Frequency-dependent shift from paired-pulse facilitation to paired-pulse depression at unitary CA3-CA3 synapses in the rat hippocampus

Paired recordings between CA3 interconnected pyramidal neurons were used to study the properties of short-term depression occurring in these synapses under different frequencies of presynaptic firing (   n = 22  ). In stationary conditions (0.05-0.067 Hz) pairs of presynaptic action potentials (50 ms apart) evoked EPSCs whose amplitude fluctuated from trial to trial with occasional response failures. In 15/20 cells, paired-pulse ratio (PPR) was characterized by facilitation (PPF) while in the remaining five by depression (PPD). Increasing stimulation frequency from 0.05-0.067 Hz to 0.1-1 Hz induced low frequency depression (LFD) of EPSC amplitude with a gradual increase in the failure rate. Overall, 9/12 cells at 1 Hz became almost 'silent'. In six cells in which the firing rate was sequentially shifted from 0.05 to 0.1 and 1 Hz, changes in synaptic efficacy were so strong that PPR shifted from PPF to PPD. The time course of depression of EPSC1 could be fitted with single exponentials with time constants of 98 and 36 s at 0.1 and 1 Hz, respectively. In line with the inversion of PPR at 1 Hz, the time course of depression of EPSC2 was faster than EPSC1 (7 s). Recovery from depression could be obtained by lowering the frequency of stimulation to 0.025 Hz. These results could be explained by a model that takes into account two distinct release processes, one dependent on the residual calcium and the other on the size of the readily releasable pool of vesicles.     

Chemokines and pro-inflammatory cytokines in Down's syndrome: an early marker for Alzheimer-type dementia?

BACKGROUND: People with Down's syndrome (DS) show early Alzheimer-like dementia. It has been suggested that the pro-inflammatory cytokine class plays a role in Alzheimer's disease (AD). The study aims at verifying whether pro-inflammatory cytokines in DS are correlated with age, affective symptoms and intellectual decline to a different degree than in subjects with non-DS learning disabilities. METHODS: Cases: 19 subjects with DS; controls: sex- and age-matched individuals with learning disabilities caused by perinatal ischaemic damage. The level of mental retardation was assessed according to DSM-IV; psychopathological symptoms were measured by the Assessment and Information Rating Profile. Serum levels of cytokines were determined with ELISA. RESULTS: DS patients showed higher levels of cytokines and chemokines, with the exception of RANTES; but the only significant difference detected was for MIP-1alpha. A correlation between the degree of mental retardation and IL-6, and between MIP-lalpha and age was found in patients with DS, but not in controls. CONCLUSIONS: The data obtained suggest a possible involvement of chemokines in the inflammatory and degenerative processes similar to AD in DS. Further longitudinal research is required to confirm these findings.     

Design,Preparation, and Characterization of Thermoresponsive Hybrid Nanogels Using a Novel Ulvan‐Acrylate Crosslinker as Potential Carriers for Protein Encapsulation

The aim of the present study is the design and development of thermoresponsive nanogels based on ulvan, a sulphated heteropolysaccharide of algal origins with unique biological and chemical properties. Hybrid nanogels are successfully synthesized by means of UV‐initiated radical copolymerization of N‐vinylcaprolactam with an ulvan derivate as a novel crosslinker. In nanogels, the ulvan‐grafted poly(N‐vinylcaprolactam) chains represent the thermoresponsive component. The most promising candidates, selected after a thorough physical–chemical characterization of nanogels in terms of size and responsivity to thermal variation at physiological conditions, are loaded with bovine serum albumin (BSA) as model bioactive compound. The developed nanogels display BAS loading efficiency values similar to those obtained by using synthetic crosslinkers, and thus indicating the suitability of the developed ulvan‐acrylate to act as novel macromolecular crosslinker for thermoresponsive nanogels preparation.     

Micronized palmitoylethanolamide reduces joint pain and glial cell activation

Objective and design

Temporomandibular disorder (TMD) is a common painful condition in the temporomandibular joint (TMJ). Joint inflammation is believed to be a chief cause of pain in patients with TMD, through the release of pro-inflammatory cytokines that induce peripheral sensitization of nerve terminals followed by microglial stimulation.

Materials and subject

TMJ was induced in rats with the injection of complete Freund’s adjuvant (CFA) emulsion into the left TMJ capsule.

Treatment

The present study would assess the effects of micronized palmitoylethanolamide (m-PEA) on glial activation and trigeminal hypersensitivity.

Methods

Ten mg/kg m-PEA or corresponding vehicle was administered 1 h after CFA and mechanical allodynia and edema were evaluated at 24 and 72 h after CFA injection.

Results

CFA-injected animals showed TMJ edema and ipsilateral mechanical allodynia accompanied by a robust growth in GFAP protein-positive satellite glial cells and activation of resident macrophages in the TG. Moreover, m-PEA administration significantly reduced the degree of TMJ damage and pain, macrophage activation in TG and up-regulation of Iba1.

Conclusions

The results confirm that m-PEA could represent a novel approach for monitoring pain during trigeminal nerve sensitization.

     

Air- breathing in fish: Air- breathing organs and control of respiration: Nerves and neurotransmitters in the air-breathing organs and the skin

In fishes, exploitation of aerial gas exchange has evolved independently many times, involving a variety of air-breathing organs. Indeed, air-breathing occurs in at least 49 known families of fish (Graham, 1997). Many amphibious vertebrates, at some stage of their development are actually trimodal breathers that use various combinations of respiratory surfaces to breath both water (skin and/or gill) and air (skin and/or lung). The present review examines the evolutionary implications of air-breathing organs in fishes and the morphology of the peripheral receptors and the neurotransmitter content of the cells involved in the control of air-breathing. Control of breathing, whether gill ventilation or air-breathing, is influenced by feedback from peripheral and/or central nervous system receptors that respond to changes in PO2, PCO2 and/or pH. Although the specific chemoreceptors mediating the respiratory reflexes have not been conclusively identified, studies in water-breathing teleosts have implicated the neuroepithelial cells (NECs) existing in gill tissues as the O2 sensitive chemoreceptors that initiate the cardiorespiratory reflexes in aquatic vertebrates. Some of the air-breathing fishes, such as Protopterus, Polypterus and Amia have been shown to have NECs in the gills and/or lungs, although the role of these receptors and their innervation in the control of breathing is not known. NECs have been also reported in the specialized respiratory epithelia of accessory respiratory organs (ARO’s) of some catfish species and in the gill and skin of the mudskipper Periophthalmodon schlosseri. Unlike teleosts matching an O2-oriented ventilation to ambient O2 levels, lungfishes have central and peripheral H+/CO2 receptors that control the acid-base status of the blood.     

A Comparison of the Conditioning Regimens BEAM and FEAM for Autologous Hematopoietic Stem Cell Transplantation in Lymphoma: An Observational Study on 1038 Patients From Fondazione Italiana Linfomi

BEAM (carmustine [bis-chloroethylnitrosourea (BCNU)]-etoposide-cytarabine-melphalan) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. We conducted a retrospective cohort study in 18 Italian centers to compare the safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. We enrolled 1038 patients (BEAM =?607, FEAM =?431), of which 27% had Hodgkin lymphoma (HL), 14% indolent non-Hodgkin lymphoma (NHL), and 59% aggressive NHL. Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, and overall conditioning intensity were well balanced between BEAM and FEAM; notable exceptions were median ASCT year (BEAM?=?2011 versus FEAM?=?2013, P?<?.001), Sorror score ≥3 (BEAM?=?15% versus FEAM?=?10%, P?=?.017), and radiotherapy use (BEAM?=?18% versus FEAM?=?10%, P?<?.001). FEAM conditioning resulted in higher rates of gastrointestinal and infectious toxicities, including severe oral mucositis grade ≥3 (BEAM?=?31% versus FEAM?=?44%, P?<?.001), and sepsis from Gram-negative bacteria (mean isolates/patient: BEAM?=?.1 versus FEAM?=?.19, P?<?.001). Response status at day 100 post-ASCT (overall response: BEAM?=?91% versus FEAM?=?88%, P?=?.42), 2-year overall survival (83.9%; 95% confidence interval [CI], 81.5% to 86.1%) and progression-free survival (70.3%; 95% CI, 67.4% to 73.1%) were not different in the two groups. Mortality from infection was higher in the FEAM group (subhazard ratio, 1.99; 95% CI, 1.02 to 3.88; P?=?.04). BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, fotemustine substitution in BEAM does not seem justified, if not for easier supply.     

Cognitive abilities in siblings of children with autism spectrum disorders

The aim of the present study was to assess the cognitive profiles of children with autistic spectrum disorder and of their healthy siblings (Siblings). With the term cognitive profile, we indicate the relationship extant among the values of verbal and performance subtests of the Wechsler Intelligence Scale. The conducted statistical analyses indicated that, although siblings showed a normal intelligent quotient and did not differ in this aspect from typically developing group, their cognitive profile was amazingly similar to that of their relatives affected by autism. A k-means clustering analysis on the values of single subtests further confirmed this result, showing a clear separation between typically developing children on the one side, and autistics and their siblings on the other. We suggest that the common cognitive profile observed in autistic children and their siblings could represent a marker of liability to autism and, thus, a possible intermediate phenotype of this syndrome.     

Functional Analysis of a Large set of BRCA2 exon 7 Variants Highlights the Predictive Value of Hexamer Scores in Detecting Alterations of Exonic Splicing Regulatory Elements

Exonic variants can alter pre‐mRNA splicing either by changing splice sites or by modifying splicing regulatory elements. Often these effects are difficult to predict and are only detected by performing RNA analyses. Here, we analyzed, in a minigene assay, 26 variants identified in the exon 7 of BRCA2, a cancer predisposition gene. Our results revealed eight new exon skipping mutations in this exon: one directly altering the 5′ splice site and seven affecting potential regulatory elements. This brings the number of splicing regulatory mutations detected in BRCA2 exon 7 to a total of 11, a remarkably high number considering the total number of variants reported in this exon (n = 36), all tested in our minigene assay. We then exploited this large set of splicing data to test the predictive value of splicing regulator hexamers’ scores recently established by Ke et al. ( 2011 ). Comparisons of hexamer‐based predictions with our experimental data revealed high sensitivity in detecting variants that increased exon skipping, an important feature for prescreening variants before RNA analysis. In conclusion, hexamer scores represent a promising tool for predicting the biological consequences of exonic variants and may have important applications for the interpretation of variants detected by high‐throughput sequencing.     

Accumulation of neutral lipids in peripheral blood mononuclear cells as a distinctive trait of Alzheimer patients and asymptomatic subjects at risk of disease

Varicella is a common viral disease affecting almost the entire birth cohort. Although usually self-limiting, some cases of varicella can be serious, with 2 to 6% of cases attending a general practice resulting in complications. The hospitalisation rate for varicella in Europe ranges from 1.3 to 4.5 per 100,000 population/year and up to 10.1% of hospitalised patients report permanent or possible permanent sequelae (for example, scarring or ataxia). However, in many countries the epidemiology of varicella remains largely unknown or incomplete. In countries where routine childhood vaccination against varicella has been implemented, it has had a positive effect on disease prevention and control. Furthermore, mathematical models indicate that this intervention strategy may provide economic benefits for the individual and society. Despite this evidence and recommendations for varicella vaccination by official bodies such as the World Health Organization, and scientific experts in the field, the majority of European countries (with the exception of Germany and Greece) have delayed decisions on implementation of routine childhood varicella vaccination, choosing instead to vaccinate high-risk groups or not to vaccinate at all. In this paper, members of the Working Against Varicella in Europe group consider the practicalities of introducing routine childhood varicella vaccination in Europe, discussing the benefits and challenges of different vaccination options (vaccination vs. no vaccination, routine vaccination of infants vs. vaccination of susceptible adolescents or adults, two doses vs. one dose of varicella vaccine, monovalent varicella vaccines vs. tetravalent measles, mumps, rubella and varicella vaccines, as well as the optimal interval between two doses of measles, mumps, rubella and varicella vaccines). Assessment of the epidemiology of varicella in Europe and evidence for the effectiveness of varicella vaccination provides support for routine childhood programmes in Europe. Although European countries are faced with challenges or uncertainties that may have delayed implementation of a childhood vaccination programme, many of these concerns remain hypothetical and with new opportunities offered by combined measles, mumps, rubella and varicella vaccines, reassessment may be timely.     

NANC nerves in the respiratory air sac and branchial vasculature of the Indian catfish,Heteropneustes fossilis

Gill and air sac of the Indian catfish Heteropneustes fossilis harbour a nerve network comprising an innervated system of neuroepithelial endocrine cells; the latter cells are found especially in the gill. A series of antibodies was used for the immunohistochemical detection of neurotransmitters of the neural non-adrenergic, non-cholinergic (NANC) systems such as the sensory neuropeptides (enkephalins), the inhibitory neuropeptide VIP and neuronal nitric oxide synthase (nNOS) responsible for nitric oxide (NO) production which is an inhibitory NANC neurotransmitter. NADPH-diaphorase (NADPH-d) histochemistry was used as marker of nNOS although it is not a specific indicator of constitutively-expressed NOS in gill and air sac tissues. A tyrosine hydroxylase antibody was used to investigate adrenergic innervation. Nitrergic and VIP-positive sensory innervation was found to be shared by gill and air sac. Immunohistochemistry revealed the presence of enkephalins, VIP, NOS and NADPH-d in nerves associated with branchial and air sac vasculature, and in the neuroendocrine cell systems of the gill. Adrenergic nerve fibers were found in some parts of the air sac vasculature. The origin of the nerve fibers remains unclear despite previous findings showing the presence of both NADPH-d and nNOS in the sensory system of the glossopharyngeal and vagus nerves including the branchial structure. Scarce faintly stained nNOS-positive neurons were located in the gill but were never detected in the air sac. These findings lead to the conclusion that a postganglionic innervation of the airways is absent. Mucous goblet cells in the gill were found to express nNOS and those located in the non-respiratory interlamellar areas of the air sac were densely innervated by nNOS-positive and VIP-positive nerve fibers. Our immunohistochemical studies demonstrate that most arteries of the gill and air sac share a NANC (basically nitrergic) innervation which strongly suggests that they are homologous structures.