Functional Differences in Visceral and Subcutaneous Fat Pads Originate from Differences in the Adipose Stem Cell

Metabolic pathologies mainly originate from adipose tissue (AT) dysfunctions. AT differences are associated with fat-depot anatomic distribution in subcutaneous (SAT) and visceral omental (VAT) pads. We address the question whether the functional differences between the two compartments may be present early in the adipose stem cell (ASC) instead of being restricted to the mature adipocytes. Using a specific human ASC model, we evaluated proliferation/differentiation of ASC from abdominal SAT-(S-ASC) and VAT-(V-ASC) paired biopsies in parallel as well as the electrophysiological properties and functional activity of ASC and their in vitro-derived adipocytes. A dramatic difference in proliferation and adipogenic potential was observed between the two ASC populations, S-ASC having a growth rate and adipogenic potential significantly higher than V-ASC and giving rise to more functional and better organized adipocytes. To our knowledge, this is the first comprehensive electrophysiological analysis of ASC and derived-adipocytes, showing electrophysiological properties, such as membrane potential, capacitance and K+-current parameters which confirm the better functionality of S-ASC and their derived adipocytes. We document the greater ability of S-ASC-derived adipocytes to secrete adiponectin and their reduced susceptibility to lipolysis. These features may account for the metabolic differences observed between the SAT and VAT. Our findings suggest that VAT and SAT functional differences originate at the level of the adult ASC which maintains a memory of its fat pad of origin. Such stem cell differences may account for differential adipose depot susceptibility to the development of metabolic dysfunction and may represent a suitable target for specific therapeutic approaches

Role of the PPAR-γ System in Normal and Tumoral Pituitary Corticotropic Cells and Adrenal Cells

PPAR-γ is a member of the nuclear hormone receptor superfamily of transcription factors, whose thiazolidinedione ligands (TZD) have been recently demonstrated to also possess anticancer properties in addition to their well-known insulin-sensitizer and glucose/lipid regulation activity. In this minireview, we summarize the current knowledge on PPAR-γ in normal and tumoral corticotropic pituitary and adrenal cells. The receptor expression has been shown in ACTH-secreting cells in both normal and adenomal pituitary as well as in normal and tumor adrenal cortex. Preclinical studies conducted both in vitro on tumor cells and in vivo on xenograft tumor models obtained by subcutaneous injection of cancer cells have evidenced the anticancer properties of TZD, in particular rosiglitazone (RGZ) and pioglitazone (PIO). In both pituitary and adrenocortical cancer, RGZ treatment results in inhibition of cell proliferation, through G0/G1 cell-cycle arrest and induction of cell apoptosis, leading to significant inhibition of tumor growth in the xenograft tumor models. In addition, since RGZ can reduce ACTH and corticosterone secretion in mouse corticotropic pituitary tumors, both RGZ and PIO have been used in the treatment of Cushing's disease with variable but generally unsatisfactory results. Discrepancies in the antitumor effects of TZD observed between successful preclinical and unsuccessful clinical studies may be particularly due to differences in treatment duration and doses used

T-PEC: a novel test for the elicited production of clitic pronouns in Italian. Preliminary data.

The study presented in this article aims at investigating the clinical usefulness of a novel test, called T-PEC, for the diagnosis of Developmental Language Disorder in Italian preschool children. The instrument exploits the production of clitic pronouns, in particular third person direct object clitics (3PDO-CL), as a clinical marker for the disorder. Psychometric properties and normative data were computed on a sample of 70 children ranging in age from 4.6 to 5.8 years: 22 children diagnosed as language-impaired by expert clinicians according to international guidelines, and 48 typically developing peers. The statistical analysis of the collected data revealed good internal consistency (Cronbach’s α = 0.86) and confirmed the effectiveness of the T-PEC test in distinguishing typically developing and DLD children, especially when the latter showed morphosyntactic deficits (AUC = 79.9%). Its high accuracy, combined with the rapidity and easiness of its administration, makes the T-PEC test suitable for use in clinical settings

DILLo: an Italian lexical database for speech-language pathologists

A novel lexical resource for treating speech impairments from childhood to senility: DILLo—Database Italiano del Lessico per Logopedisti (i.e., Italian Database for Speech-Language Pathologists) is presented. DILLo is a free online web application that allows extraction of filtered wordlists for flexible rehabilitative purposes. Its major aim is to provide Italian speech-language pathologists (SLPs) with a resource that takes advantage of Information and Communication Technologies for language in a healthcare setting. DILLo’s design adopts an integrated approach that envisages fruitful cooperation between clinical and linguistic professionals. The 7690 Italian words in the database have been selected based on phonological, phonotactic, and morphological properties, and their frequency of use. These linguistic features are encoded in the tool, which includes the orthographic and phonological transcriptions, and the phonotactic structure of each word. Moreover, most of the entries are associated with their respective ARASAAC pictogram, providing an additional and inclusive tool for treating speech impairments. The user-friendly interface is structured to allow for different and adaptable search options. DILLo allows Speech-Language Pathologists (SLPs) to obtain a rich, tailored, and varied selection of suitable linguistic stimuli. It can be used to customize the treatment of many impairments, e.g., Speech Sound Disorders, Childhood Apraxia of Speech, Specific Learning Disabilities, aphasia, dysarthria, dysphonia, and the auditory training that follows cochlear implantations

DILLo: an Italian lexical database for speech-language pathologists

A novel lexical resource for treating speech impairments from childhood to senility: DILLo—Database Italiano del Lessico per Logopedisti (i.e., Italian Database for Speech-Language Pathologists) is presented. DILLo is a free online web application that allows extraction of filtered wordlists for flexible rehabilitative purposes. Its major aim is to provide Italian speech-language pathologists (SLPs) with a resource that takes advantage of Information and Communication Technologies for language in a healthcare setting. DILLo’s design adopts an integrated approach that envisages fruitful cooperation between clinical and linguistic professionals. The 7690 Italian words in the database have been selected based on phonological, phonotactic, and morphological properties, and their frequency of use. These linguistic features are encoded in the tool, which includes the orthographic and phonological transcriptions, and the phonotactic structure of each word. Moreover, most of the entries are associated with their respective ARASAAC pictogram, providing an additional and inclusive tool for treating speech impairments. The user-friendly interface is structured to allow for different and adaptable search options. DILLo allows Speech-Language Pathologists (SLPs) to obtain a rich, tailored, and varied selection of suitable linguistic stimuli. It can be used to customize the treatment of many impairments, e.g., Speech Sound Disorders, Childhood Apraxia of Speech, Specific Learning Disabilities, aphasia, dysarthria, dysphonia, and the auditory training that follows cochlear implantations

One dose of an MF59-adjuvanted pandemic A/H1N1 vaccine recruits pre-existing immune memory and induces the rapid rise of neutralizing antibodies

Protective antibody responses to a single dose of 2009 pandemic vaccines have been observed in the majority of healthy subjects aged more than 3 years. These findings suggest that immune memory lymphocytes primed by previous exposure to seasonal influenza antigens are recruited in the response to A/H1N1 pandemic vaccines and allow rapid seroconversion. However, a clear dissection of the immune memory components favoring a fast response to pandemic vaccination is still lacking. Here we report the results from a clinical study where antibody, CD4+ T cell, plasmablast and memory B cell responses to one dose of an MF59-adjuvanted A/H1N1 pandemic vaccine were analyzed in healthy adults. While confirming the rapid appearance of antibodies neutralizing the A/H1N1 pandemic virus, we show here that the response is dominated by IgG-switched antibodies already in the first week after vaccination. In addition, we found that vaccination induces the rapid expansion of pre-existing CD4+ T cells and IgG-memory B lymphocytes cross-reactive to seasonal and pandemic A/H1N1 antigens. These data shed light on the different components of the immune response to the 2009 H1N1 pandemic influenza vaccination and may have implications in the design of vaccination strategies against future influenza pandemics

A phase I, randomized, controlled, dose-ranging study of investigational acellular pertussis (aP) and reduced tetanus-diphtheria-acellular pertussis (TdaP) booster vaccines in adults

Despite high vaccination coverage worldwide, pertussis has re-emerged in many countries. This randomized, controlled, observer-blind phase I study and extension study in Belgium (March 2012–June 2015) assessed safety and immunogenicity of investigational acellular pertussis vaccines containing genetically detoxified pertussis toxin (PT) (NCT01529645; NCT02382913). 420 healthy adults (average age: 26.8 ± 5.5 years, 60% female) were randomized to 1 of 10 vaccine groups: 3 investigational aP vaccines (containing pertussis antigens PT, filamentous hemagglutinin [FHA] and pertactin [PRN] at different dosages), 6 investigational TdaP (additionally containing tetanus toxoid [TT] and diphtheria toxoid [DT]), and 1 TdaP comparator containing chemically inactivated PT. Antibody responses were evaluated on days 1, 8, 30, 180, 365, and approximately 3 years post-booster vaccination. Cell-mediated immune responses and PT neutralization were evaluated in a subset of participants in pre-selected groups. Local and systemic adverse events (AEs), and unsolicited AEs were collected through day 7 and 30, respectively; serious AEs and AEs leading to study withdrawal were collected through day 365 post-vaccination. Antibody responses against pertussis antigens peaked at day 30 post-vaccination and then declined but remained above baseline level at approximately 3 years post-vaccination. Responses to FHA and PRN were correlated to antigen dose. Antibody responses specific to PT, toxin neutralization activity and persistence induced by investigational formulations were similar or significantly higher than the licensed vaccine, despite lower PT doses. Of 15 serious AEs, none were considered vaccination-related; 1 led to study withdrawal (premature labor, day 364; aP4 group). This study confirmed the potential benefits of genetically detoxified PT antigen. All investigational study formulations were well tolerated

Systems analysis of human responses to an aluminium hydroxide-adsorbed TLR7 agonist (AS37) adjuvanted vaccine reveals a dose-dependent and specific activation of the interferon-mediated antiviral response

The candidate Adjuvant System AS37 contains a synthetic toll-like receptor agonist (TLR7a) adsorbed to alum. In a phase I study (NCT02639351), healthy adults were randomised to receive one dose of licensed alum-adjuvanted meningococcal serogroup C (MenC-CRM197) conjugate vaccine (control) or MenC-CRM197conjugate vaccine adjuvanted with AS37 (TLR7a dose 12.5, 25, 50 or 100 µg). A subset of 66 participants consented to characterisation of peripheral whole blood transcriptomic responses, systemic cytokine/chemokine responses and multiple myeloid and lymphoid cell responses as exploratory study endpoints. Blood samples were collected pre-vaccination, 6 and 24 h post-vaccination, and 3, 7, 28 and 180 days post-vaccination. The gene expression profile in whole blood showed an early, AS37-specific transcriptome response that peaked at 24 h, increased with TLR7a dose up to 50 µg and generally resolved within one week. Five clusters of differentially expressed genes were identified, including those involved in the interferon-mediated antiviral response. Evaluation of 30 cytokines/chemokines by multiplex assay showed an increased level of interferon-induced chemokine CXCL10 (IP-10) at 24 h and 3 days post-vaccination in the AS37-adjuvanted vaccine groups. Increases in activated plasmacytoid dendritic cells (pDC) and intermediate monocytes were detected 3 days post-vaccination in the AS37-adjuvanted vaccine groups. T follicular helper (Tfh) cells increased 7 days post-vaccination and were maintained at 28 days post-vaccination, particularly in the AS37-adjuvanted vaccine groups. Moreover, most of the subjects that received vaccine containing 25, 50 and 100 µg TLR7a showed an increased MenC-specific memory B cell responses versus baseline. These data show that the adsorption of TLR7a to alum promotes an immune signature consistent with TLR7 engagement, with up-regulation of interferon-inducible genes, cytokines and frequency of activated pDC, intermediate monocytes, MenC-specific memory B cells and Tfh cells. TLR7a 25-50 µg can be considered the optimal dose for AS37, particularly for the adjuvanted MenC-CRM197conjugate vaccine

Electrophysiological properties of ASC and of the derived <i>in vitro</i>-differentiated adipocytes.

<p>Electrophysiological analysis was performed on ASC and their corresponding <i>in vitro</i>-differentiated adipocytes in patch clamp condition. RMP: resting membrane potential. C_m: membrane capacitance. G_m and G_m/C_m: total and specific membrane conductance, respectively. V_th: voltage threshold of activation of the three types of K⁺ currents investigated (I_BK, I_Ks and I_Kir). K⁺ current activation time constant (τ) for I_BK and I_Ks and current density I_BK/C_m and I_Ks/C_m values have been obtained at 50 mV and I_Kir/C_m at −110 mV. Mean ±SE values are reported. Student's <i>t</i> test was applied to compare paired samples: **,***P<0.01 and 0.001 V- versus S-ASC and V- versus S-ADIPO; §, §§, §§§ P<0.05, 0.01, 0.001 S- or V-ADIPO versus the corresponding ASC. Total number of analyzed cells (n) in populations obtained from 5 different subjects were: S-ASC (n = 84), V-ASC (n = 82), S-ADIPO (n = 54), V-ADIPO (n = 52); for I_Kir: S-ASC (n = 17), V-ASC (n = 18), S-ADIPO (n = 28), V-ADIPO (n = 24). mV: milli Volt; pF: pico Faraday; nS: nano Siemens; ms: milli seconds; pA: pico Ampere.</p