diabetic bone marrow derived EPCs treated in culture with NT (100 nM) for 3 days, or EPCs without NT treatment, or vehicle. Angiogenesis was evaluated by immunohistochemistry. The viability of EPCs cultured under high glucose or EPCs from diabetic mice was improved by NT treatment. Also, EPCs from diabetic mice showed decreased adhesion (58% of control, p Disclosure E.C. Leal: None. A. Figueiredo: None. E. Carvalho: None. Funding Portuguese Foundation for Science and Technology; European Foundation for the Study of Diabetes; Portuguese Society of Diabetology

Background: Optimal management of bone marrow metastasis (BMM) in advanced breast cancer (ABC) remains unknown. Associated severe cytopenias often urge treatment, but they are also a challenging factor for delivering chemotherapy (CT). Since BMM in ABC is infrequent, available data are scarce. Aim: Clinical and prognostic characterization of ABC patients with BMM and its management; evaluation of the effectiveness of treating BMM with more myelosuppressive CT regimen (that we hypothesized that could be more active in the BMM) Vs. less myelosuppressive regimen. Methods: Retrospective cohort study of patients with pathological confirmation of BMM (positive myelogram or osteomedullary biopsy) between Jan'2010 and Dec'2016 in the two major Portuguese cancer centers. Patients with diagnosis of a second carcinoma or active hemato-oncological condition within 5 years before BMM were excluded. We considered the more myelosuppressive regimens those with > 5% risk of febrile neutropenia according to Truong et al 2015(1). Kaplan-Meier and log-rank methodology were used to estimate survival and Cox regression to identify the covariates with independent prognostic value. Statistical level of significance was 5%. Results: We included 74 patients: 74% with disease stage I-III at presentation, 74% ductal and 12% lobular invasive carcinomas, 58% grade 2 and 27% grade 3, 80% hormone receptor + / HER2-, 4% HER2+ and 12% triple negative (TN). Median time from ABC diagnosis to BMM was 10 months (IQR 2-36), synchronous in 34%. At diagnosis of BMM, median age was 57 years-old (IQR 47-65), 57% were post-menopausal, 97% had bone metastasis, 50% had visceral metastasis, 53% performed ≥ 2 previous palliative systemic treatments and 53% were exposed to bisphosphonates. The most frequent immunohistochemistry change in BMM biopsy was the loss of progesterone receptor expression (37%). Bicytopenia (anemia/thrombocytopenia) was the trigger for BMM investigation in 69% of cases, with grade 3-4 anemia in 16% and grade 3-4 thrombocytopenia in 26%. Median survival after BMM diagnosis was 5 months (95% CI, 3-11); overall survival at 12 and 24 months were 35% (CI 26-48%) and 24% (CI 15-36%), respectively. First treatment after BMM was CT in 58% (median survival, 11 months) and endocrine therapy in 14% (median survival, 3 months). An anti-HER2 regimen was used in 4% and 22% did not receive any treatment after BMM. On multivariate analysis, TN subtype (HR 4.02, CI 1.46-11.01), thrombocytopenia (G0 reference; G1-2: HR 2.47, CI 1.11-5.56; G3-4: HR 4.89, CI 1.85-12.91) and ≥ 2 palliative systemic treatments (HR 2.77, CI 1.46-5.27) were associated with worse prognosis. Within those treated with CT, there was a trend for a deleterious survival effect of more myelosuppressive regimens (HR 2.19, CI 0.94-5.09; 5 months Vs. 14 months, n=31), after controlling for subtype, number of previous regimens and thrombocytopenia. Conclusion: BMM was not a late event in ABC disease course and had worse prognosis in multi-treated patients, in TN subtype and in the presence of thrombocytopenia. No benefit was shown with the use of more myelosuppressive CT regimens. (1)Truong J et al, Ann Oncol. 2016 Apr;27(4):608-18. Citation Format: Martins-Branco D, Ferreira SC, Pereira I, André S, Varelas A, Leal C, Esteves S, Abreu MH, Sousa S, Moreira A, Brito M. Management of bone marrow involvement in advanced breast cancer: Retrospective multicenter cohort study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-18-05.

Background The addition of carboplatin to an anthracycline/taxane-based chemotherapy(CT) in neoadjuvant setting has been suggested to improve pathological complete response(pCR) in TNBC. However, the impact of pCR in prognosis is unknown. We aim to study the value and feasibility of the addition of carboplatin in neoadjuvant setting. Methods Demographic and clinical data of TNBC patients treated with neoadjuvant CT in a comprehensive cancer center between 2010-2018 were retrospectively collected. Two cohorts were defined: one treated with Carboplatin/Paclitaxel followed by dose-dense Doxorrubicin/Cyclophosphamide(CP-AC) and other with AC followed by Docetaxel(AC-D). Median follow-up time was 3.1 and 6.9 years, respectively. pCR was defined as absence of residual invasive tumor in breast/axilla. Survival analysis using Kaplan-Meier method and Cox proportional-hazards model were applied. Statistical significance was set at p Results One-hundred and sixty patients were enrolled: 78 CP-AC and 38 AC-D. Groups were balanced regarding patients and tumor characteristics with exception of pre-menopausal status, more frequent in CP-AC(68% vs 47%;p=.04). Age at diagnosis was 47(28-76)years, the majority had ECOG 0(92%) ductal carcinomas(82%), clinicalT2/3 stages(76%), grade 3(81%) with lymph node involvement(N+)(57%). 14% had Inflammatory breast cancer(IBC)(CP-AC 14%;AC-D 13%; p=.9). Neutropenia was the most prevalent adverse event(G3/4: CP-AC 61%;AC-D 16%;p=.02), 12% and 16% of febrile neutropenia(p=.8). G3/4 thrombocytopenia occurred only in CP-AC(6%). Hypersensitivity reactions were more prevalent in CP-AC(19% vs 2.7%;p=.02), majority to paclitaxel, all G1/2. Hospital admission occurred in 12%(CP-AC 13%;AC-D 9%; p=.8). There were no treatment-related deaths. Treatment schedule was complete in 89%(CP-AC 87%;AC-D 92%;p=.5), with 20% dose reductions(CP-AC 25%;AC-D 11%;p=0.9). pCR was achieved in 42%(CP-AC 50%;AC-D 28%;p=.03). 1- and 3-year disease-free survival(DFS) was 94%/85% for CP-AC and 72%/58% for AC-D(p=.3). Risk of recurrence was higher in IBC(HR 25.1;CI95% 7.7-81.3;p Cancer-related deaths were 20%(CP-AC 10%;AC-D 40%;p=.001). 1- and 2-year overall survival (OS) was 99%/95% for CP-AC and 70%/61% for AC-D(p=.06). N+ disease was associated with higher risk of death in AC-D(HR 6.3;CI95% 1.1-24.6;p=.04). Risk of death was independently associated with IBC(HR 4.1;CI95% 2.1-18.7; p=.001) but not with N+ disease(HR 2.7;CI95% 0.8-9.5;p=.13) or pCR(HR 4.1;CI95% 0.9-19.7;p=.08) although pCR was statistically significant in univariate analysis (1- and 2-year OS 97% vs 92% and 94% vs 86% for pCR and non-PCR;p=.003). Conclusions Carboplatin addition clearly increased pCR with a trend to DFS and OS benefit. This regimen was associated with more, nevertheless manageable, adverse events with most of the patients able to tolerate and complete the full-dose regimen. Though we did not find a subgroup of patients that benefit with carboplatin regimen, we should consider avoiding AC-D at least in N+ disease. Citation Format: Coelho S, Abreu MH, Sales C, Lopes AR, Sousa MF, Couto R, Pousa I, Ferreira A, Ferreira M, Vieira C, Leal C, Castro F, Sousa S, Pereira D. Carboplatin-addition in neoadjuvant treatment of women with triple negative breast cancer (TNBC): Prognostic value in real-world patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-19.

Breast cancer is the most frequent event in Li-Fraumeni syndrome associated with germline TP53 variants. Some studies have shown that breast cancers in women with Li-Fraumeni syndrome are commonly HER2-positive, suggesting that HER2 amplification or over-expression in a young woman may be a useful criterion to test for germline variants in the TP53 gene. We assessed the prevalence of germline TP53 variants by Sanger sequencing or next-generation sequencing in 149 women with HER2-positive breast cancer diagnosed until age 40. The pattern of HER2 amplification was evaluated with dual-probe FISH in a subset of breast carcinomas from patients with germline TP53 variants as compared with those of noncarriers. Among 149 women tested, three presented a deleterious TP53 germline variant (2%), with one patient diagnosed at age 31 and the other two with bilateral breast cancer at ages 29/33 and 28/32, respectively. Three of the 36 patients (8.3%) with the first breast cancer diagnosed at age 31 or younger presented a pathogenic TP53 variant. Additionally, all TP53 deleterious variant carriers had a first degree relative diagnosed with different early-onset cancers (frequently not belonging to the Li-Fraumeni syndrome tumor spectrum) diagnosed at age 45 or younger. Higher levels of HER2 amplification were found in breast carcinomas of TP53 pathogenic variant carriers than in those of noncarriers. Deleterious germline TP53 variants account for a small proportion of early-onset HER2-positive breast cancers, but these seem to have higher HER2 amplification ratios. All TP53 pathogenic variant carriers found in this study had the first breast carcinoma diagnosed at age 31 or younger and a first-degree relative with early-onset cancer. Further studies are needed to clarify if HER2 status in early-onset breast cancer patients, in combination with other personal and/or familial cancer history, is useful to update the TP53 testing criteria.

Made available in DSpace on 2020-12-12T02:09:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-08-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) AIMS: This study aimed to investigate the effect of lymphocytes in wound healing and the underlying mechanisms, in diabetic and non-diabetic mice, using Balb/c recombination activating gene (Rag)-2 and interleukin 2 receptor gamma (IL-2Rγ) double knockout (KO) (RAG2−/− IL-2Rγ−/−) mice. MAIN METHODS: Wound healing in vivo was performed in control and STZ-induced diabetic mice, in both KO and WT mice. Inflammation and ROS production were evaluated by immunofluorescence microscopy analysis, antioxidant enzymes and angiogenesis were evaluated by quantitative PCR and immunofluorescence microscopy analysis, and wound closure kinetics evolution was evaluated by measurement of acetate tracing of the wound area. KEY FINDINGS: Wound closure was significantly delayed in KO mice, where the M1/M2 macrophage ratio and basal ROS levels were significantly increased, while antioxidant defenses and angiogenesis were significantly decreased. Moreover, the expected increase in matrix metallopeptidase (MMP)-9 protein levels in diabetic conditions was not observed in KO mice, suggesting that the mechanisms leading to the increase in MMP-9 observed in diabetic wounds may in part be lymphocyte-dependent. SIGNIFICANCE: Our results indicate that lack of lymphocytes compromises wound healing independent of diabetes. The lack of these cells, even in non-diabetic mice, mimics the phenotype observed in wounds under diabetic conditions. Moreover, the combination of diabetes and the lack of lymphocytes, further impair the wound healing conditions, indicating that when the innate regulatory function is lost in these KO mice, excessive M1 polarization, poor angiogenesis and impaired wound healing are worsen. Center for Neuroscience and Cell Biology University of Coimbra Department of Physiotherapy School of Sciences and Technology Sao Paulo State University - UNESP, Campus Presidente Prudente Instituto de Investigação Interdisciplinar University of Coimbra Innate Immunity Unit Institut Pasteur Institut National de la Santé et de la Recherche Médicale (INSERM) U1223 Cell Biology Department Federal University of Paraná The Portuguese Diabetes Association (APDP) Department of Geriatrics University of Arkansas for Medical Sciences Arkansas Children's Research Institute INEB - Instituto Nacional de Engenharia Biomédica University of Porto i3S - Instituto de Investigação e Inovação em Saúde University of Porto Department of Physiotherapy School of Sciences and Technology Sao Paulo State University - UNESP, Campus Presidente Prudente CNPq: 203179/2011-0 CNPq: 233621/2014-8

Non-healing diabetic foot ulcers (DFUs) are a serious complication in diabetic patients. Their incidence has increased in recent years. Although there are several treatments for DFUs, they are often not effective enough to avoid amputation. Protein tyrosine phosphatase 1B (PTP1B) is expressed in most tissues and is a negative regulator of important metabolic pathways. PTP1B is overexpressed in tissues under diabetic conditions. Recently, PTP1B inhibition has been found to enhance wound healing. PTP1B inhibition decreases inflammation and bacterial infection at the wound site and promotes angiogenesis and tissue regeneration, thereby facilitating diabetic wound healing. In summary, the pharmacological modulation of PTP1B activity may help treat DFUs, suggesting that PTP1B inhibition is an outstanding therapeutic target.

Introduction Polyneuropathy and myopathy, grouped under the term “intensive care unit-acquired weakness” (ICUAW), are neuromuscular pathologies to which patients in the intensive care unit (ICU) are susceptible. They are multifactorial pathologies, prolonged connection to a ventilator is one of the most common. The objective of this review was to identify the efficacy of different rehabilitative treatments in patients with ICUAW, and the relationship between ICUAW and a series of indicators. Methods A systematic review of the primary studies selected from the Medline, Scielo, Web of Science, Cochrane, Cuiden and Science Direct databases was carried out, following the guidelines of the PRISMA statement, by which the search protocol was established. Results and conclusions Of 161 articles, only 10 were selected to be part of this review, in which a total of 717 patients admitted to the ICU were studied. A statistically significant relationship was observed between ICUAW and failure in ventilator disconnection, mortality, increase in ICU stay and the time that the patients required mechanical ventilation. Moreover, all this improved in this type of patients with the application of a rehabilitation therapy. The use of corticosteroids, was not shown to be related to neuromuscular alteration.

Background and Aim: Polyethylene glycol (PEG) is the gold standard for fecal disimpaction in constipation. A regimen of PEG combined with the stimulant laxative sodium picosulphate (SPS) produced fecal disimpaction in chronically constipated children in the community, but it is unknown if it is effective for more severe constipation. To determine the stool output and effect of a combined PEG and SPS regimen on fecaloma in children with severe constipation and impaction. Methods: Children with symptoms for a duration of >= 2 years, a palpable fecaloma, and enlarged rectum on X-ray (rectal: pelvic ratio > 0.6) were recruited from a tertiary hospital. Daily diaries recorded laxative dose, stool frequency, volume, and consistency (Bristol stool scale, BSS). Abdominal X-rays were taken on day 1 and day 8, and stool loading was assessed using the Leech score. Laxative doses were based on the child's age. The dose of PEG with electrolytes taken was 2-8 sachets (14.7 g/sachet) on days 1-2, reducing to 2-6 sachets on day 3. The SPS dose was 15-20 drops on days 2-3. Results: Eighty-nine children (4-18 years) produced a large volume of soft stool (median/inter-quartile-range: 2.2/1.6-3.1 L) over 7 days. Stool volume on X-rays decreased significantly in the colon (P < 0.001). Fecalomas resolved in 40 of 89 children, while 49 needed a second high dose. Rectal: pelvic ratios did not change. Conclusions: A combined high dose of PEG and SPS on days 1 and 2 was effective in removing the fecaloma in half of the children. Administering high doses for a longer period should be tested to provide outpatient disimpaction for severe fecalomas. Rectums remained flaccid after emptying.

Pemphigus vulgaris (PV) is a rare autoimmune blistering disorder of the skin and mucous membranes. The true prevalence of esophageal involvement is unknown; esophageal symptoms almost always occur in the context of oral mucosa involvement. We report the case of a 66-year-old man with cutaneous blisters and esophageal symptoms that did not respond to acid suppression therapy. Esophagogastroduodenoscopy showed esophageal ulcers and mucosal desquamation. Biopsies were consistent with the diagnosis of PV. The patient was started on immunosuppressive therapy, achieving remission. This represents a rare case of esophageal involvement of PV without mucosal involvement and draws attention to a rare cause of dysphagia, which can be fatal if left untreated

Visible impairments in skin appearance, as well as a subtle decline in its functionality at the molecular level, are hallmarks of skin aging. Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-pathway, which is important in controlling inflammation and oxidative stress that occur during aging, can be triggered by sulforaphane (SFN), an isothiocyanate found in plants from the Brassicaceae family. This study aimed to assess the effects of SFN intake on age-related skin alterations. Male C57BL6 young (2 months) and old (21 months) mice were treated for 3 months with SFN diet (442.5 mg per kg) or control diet. The antioxidant capacities of the skin were increased in old SFN-treated animals as measured by mRNA levels of Nrf2 (P

Background The gut microbiota(GM) plays a pivotal role in the pathogenesis of inflammatory bowel disease (IBD) which includes Crohn’s disease (CD) and ulcerative colitis(UC). The degree of IBD activity, and therefore of inflammation, modifies GM composition towards an altered pattern called dysbiosis This IBD-dysbiosis pattern is different from healthy individuals(HI). The degree of dysbiosis is a good indicator of IBD activity and could be useful in monitoring IBD. The AIM of this study is to quantify the degree of IBD dysbiosis of the GM, and determine the utility as a biomarker for monitoring IBD disease compared with HI. Methods 80 IBD patients from 2 tertiary hospitals have been included. We included patients with clinical Remission (R), defined as Faecal Calprotectin (FC) levels 250 µg/gr.) with mild to moderate disease. A blood sample (to determinate RCP, albumin and hemoglobin (Hb) levels) and stool sample (to determinate Faecal calprotectin (FC) and GM analysis) has been collected. DNA was extracted from fecal samples, using real-time qPCR techniques and 3 bacterial groups (Faecalibacterium prausnitzii (FP), Escherichia coli (EC), and total eubacteria (TE) that are highly representative of GM dysbiosis degree were analyzed. In regards to these bacteria, an index called FEI has been created to quantify GM dysbiosis. GM and FEI data has been collected in order to compare with standards analytical markers (Hb, Alb, RCP, FC). The duration of this study is 6 months with samples every three months (T0, T1 and T2). Results 35 UC and 45 CD patients were included. Initial treatment in 76,25% of cases were biological drugs. 55 % of patients were in remission at first sample. The analysis of clinical data showed that only PCR and CP had significantly differences between R and A (p=0,0037) and type of disease (p=0,018) and temporal evolution (p=0,004). Higher levels of FP are been observed in UC (p=0,0013) and higher levels of EC in CD (p=0,003) in all 3 samples. FEI values are higher in UC (p=0,001) and different between CD and UC and HI (p=0,015) indicating FEI ability to differentiate between 2 disease subtypes and HI. FEI cut-off point has been set at 1,869 (S 0,44 and E0,82; AUC 0,658) in T0. The IBD-GM compared with HI-GM showed lower FP abundance (p=0,002) and higher TE abundance (p=0,0001) with increased non-significant EC abundance. The A and R abundances for FP,FEI and TE showed significant differences between CD, UC and HI, indicating capacity to differentiate between activity and remission in T0. Conclusion Microbiological markers and FEI allow to differentiate between IBD subtypes and HI, and between A and R. The combination if RCP, FC and FEI can become a potential biomarker of IBD activity.

IntroductionIn the midst of a global pandemic with a rising death toll, the children´s mental health can be easily overlooked in the country’s response. But this overlook would have devastating consequences for years to come.ObjectivesThe objective of this research is to compare children’s physical and mental development before, during and after the situation of social isolation caused by the pandemic of COVID-19.MethodsThe parents/guardians of 100 children aged between 0 and 5 years and 11 months old were asked to answer questions based on the ASQ-3 (Ages and Stages Questionnaire III), containing questions related to Communication, Gross Motor, Fine Motor, Problem Solving, and Personal-Social and ASQ- SE (Ages and Stages Questionnaires Social-Emotional) addressing issues of self-regulation, compliance, social-communication, adaptive functioning, autonomy, and affect. In addition, behavioral issues related to children’s mental health will be included, such as: aggressiveness, insomnia, lack of appetite, apathy, sadness, tiredness, lack of interest, hyperactivity, manias, tantrum, morning among others. Child development data will be collected before and during quarantine / isolation and later, in a second stage, after the end of social isolation.ResultsThe data will be analyzed in order to characterize child behavior before, during and after the period of social isolation, correlating the different areas of child development, especially mental health.ConclusionsAs argued, socially isolated children are at increased risk of health problems in adulthood. Furthermore, studies on social isolation have demonstrated that a lack of social relationships negatively impacts the development of the brain’s structure.DisclosureNo significant relationships.

Treatment resistant depression can be very disabling and has a significant negative impact on a patient, their family or caregivers, and the society. There is a growing evidence on the efficacy and safety of ketamine for treatment resistant depression. Ketamine is a racemate consisting of esketamine and arketamine, is an N-methyl D-aspartate receptor antagonist and comes in different formulations and in fact intranasal ketamine is FDA-approved in the US. Despite the existing evidence and FDA approval for treatment resistant depression, data on older individuals remains limited. Late life depression especially those that are treatment resistant can be very disabling, with significant functional and cognitive impairments, increased morbidity and mortality, and the psychosocial burdens.This presentation describes outcomes for 2 cases of older individuals with treatment resistant depression who were treated with intranasal ketamine. One improved, and one did not. The scarce available literature of the use of ketamine in the geriatric population shows ketamine is well tolerated and effective. Remission rates in 3 separate show remission rates of 46.5%, 57% and 69.5% respectively. The discussion will include a review of the mechanism of action of ketamine as a novel antidepressant, the mixed evidence for its role in treatment resistant late life depression, and the practical and operational aspects relevant to running a ketamine clinic.

Background The effect of spirulina (Arthrospira platensis), on haemoglobin and serum ferritine was tested in young women aged between 18 and 21 years and presenting an iron-deficiency anemia. Methods According to the allocation group, each participant daily consumed one placebo snack bar or one snack bar supplemented with 3 g of spirulina. At baseline, day 45, 60, and 90 after the first bar was consumed a complete blood count, serum ferritin, pregnancy test, and physical examination were performed. Results Anemia prevalence was found to be 33.7% among the age range tested in Mumbai. In total, 181 women were screened, 61 of them were randomized and allocated into the two groups and finally 47 young women completed the study. Conclusions Spirulina or placebo snack bars were well tolerated. However, we did not observe significant changes in serum ferritin and hemoglobin in both groups at the end of the study.

Background NRTIs-sparing regimens exert favourable profiles on T-cell homeostasis associated parameters. Our aim was to analyze the effect of NRTIs sparing regimen (NRTI-sparing-cART) vs NRTIs-containing regimen (NRTI-cART), on T-cell homeostasis associated parameters in naive HIV-infected patients. Methods Biomarkers of cell survival (CD127) and replicative senescence (CD57), were measured by multiparametric flow cytometry for T-cell phenotyping on peripheral blood mononuclear cells (PBMCs) samples just before (baseline) and after 48 weeks of undetectable viral load in patients on NRTI-sparing-cART (N = 13) and NRTI-cART (N = 14). After 48 weeks a subgroup of patients (n = 5) on NRTI-cART switched to NRTI-sparing-cART for another additional 48 weeks. In vitro assays were performed on PBMCs from HIV-uninfected healthy donors exposed or not to HIV. To analyze the independent factors associated with type of cART bivariate and stepwise multivariate analysis were performed after adjusting for basal CD4+, CD8+ and nadir CD4+ T-cell counts. Results After 48 weeks of a NRTI-sparing-cART vs NRTI-cART patients have higher effector memory (EM) CD4+ CD127+ T-cell levels, lower EM CD4+ CD57+ T-cell levels, higher CD8+ CD127+ T-cell levels, lower CD8+ CD57+ T-cell levels and higher memory CD8+ T-cell levels. This effect was confirmed in the subgroup of patients who switched to NRTI-sparing-cART. In vitro assays confirmed that the deleterious effect of a NRTIs-containing regimen was due to NRTIs. Conclusions The implementation of NRTI-sparing regimens, with a favourable profile in CD127 and CD57 T-cell expression, could benefit cART-patients. These results could have potential implications in a decrease in the number of Non-AIDS events. Electronic supplementary material The online version of this article (10.1186/s12967-017-1367-5) contains supplementary material, which is available to authorized users.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that up to now has been associated with a poor prognosis. However, the results of the INPULSIS and ASCEND trials and the approval of nintedanib and pirfenidone have marked the beginning of a new era for IPF patients. Questions remain, however. Should these drugs be used earlier? What effect will they have on more severe disease? Will their effects last beyond the trial period? This manuscript is the outcome of a multidisciplinary meeting between pulmonology, radiology, and pathology clinicians on the use of antifibrotic agents in IPF. In our opinion, the existing data show that pirfenidone and nintedanib slow functional decline in early stages of disease. These drugs also appear to result in therapeutic benefits when administered to patients with advanced disease at diagnosis and maintain effective over time. The data also suggest that continuing antifibrotic therapy after disease progression may confer benefits, but more evidence is needed. Early diagnosis and treatment are crucial for reducing functional decline, slowing disease progression, and improving quality of life. Keywords: Idiopathic pulmonary fibrosis, Interstitial lung disease, Nintedanib, Pirfenidone

Cancer patients are at an increased risk of developing thromboembolic complications. Several mechanisms have been proposed to explain cancer-associated thrombosis including the release of tumor-derived extracellular vesicles and the activation of host vascular cells. It was proposed that neutrophil extracellular traps (NETs) contribute to the prothrombotic phenotype in cancer. In this study, we evaluated the possible cooperation between tumor-derived exosomes and NETs in cancer-associated thrombosis. Female BALB/c mice were orthotopically injected with 4T1 breast cancer cells. The tumor-bearing animals exhibited increased levels of plasma DNA and myeloperoxidase in addition to significantly increased numbers of circulating neutrophils. Mice were subjected to either Rose Bengal/laser-induced venous thrombosis or ferric chloride-induced arterial thrombosis models. The tumor-bearing mice exhibited accelerated thrombus formation in both models compared to tumor-free animals. Treatment with recombinant human DNase 1 reversed the prothrombotic phenotype of tumor-bearing mice in both models. Remarkably, 4T1-derived exosomes induced NET formation in neutrophils from mice treated with granulocyte colony-stimulating factor (G-CSF). In addition, tumor-derived exosomes interacted with NETs under static conditions. Accordingly, the intravenous administration of 4T1-derived exosomes into G-CSF-treated mice significantly accelerated venous thrombosis in vivo. Taken together, our observations suggest that tumor-derived exosomes and neutrophils may act cooperatively in the establishment of cancer-associated thrombosis.

Introduction Breast radial scar (RS) management remains controversial. The need for surgical excision is supported by the concern of an associated high-grade lesion missed in the biopsy. The aim of this study was to assess histologic upgrade rate after a percutaneous biopsy, to determine if vacuum assisted biopsy prevents the need for subsequent RS surgical resection and to evaluate the upgrade risk factors. Patients and methods This was a uni-institutional retrospective study of consecutive patients with RS histologically diagnosed from January 2010 to December 2015. Results A total of 113 cases of RS were diagnosed. We verify that there was a histologic upgrade in 22 (19.5%) cases. The upgrade risk factors were the type of biopsy performed, the presence of atypia, the presence of calcifications and the number of fragments obtained in the biopsy ( p The biopsy type was vacuum assisted in 25 (22.1%). The upgrade rate in the vacuum assisted biopsy group was 4.0%, whereas in the standard core needle biopsy group was 23,9% ( p = 0.041). Discussion and conclusion We demonstrated that the risk of upgrade after a RS diagnosis depends on the type of biopsy performed, the presence of atypia, the presence of calcifications and the number of fragments obtained. When a standard core biopsy is performed the risk of upgrade and malignancy is not negligible, and surgery is indicated. When the biopsy is vacuum assisted, the risk of upgrade and malignancy is significantly decreased and so the indication for excisional biopsy seems not to be so imperative.

The aim of this study was to determine fresh and frozen sperm quality evaluated over two spawning seasons (2013-2014; 2014-2015) in Prochilodus lineatus and Brycon orbignyanus. The spawning seasons were divided into two sampling periods: November to December and January to February. Males were hand-stripped after carp pituitary treatment. Fresh sperm motility rate, velocities (curvilinear = VCL; straight-line = VSL; average path = VAP), and the beat cross frequency (BCF) were determined using a Computer-Assisted Sperm Analyzer (CASA). Sperm of each species was frozen using methyl glycol as cryoprotectant and a glucose solution for P. lineatus or a NaCl solution for B. orbignyanus as extender. Diluted sperm was loaded into 0.25 mL straws, frozen in a nitrogen vapor vessel (dry shipper) and stored in a liquid nitrogen vessel. Six months later, straws were thawed in a water bath at 60 °C for 3 s and sperm quality was determined, as described for fresh sperm. No significant difference was observed for any of the fresh and frozen sperm features between the two spawning seasons or the two sampling periods in P. lineatus and in B. orbignyanus. Motility rate and velocities, but not BCF, was always higher in fresh sperm when compared with frozen sperm. Comparing both species, higher motility in frozen sperm and higher VCL and VAP in both fresh and frozen sperm were observed for P. lineatus, while higher VSL in fresh sperm and higher BCF in both fresh and frozen sperm were observed for B. orbignyanus. Sperm quality and its freezing ability of both species were sustained over the spawning season and thus fish farmers can reproduce these species and freeze their sperm in any time throughout the spawning season. P. lineatus sperm is more resistant to the cryopreservation process than B. orbignyanus.

We aimed to analyze the efficacy and safety of arketamine, the R(−)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans. Open-label pilot trial, seven subjects with TRD received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery–Asberg Depression Rating Scale (MADRS) 24 h after. Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean difference of 20.3 points [CI 95% 13.6–27.0; p