Effect of sow mass vaccination against Mycoplasma hyopneumoniae on the humoral immune response of newborn piglets.

Pneumonia caused by Mycoplasma (M.) hyopneumoniae is one of the major respiratory diseases in swine production. Commercial vaccines for M. hyopneumoniae are widely used in weaned piglets to reduce lung lesions and clinical signs in the downstream flow; however, no information regarding the effect of mass immunization of the breeding herd is available. The aim of this work was to evaluate a mass vaccination protocol for M. hyopneumoniae on the humoral response of sows and their offspring 24 h post-partum (trial registration number 40156). A total of 52 sows from two different farms (13 primiparous and 13 multiparous sows on each farm), one with mass vaccination (MVF) and one without mass vaccination against M. hyopneumoniae (control farm (CF)) were enrolled in this study. Five piglets from each litter were selected, resulting in 260 piglets. Blood was collected from sows and piglets 24 h post-partum for M. hyopneumoniae antibody detection by ELISA. The results showed that primiparous sows from MVF had higher antibody titers compared to multiparous sows of the same farm, and multiparous and primiparous sows from the CF. Similar results were evidenced in their offspring. The findings of this study suggest that mass vaccination results in a more robust serologic response on primiparous sows, which could be the main target of vaccination strategies for the breeding herd.

Serum DBI and biomarkers of neuroinflammation in Alzheimer's disease and delirium.

BACKGROUND: Alzheimer's disease (AD) patients often express significant behavioral symptoms: for this reason, accessible related biomarkers could be very useful. Neuroinflammation is a key pathogenic process in both AD and delirium (DEL), a clinical condition with behavioral symptoms resembling those of AD. METHODS: A total of n = 30 AD patients were recruited together with n = 30 DEL patients and n = 15 healthy controls (CTRL). Serum diazepam binding inhibitor (DBI), IL-17, IL-6, and TNF-α were assessed by ELISA. RESULTS: DBI serum levels were increased in AD patients with respect to CTRL (+ 81%), while DEL values were 70% higher than AD. IL-17 was increased in DEL with respect to CTRL (+ 146%), while AD showed dispersed values and failed to reach significant differences. On the other hand, IL-6 showed a more robust increase in DEL with respect to the other two groups (+ 185% and + 205% vs. CTRL and AD, respectively), and TNF-α failed to show any change. CONCLUSIONS: DBI may be a very promising candidate for AD, perhaps marking psychomotor DEL-like symptoms, in view of developing future helping tool for practicing physicians. Furthermore, DBI rise in DEL offers novel cues for a better comprehension of the pathogenesis of this potentially fatal condition.

Efficacy of the DigniCap System in preventing chemotherapy-induced alopecia in breast cancer patients is not related to patient characteristics or side effects of the device.

BACKGROUND: The DigniCap System is an effective scalp cooling device for the prevention of chemotherapy-induced alopecia in early breast cancer patients. AIM: This prospective study was designed to confirm the efficacy and tolerability of the device, to explore potential factors associated with its efficacy and to collect data on patient perceptions and satisfaction. METHODS: Between January 2016 and June 2018, 163 early breast cancer patients eligible for adjuvant chemotherapy were enrolled. Hair loss was assessed using the Dean scale, where a score of 0-2 (hair loss ≤50%) was defined as successful. RESULTS: Hair preservation was successful in 57% of patients in the overall series. The proportion was even higher (81%) in the patient subgroup treated with a paclitaxel and trastuzumab regimen. Side effects (feeling cold, headache, head heaviness, scalp and cervical pain) were mild to moderate and did not correlate with the rate of hair loss. Lifestyle, anthropometric factors and hair characteristics failed to be associated with device efficacy. CONCLUSIONS: The DigniCap System was well tolerated and found to be effective in preventing alopecia in early breast cancer patients. Our study failed to identify factors other than type of chemotherapy regimen associated with hair preservation.

QTc dispersion and interval changes in drug-free borderline personality disorder adolescents.

Emotional instability and dysregulation represent a core feature of borderline personality disorder (BPD) and abnormal patterns of sympathetic/parasympathetic activity have been repeatedly investigated in individuals with this disorder. Such abnormalities may represent the substrate for an arrhythmogenic risk that could materialize the following specific drug exposure. In this work, we decided to assess basal-corrected QT interval and dispersion (QTc and QTcd) for estimating such risk in a sample of drug-free adolescents with diagnosis of BPD. In this cross-sectional comparative study, we recruited n = 70 female adolescent BPD (14.7 ± 1.3 years), free of medications, alcohol or recreational drugs. Furthermore, n = 70 matched female healthy controls (CTRL, 14.6 ± 1.5 years) were enrolled. QTc and QTcd were manually assessed on a standard 12-lead ECG by a single experienced investigator who was unaware of clinical outcomes. QTcd was increased by 7 ms on average in BPD vs. CTRL (+ 18%, p = 0.03). QTc was decreased by about 15 ms on average in BPD vs. CTRL (p = 0.003). A mild correlation was found between QTc and QTcd in BPD (r = 0.25, p = 0.03) that was not present in CTRL. No correlation was found between either QTc or QTcd, and age in both groups. Mildly increased QTcd characterizes the cardiac activity regardless of drug exposure in female adolescents with BPD. This information may be of value to clinicians striving to use neuroleptic and antidepressant drugs with a lower risk of QTcd increase.

Irisin and BDNF serum levels and behavioral disturbances in Alzheimer's disease.

Behavioral dysfunctions (BPSD) represent the most important problem in Alzheimer's dementia (AD) management. We assessed the serum levels of two myokines in AD patients, preliminary investigating, as secondary aim, their role as potential biomarkers for agitation/aggression (AA) and aberrant motor behavior (AMB): irisin, since it is able to modify the motor pattern, and BDNF, since it was transcribed following irisin stimulation. Forty AD patients were recruited and characterized according to the expressed neuropsychiatric syndrome. Myokines were measured by ELISA. Irisin serum levels were slightly elevated in AA+ patients (+ 10.0%; p < 0.05) and correlated with the duration of AA (r = 0.74, p < 0.03). BDNF failed to show such differences. We propose that these selected myokines are not useful as surrogate markers for agitation in AD, but might represent interesting secondary outcomes when testing drugs for those BPSD implying elevated motor activity.

QT interval and dispersion in drug-free anorexia nervosa adolescents: a case control study.

Long QT values have been reported in patients with anorexia nervosa of the restricting type (ANr) potentially increasing the risk of fatal arrhythmia, especially if psychotropic drug treatment is required. Nevertheless, the previous studies on this topic are biased by drug exposure, long disease durations, and small sample sizes. This study is aimed at assessing QTc and QTcd values in ANr adolescents with recent onset and drug free, as compared to subjects affected by psychiatric disorders other than ANr. We evaluated QTc and its dispersion (QTcd) in a population of 77 drug-free ANr female adolescents and compared to an equal number of healthy controls (H-CTRL) and pathological controls (P-CTRL, mixed psychiatric disorders). The QT determination was performed on a standard simultaneous 12-lead ECG in blind by a single experienced investigator. QTc was calculated by the Bazett's formula and QTcd was determined as the difference between the maximum and minimum QTc intervals in different leads. Only for ANr patients, clinico-demographic data, hormones, and electrolytes were obtained. QTc was slightly reduced in ANr patients (27.7 ms, < 10%, p < 0.0003) vs. controls, while QTcd was increased in P-CTRL (30%, p < 0.0003). Heart rate was significantly lower in ANr patients vs. controls (25%; p < 0.003). Tyroid hormones and serum potassium showed weak although significant positive correlations with QTc in ANr patients. QTcd displayed a weak negative correlation with the BMI percentile (r = - 0.262, p = 0.03). We reject the hypothesis that QTc and QTcd are increased in drug-free ANr adolescents with a relatively short-disease duration. Further studies are needed to understand if the previously reported increase might be related to other associated chronic disorders, such as hormonal or electrolyte imbalance.

Donepezil modulates the endogenous immune response: implications for Alzheimer's disease.

OBJECTIVE: Donepezil (DNPZ) is a drug commonly used for Alzheimer's disease (AD) that may favour a T helper 2 phenotype leading to increased naturally occurring auto-antibodies (NAb) against beta-amyloid (Aß). We hypothesized the involvement of the cholinergic receptors [α7-nicotnic acetylcholine receptor (α7nAChR)] expressed on peripheral blood mononuclear cells (PBMC). METHODS: Fifty patients with mild-to-moderate AD, DNPZ treated (DNPZ+, n = 25) or not (DNPZ-, n = 25), and 25 matched controls were enrolled and PBMC extracted for both in vitro cultures, and real-time polymerase chain reaction and chromatin immunoprecipitation assay. Plasma samples were also obtained for Aß and NAb determination. RESULTS: Donepezil increased in vitro the expression of the transcription factor GATA binding protein 3 (GATA3) through α7nAChR, because prevented by the specific antagonist methyllycaconitine. Ex vivo PBMC α7nAChR mRNA expression was increased in both AD groups, while GATA3 expression was not. A significant increase in the GATA3/interleukin 5 promoter association was found in DNPZ+ patients. Finally, DNPZ+ patients showed both significantly higher plasma levels of anti-Aß NAb with respect to DNPZ- patients and Aß 1-42 with respect to normal controls. CONCLUSIONS: Donepezil might modulate a T helper 2 bias via α7nAChR leading to increased expression of NAb. Further studies on the role of the modulation of the immune response against Aß may pave the way to innovative therapeutic strategies for AD. Copyright © 2016 John Wiley & Sons, Ltd.

BDNF Serum Levels with Respect to Multidimensional Assessment in Amyotrophic Lateral Sclerosis.

BACKGROUND: The clinical presentation of amyotrophic lateral sclerosis (ALS) is characterized by high heterogeneity, the greatest part of which still remains unexplained. OBJECTIVE: To assess serum levels of brain-derived neurotrophic factor (BDNF) in ALS patients, implementing a multidimensional characterization focused on four a priori chosen elements of phenotypic variability: ALS bulbar/spinal subtype, cognitive impairment, mood dysfunction and disease progression speed. METHODS: Serum samples were obtained from 45 ALS outpatients (16% bulbar onset) and 22 healthy controls. Each patient underwent the Montreal Cognitive Assessment (MoCA) and the Beck Depression Inventory (BDI), and disease progression speed was estimated by calculating the decay of the ALSFRS-R score over time. RESULTS: BDNF serum levels did not differ between patients and controls, although ∼25% lower levels characterized those patients carrying a depressive trait. Finally, BDNF serum levels were significantly lower in ALS patients expressing lower ALSFRS-R scores (r = 0.39, p < 0.01). No differences were found when considering cognitive impairment, disease progression speed and site of onset. CONCLUSION: BDNF serum levels might mark and possibly contribute in part to ALS phenotypic variability.

Beta-amyloid plasma levels in adolescents with anorexia nervosa of the restrictive type.

BACKGROUND: Reduced plasma leptin and elevated homocysteine (Hcy) are known to lead to increased ß-amyloid (Aß) production, besides being hallmarks of anorexia nervosa (AN) of the restrictive type. AN subjects display several neuropsychiatric manifestations, which may entail Aß-mediated altered synaptic functions. The aim of this study consisted in assessing Aß plasma levels in AN patients. METHODS: A total of 24 adolescent female AN outpatients were recruited together with 12 age-comparable healthy controls. For each subject we assessed Aß40 and leptin plasma levels, as well as APOE genotype. Hcy plasma levels were also determined in AN patients who underwent clinical characterization, including the Eating Disorder Inventory-3 (EDI-3), the Children's Depression Inventory (CDI) and the estimation of the speed of BMI loss (DPI, disease progression index). RESULTS: Plasma Aß40 levels were similar between patients and controls, while a marked reduction was observed for leptin (∼80%) in AN patients. Aß40 plasma levels failed to correlate with leptin, while a linear correlation was present with Hcy (r = 0.50, p < 0.03). Examined clinical features were not related with Aß40 plasma levels, with the only exception of the DPI (r = 0.47, p < 0.03). CONCLUSION: This exploratory study does not support a significant role for altered Aß production in AN-associated dysfunctions. Further studies are required to clarify whether exceptions to this conclusion can be drawn for those patients expressing significantly elevated Hcy plasma levels or for those progressing more rapidly.

Paradoxical increase of plasma vitamin B12 and folates with disease severity in anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) is a complex disorder involving severe psychological manifestations and multiple organ damage, including liver dysfunction. The primary aim of this study consisted in assessing plasma levels of vitamin B12 and folates with respect to liver function enzymes considering the liver-storage properties of this vitamin. METHOD: We recruited 70 restrictive type AN adolescents and the severity of psychopathological traits was assessed using EDI-3 scale. Plasma levels of vitamin B12 , folates, transaminases (AST, ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and cholinesterase (CHE) were determined. RESULTS: About 38.5% of patients displayed vitamin B12 values (H-B12) above the upper range of normal reference; 4.3% of patients had increased values of folates; 20 and 11.4% of patients displayed ALT and AST values above reference limits; none had GGT values above normal range. Albeit low CHE and ALP values were found in 55 and 20% of patients, respectively, a linear correlation with both transaminases was present only for vitamin B12 and folates; furthermore, H-B12 patients had both higher AST and ALT values. EDI- 3 subscores significantly correlated with vitamin B12 and folates plasma values and H-B12 patients displayed EDI-3 higher values. DISCUSSION: These data suggest that plasma levels of vitamin B12 might be an early marker of liver dysfunction, possibly also related to more severe psychopathological aspects. The identification of patients with higher fasting plasma vitamin B12 levels could therefore lead to earlier and more careful refeeding interventions. Further studies will clarify the potential role of this vitamin in AN clinical practice.

Diazepam binding inhibitor and dehydroepiandrosterone sulphate plasma levels in borderline personality disorder adolescents.

BACKGROUND: Borderline personality disorder (BPD) patients display a complex and heterogeneous clinical phenotype that plausibly implies variable underlying pathogenic mechanisms. A dysregulation of peripheral benzodiazepine receptors has previously been shown in BPD peripheral tissues, implying possible alterations of its ligand, the diazepam binding inhibitor (DBI) or of the downstream products of its activation, i.e. neuroactive steroids. METHODS: The aim of this work consisted in assessing, by ELISA, fasting plasma levels of DBI and dehydroepiandrosterone sulphate (DHEA-S), including cortisol and the cortisol-to-DHEA-S molar ratio (CDR), in 17 BPD adolescents versus 13 healthy controls, testing the possibility that clinical scales related to depressive or anxious traits (CDI, STAI-Y) or to disease severity (BPDCL) might be associated with a selective dysregulation of these parameters. RESULTS: DBI plasma levels were unchanged, while DHEA-S ones were significantly increased (approx. 70%) and the CDR decreased in BPD patients. No meaningful correlations with clinical variables emerged. CONCLUSION: Our results indicate that a dysfunction of the neurosteroid system might be operative in BPD in spite of unchanged DBI plasma levels and that DHEA-S might represent a generalized trait marker for the altered stress response that is associated with this disorder.

Assessment of sow herd frequency of PCV-2 using placental umbilical cord serum and serology in 18 breeding farms in Brazil.

Porcine circovirus type 2 (PCV-2) is the agent of one of the most important diseases in the swine industry. Although it has been controlled through vaccination, viremic piglets at birth may represent a risk by reducing vaccination efficacy. Since there are few reports on the viremic status of pre-suckling piglets regarding PCV-2 infection, we assessed the PCV-2 frequency in sows housed in 18 breeding farms with no history of clinical PCVAD in Brazil, using placental umbilical cord serum (PUCS). The selection criteria were: breeding farms with more than 1,000 sows; sows not vaccinated for PCV-2 at least for 2 years prior to the study; farms with no history of PCV-2 clinical disease in the last 12 months; and production systems with a maximum of two sites. Blood from the umbilical cords in sow placenta or directly from piglet's immediately after birth was collected from 30 litters on each farm for PCR. In addition, blood from 538 sows was collected for PCV-2 antibody detection. A total of 17.29% of the PUCS tested positive. The PCV-2 DNA was detected in PUCS from 94.4% of all farms. A total of 94.8% of the sows was positive for PCV-2 antibodies. However, seronegative sows were detected in 44.4% of farms. All 18 farms had at least 46.9% seropositive dams. A higher percentage of seronegative sows was observed for farms with more than 10% of PCV-2-positive litters compared to those with ≤10% of PCV-2 positive litters (8.9 +/-1.7% vs. 1.5 +/- 0.7%, p < 0.01, respectively).

Reduced fasting plasma levels of diazepam-binding inhibitor in adolescents with anorexia nervosa.

OBJECTIVE: Altered expression and/or function, both peripherally and centrally, of various neuropeptides is involved in the neurophysiology of anorexia nervosa (AN). Diazepam-binding inhibitor (DBI) is an interesting peptide for understanding this crosstalk. The aim of this work was to assess fasting plasma levels of DBI and leptin in patients with AN. METHOD: Twenty-four AN adolescents were recruited together with 10 age-comparable healthy controls. Neuropeptide determinations were performed on plasma samples by enzyme-linked immunosorbent assays. Patients with AN were further characterized for the presence of a depressive state or anxiety by using, respectively, the Children's Depression Inventory or the State-Trait Anxiety Inventory form Y. RESULTS: Levels of both plasma DBI and leptin were reduced in patients with AN (∼40 and ∼70%, respectively). DBI levels displayed a tendency to increase in the presence of a depressive state, although not with anxiety, whereas leptin levels correlated exclusively with body mass index. DISCUSSION: These data further extend our knowledge of neuropeptide dysfunction in AN, and plasma DBI may represent a marker for this disease, in particular considering its correlation with comorbid mood disorders.

Relationship between dexamethasone treatment around parturition of primiparous sows and farrowing performance and newborn piglet traits.

This study evaluated the relationship between the steroidal anti-inflammatory action of dexamethasone treatment in primiparous sows and farrowing and piglet performance in the first 5 d of life. For this purpose, 234 gilts were selected on the day of farrowing and distributed among three treatments: CON - control, without dexamethasone treatment; DexaPF - treatment with dexamethasone (20 mg im) per female at the moment of copious colostrum secretion (pre-farrowing); and DexaFO - treatment with dexamethasone (20 mg im), per female when the first piglet was born (farrowing onset). All females and their litters were evaluated regarding farrowing duration, obstetric interventions, colostrum yield and intake, newborn piglet traits, and piglet performance until 5 d of age. A subsample of 79 females (∼26 per treatment) had their blood glucose concentration evaluated hourly shortly after the first piglet was born until the end of farrowing. Additionally, blood samples from 11 litters per treatment were collected for immunocrit evaluation. As a result, faster farrowing was observed in the DexaPF treatment (188.14 min; P = 0.002) compared with CON (229.99 min) and DexaFO (221.79 min). Additionally, lower obstetric intervention rates were observed in sows treated with dexamethasone (DexaPF = 7.69%; DexaFO = 5.13%) compared with CON (19.23%; P = 0.02). The sow's blood glucose concentration during farrowing was higher in DexaPF (90.55 mg/dL) than in CON (73.15 mg/dL) and DexaFO (80.06 mg/dL) treatments (P < 0.01). Besides the effect on farrowing duration, no differences among treatments were observed regarding piglets born alive and stillbirths, newborn piglet vitality, colostrum consumption, immunocrit, and colostrum yield (P ≥ 0.17). Regarding piglet traits, higher percentages of piglets born without meconium staining and lower percentages of piglets with meconium scores 2 and 3 were observed in the groups treated with dexamethasone (DexaPF and DexaFO; P < 0.01) compared with CON. However, piglet weight gain and survival rate until 5 d of age were not affected by the treatment (P ≥ 0.61). In summary, dexamethasone treatment before farrowing onset, in primiparous sows, had the potential to reduce the farrowing duration and the necessity of obstetric intervention, but it did not affect the main productive parameters such as the occurrence of stillbirths, piglet weight gain, and survival rates until 5 d of age.

TSPO Modulates Oligomeric Amyloid-ß-Induced Monocyte Chemotaxis: Relevance for Neuroinflammation in Alzheimer's Disease.

BACKGROUND: Neuroinflammation is one of the cardinal mechanisms of Alzheimer's disease (AD). with amyloid-ß (Aß) playing a critical role by activating microglia to produce soluble inflammatory mediators, including several chemokines. Peripheral monocytes are, therefore, attracted into the central nervous system (CNS), where they change into blood-born microglia and participate in the attempt of removing toxic Aß species. The translocator protein-18 kDa (TSPO) is a transmembrane protein overexpressed in response to neuroinflammation and known to regulate human monocyte chemotaxis. OBJECTIVE: We aimed to evaluate the role of the oligomeric Aß1-42 isoform at inducing peripheral monocyte chemotaxis, and the possible involvement of TSPO in this process. METHODS: In vitro cell lines, and ex vivo monocytes from consecutive AD patients (n = 60), and comparable cognitively intact controls (n = 30) were used. Chemotaxis analyses were carried out through both µ-slide chambers and Boyden assays, using 125 pM oligomeric Aß1-42 as chemoattractant. TSPO agonists and antagonists were tested (Ro5-4864, Emapunil, PK11195). RESULTS: Oligomeric Aß directly promoted chemotaxis in all our models. Interestingly, AD monocytes displayed a stronger response (about twofold) with respect to controls. Aß-induced chemotaxis was prevented by the TSPO antagonist PK11195; the expression of the TSPO and of the C-C chemokine receptor type 2 (CCR2) was unchanged by drug exposure. CONCLUSION: Oligomeric Aß1-42 is able to recruit peripheral monocytes, and we provide initial evidence sustaining a role for TSPO in modulating this process. This data may be of value for future therapeutic interventions aimed at modulating monocytes motility toward the CNS.

Intravaginal devices impregnated with medroxyprogesterone acetate avoid early parturition and synchronize farrowing in sows.

Two experiments were performed to evaluate the use of an intravaginal device (IVD) impregnated with medroxyprogesterone acetate (MPA) to avoid early parturition and synchronize farrowing in sows. In both experiments with IVDs, the gestation length, stillbirth rate, birth weight, colostrum yield, lactational litter performance, and subsequent reproductive performance of sows were assessed. In Experiment 1 (Exp. 1; n = 91), sows were assigned to four treatments to evaluate the minimum required MPA dose: without IVD (CONT; control), 400 mg (MPA400), 600 mg (MPA600), and 800 mg (MPA800) of MPA in the IVD. The IVD was inserted on day 110 of gestation and removed on day 115. No sows farrowed during IVD treatment. Gestation length was increased in treatments with MPA (116.4 days) compared to the control (CONT; 114.9 days; P < 0.01), without effects on piglet birth weight (P = 0.98). A lower percentage of deaths around the farrow (P = 0.02) was observed in the CONT (1.8%) compared to MPA treatments (6.8%). The dose of 400 mg of MPA, validated in Exp. 1, was used in Experiment 2 (Exp. 2; n = 84) to evaluate the performance of sows and piglets in a sow farrowing synchronization protocol. Sows were treated with MPA from days 110-114 of gestation with or without 0.168 mg of cloprostenol sodium (PGF2α), for luteolysis induction, at IVD removal. Thus, four treatments were considered: CONT - without MPA or luteolysis induction (no interventions); PGF2α - luteolysis induction on day 114 of gestation without MPA; MPA114 - MPA treatment till 114 days of gestation without luteolysis induction; MPA114 + PGF2α - MPA treatment and luteolysis induction on day 114 of gestation. The gestation length in treatments with IVDs was longer (P < 0.01) than CONT without a difference for PGF2α treatment (P = 0.46). No impact of IVD use on piglet birth weight (P = 0.67) and deaths around the farrow (P = 0.50) were observed. The colostrum yield (P = 0.65), immunocrit (P = 0.72), piglet performance during lactation (P = 0.81), and weaning-to-estrus interval (P = 0.21) were similar among treatments. In conclusion, the use of IVDs impregnated with 400 mg of MPA between days 110 and 114 of gestation prevented early parturition with no implications for piglet survival at birth, colostrum yield, or litter performance.

Plasma and cerebrospinal fluid cholesterol esterification is hampered in Alzheimer's disease.

OBJECTIVE: The purpose of this study was to evaluate cholesterol esterification and HDL subclasses in plasma and cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients. METHODS: The study enrolled 70 AD patients and 74 cognitively normal controls comparable for age and sex. Lipoprotein profile, cholesterol esterification, and cholesterol efflux capacity (CEC) were evaluated in plasma and CSF. RESULTS: AD patients have normal plasma lipids but significantly reduced unesterified cholesterol and unesterified/total cholesterol ratio. Lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate (CER), two measures of the efficiency of the esterification process, were reduced by 29% and 16%, respectively, in the plasma of AD patients. Plasma HDL subclass distribution in AD patients was comparable to that of controls but the content of small discoidal preß-HDL particles was significantly reduced. In agreement with the reduced preß-HDL particles, cholesterol efflux capacity mediated by the transporters ABCA1 and ABCG1 was reduced in AD patients' plasma. The CSF unesterified to total cholesterol ratio was increased in AD patients, and CSF CER and CEC from astrocytes were significantly reduced in AD patients. In the AD group, a significant positive correlation was observed between plasma unesterified cholesterol and unesterified/total cholesterol ratio with Aß1-42 CSF content. CONCLUSION: Taken together our data indicate that cholesterol esterification is hampered in plasma and CSF of AD patients and that plasma cholesterol esterification biomarkers (unesterified cholesterol and unesterified/total cholesterol ratio) are significantly associated to disease biomarkers (i.e., CSF Aß1-42).

Value of Including the Children's Experience for Improving Their Rights During Hospitalization: Protocol for the VoiCEs Project.

BACKGROUND: Users' feedback is a key asset for organizations that want to improve their services. Studying how organizations are enabling their users to participate in evaluation activities is particularly important, especially when there are vulnerable or disadvantaged people, and the services to be evaluated can be life-changing. This is the case in the coassessment by pediatric patients experiencing hospital stay. The international literature reports a few attempts and several challenges in systematically collecting and using the pediatric patient experience with respect to hospitalization, to undertake quality improvement actions. OBJECTIVE: This paper describes the research protocol of a European project intended to develop and implement a systematic pediatric patient-reported experience measures (PREMs) observatory that will be shared by 4 European children's hospitals in Finland, Italy, Latvia, and the Netherlands. METHODS: The VoiCEs (Value of including the Children's Experience for improving their rightS during hospitalization) project uses a participatory action research approach, based on a mixture of qualitative and quantitative methods. It consists of 6 different phases, including a literature review, an analysis of the previous experiences of pediatric PREMs reported by project partners, a Delphi process, a cycle of focus groups or in-depth interviews with children and their caregivers, a series of workshops with interactive working groups, and a cross-sectional observational survey. The project guarantees the direct participation of children and adolescents in the development and implementation phases of the project. RESULTS: The expected results are (1) a deeper knowledge of published methodologies and tools on collecting and reporting pediatric patients' voice; (2) lessons learnt from the analysis of previous experiences of pediatric PREMs; a consensus reached through a participatory process (3) among experts, (4) pediatric patients and caregivers about a standard set of measures for the evaluation of hospitalization by patients; (5) the implementation of a European observatory on pediatric PREMs; and (6) the collection and comparative reporting of the pediatric patients' voice. In addition, the project is aimed at studying and proposing innovative methodologies and tools for capturing the pediatric patients' feedback directly, avoiding the intermediation of parents/guardians. CONCLUSIONS: Over the last decade, the collection and use of PREMs have gained importance as a research field. Children and adolescents' perspectives have also been increasingly taken into consideration. However, to date, there are limited experiences regarding the continuous and systematic collection and use of pediatric PREMs data for implementing timely improvement actions. In this perspective, the VoiCEs project provides room for innovation, by contributing to the creation of an international, continuous, and systematic pediatric PREMs observatory that can be joined by other children's hospitals or hospitals with pediatric patients, and foresees the return of usable and actionable data in benchmarking. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42804.

Glibenclamide-Loaded Engineered Nanovectors (GNVs) Modulate Autophagy and NLRP3-Inflammasome Activation.

Activation of the NLRP3 inflammasome in response to either exogenous (PAMPs) or endogenous (DAMPs) stimuli results in the production of IL-18, caspase-1 and IL-1ß. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status plays a role in human pathologies, including Alzheimer's disease (AD). Autophagic removal of NLRP3 inflammasome activators can reduce inflammasome activation and inflammation. Likewise, inflammasome signaling pathways regulate autophagy, allowing the development of inflammatory responses but preventing excessive and detrimental inflammation. Nanotechnology led to the development of liposome engineered nanovectors (NVs) that can load and carry drugs. We verified in an in vitro model of AD-associated inflammation the ability of Glibenclamide-loaded NVs (GNVs) to modulate the balance between inflammasome activation and autophagy. Human THP1dM cells were LPS-primed and oligomeric Aß-stimulated in the presence/absence of GNVs. IL-1ß, IL-18 and activated caspase-1 production was evaluated by the Automated Immunoassay System (ELLA); ASC speck formation (a marker of NLRP3 activation) was analyzed by FlowSight Imaging flow-cytometer (AMNIS); the expression of autophagy targets was investigated by RT-PCR and Western blot (WB); and the modulation of autophagy-related up-stream signaling pathways and Tau phosphorylation were WB-quantified. Results showed that GNVs reduce activation of the NLRP3 inflammasome and prevent the Aß-induced phosphorylation of ERK, AKT, and p70S6 kinases, potentiating autophagic flux and counteracting Tau phosphorylation. These preliminary results support the investigation of GNVs as a possible novel strategy in disease and rehabilitation to reduce inflammasome-associated inflammation.

Predictors of response to acetylcholinesterase inhibitors in dementia: A systematic review.

Background: The mainstay of therapy for many neurodegenerative dementias still relies on acetylcholinesterase inhibitors (AChEI); however, there is debate on various aspects of such treatment. A huge body of literature exists on possible predictors of response, but a comprehensive review is lacking. Therefore, our aim is to perform a systematic review of the predictors of response to AChEI in neurodegenerative dementias, providing a categorization and interpretation of the results. Methods: We conducted a systematic review of the literature up to December 31st, 2021, searching five different databases and registers, including studies on rivastigmine, donepezil, and galantamine, with clearly defined criteria for the diagnosis of dementia and the response to AChEI therapy. Records were identified through the string: predict * AND respon * AND (acetylcholinesterase inhibitors OR donepezil OR rivastigmine OR galantamine). The results were presented narratively. Results: We identified 1,994 records in five different databases; after exclusion of duplicates, title and abstract screening, and full-text retrieval, 122 studies were finally included. Discussion: The studies show high heterogeneity in duration, response definition, drug dosage, and diagnostic criteria. Response to AChEI seems associated with correlates of cholinergic deficit (hallucinations, fluctuating cognition, substantia innominate atrophy) and preserved cholinergic neurons (faster alpha on REM sleep EEG, increased anterior frontal and parietal lobe perfusion after donepezil); white matter hyperintensities in the cholinergic pathways have shown inconsistent results. The K-variant of butyrylcholinesterase may correlate with better response in late stages of disease, while the role of polymorphisms in other genes involved in the cholinergic system is controversial. Factors related to drug availability may influence response; in particular, low serum albumin (for donepezil), CYP2D6 variants associated with reduced enzymatic activity and higher drug doses are the most consistent predictors, while AChEI concentration influence on clinical outcomes is debatable. Other predictors of response include faster disease progression, lower serum cholesterol, preserved medial temporal lobes, apathy, absence of concomitant diseases, and absence of antipsychotics. Short-term response may predict subsequent cognitive response, while higher education might correlate with short-term good response (months), and long-term poor response (years). Age, gender, baseline cognitive and functional levels, and APOE relationship with treatment outcome is controversial.