AN IMMUNOCYTOCHEMICAL STUDY OF PUTATIVE NEUROTRANSMITTERS IN THE METACERCARIAE OF 2 STRIGEOID TREMATODES FROM RAINBOW-TROUT (ONCORHYNCHUS-MYKISS)

Whole mounts of the metacercariae of Diplostomum sp. and Cotylurus erraticus from rainbow trout have been treated cytochemically for the demonstration of cholinergic, serotoninergic (5-hydroxytryptamine) and peptidergic elements in the nervous system. Antisera directed against four vertebrate (pancreatic polypeptide, peptide YY, substance P and peptide histidine isoleucine) and two invertebrate peptides (neuropeptide F and FMRFamide) were used in an indirect immunofluorescence procedure in conjunction with confocal scanning laser microscopy (CSLM). Of the seven antisera tested, all except peptide histidine isoleucine showed significant immunoreactivity. Cholinergic and serotoninergic staining was found primarily in the central nervous system (CNS) and in cell bodies associated with the ventral and dorsal nerve cords in both trematodes. Peptidergic immunoreactivity was localised in the CNS and PNS of both genera, revealing an extensive innervation within the holdfast organ and in and around the oral and ventral suckers.

Modeled structure of a G-protein-coupled receptor:The cholecystokinin-1 receptor

The Cholecystokinin-1 receptor (CCK1R) mediates actions of CCK in areas of the central nervous system and of the gut. It is a potential target to treat a number of diseases. As for all G-protein-coupled receptors, docking of ligands into modeled CCK1R binding site should greatly help to understand intrinsic mechanisms of activation. Here, we describe the procedure we used to progressively build a structural model for the CCK1R, to integrated, and on the basis of site-directed mutagenesis data on its binding site. Reliability of the CCK1R model was confirmed by interaction networks that involved conserved and functionally crucial motifs in G-protein-coupled receptors, such as Glu/Asp-Arg-Tyr and Asn-Pro-Xaa-Xaa-Tyr motifs. In addition, the 3-D structure of CCK1R-bound CCK resembled that determined by NMR in a lipid environment. The derived computational model was also used for revealing binding modes of several nonpeptide ligands and for rationalizing ligand structure-activity relationships known from experiments. Our findings indeed support that our "validated CCK1R model" could be used to study the intrinsic mechanism of CCK1R activation and design new ligands.

UROTENSIN II FROM THE RIVER LAMPREY (LAMPETRA-FLUVIATILIS), THE SEA LAMPREY (PETROMYZON-MARINUS), AND THE PADDLEFISH (POLYODON SPATHULA)

Urotensin II was isolated from extracts of the whole brain of the river lamprey (Lampetra fluviatilis) and the sea lamprey (Petromyzon marinus). The primary structure of the peptide from both species is the same (Asn-Asn-Phe-Ser-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val) and this amino acid sequence is identical to that of urotensin II from the dogfish and skate. Consistent with previous morphological studies indicating that the Agnatha lack a caudal neurosecretory system, urotensin II was not detected in an extract of P. marinus spinal cord. The data suggest that the urotensin II may have functioned in the earliest vertebrates as a neurotransmitter/neuromodulator in the central nervous system rather than as a neurohormone of the caudal neurosecretory system. Urotensin II was also isolated from an extract of the spinal cord of a chondrostean fish, the paddlefish (Polyodon spathula). The primary structure of the paddlefish urotensin II (Gly-Ser-Thr-Ser-Glu-Cys-Phe-Trp-Lys-Tyr-Cys-Val) is the same as that of another chondrostean, the sturgeon (Acipenser ruthenus). The study provides further evidence for a widespread distribution of urotensin II in vertebrate species and suggests that the primary structure of the peptide is better conserved in these phylogenetically ancient fish than in teleosts. (C) 1995 Academic Press, Inc.

Orally bioavailable small molecule drug protects memory in Alzheimer's disease models

Oligomers of beta-amyloid (Aß) are implicated in the early memory impairment seen in Alzheimer's disease before to the onset of discernable neurodegeneration. Here, the capacity of a novel orally bioavailable, central nervous system-penetrating small molecule 5-aryloxypyrimidine, SEN1500, to prevent cell-derived (7PA2 [conditioned medium] CM) Aß-induced deficits in synaptic plasticity and learned behavior was assessed. Biochemically, SEN1500 bound to Aß monomer and oligomers, produced a reduction in thioflavin-T fluorescence, and protected a neuronal cell line and primary cortical neurons exposed to synthetic soluble oligomeric Aß1-42. Electrophysiologically, SEN1500 alleviated the in vitro depression of long-term potentiation induced by both synthetic Aß1-42 and 7PA2 CM, and alleviated the in vivo depression of long-term potentiation induced by 7PA2 CM, after systemic administration. Behaviorally, oral administration of SEN1500 significantly reduced memory-related deficits in operant responding induced after intracerebroventricular injection of 7PA2 CM. SEN1500 reduced cytotoxicity, acute synaptotoxicity, and behavioral deterioration after in vitro and in vivo exposure to synthetic Aß and 7PA2 CM, and shows promise for development as a clinically viable disease-modifying Alzheimer's disease treatment. © 2013 Elsevier Inc.

Plasma somatostatin and gastrointestinal peptides in Alzheimer's disease and vascular dementia

Few markers distinguish between different dementia types. As dementia affects many body systems outside the central nervous system, we investigated gastrointestinal regulatory peptides as possible disease markers in Alzheimer's Disease (AD) and vascular dementia (VaD). Subjects with mild-to-moderate dementia were diagnosed as probable AD and VaD according to defined criteria. Gastrointestinal peptides were stimulated using a standardized meal test, administered after an overnight fast to 58 dementia patients (40 AD, 18 VaD) and 47 controls matched for age and sex. Blood samples were taken at designated time intervals, and basal and stimulated plasma concentrations of eleven peptides were determined by radio-immunoassay. Results were analysed using the Kruskal-Wallis one-way analysis of variance; the Mann-Whitney U test was used in post hoc analysis where appropriate. There were significant differences in somatostatin levels but in none of the other peptides. Basal somatostatin was significantly increased in VaD compared to controls (p

Corticosteroids and peritonsillar abscess formation in infectious mononucleosis

Peritonsillar abscess formation is an uncommon complication of infectious mononucleosis (IM). Early case reports implicated corticosteroids in the development of such abscesses, however, subsequent studies suggested that these drugs do not promote the formation of abscesses at several sites outside the central nervous system. It has recently been demonstrated that zwitterionic polysaccharides, in bacterial capsules, form complexes with CD4(+) T lymphocytes leading to abscess formation. A patient is presented who developed peritonsillar abscess a few days after initiation of corticosteroid therapy for IM; the medical literature was reviewed in respect of this subject. It appears that the occurrence of these abscesses in IM is not strongly linked to corticosteroid treatment. The authors, therefore, recommend that steroids should not be withheld from patients with severe IM on the basis that they may precipitate the development of peritonsillar abscess.

Recombinant canine distemper virus strain Snyder Hill expressing green or red fluorescent proteins causes meningoencephalitis in the ferret

The propensity of canine distemper virus (CDV) to spread to the central nervous system is one of the primary features of distemper. Therefore, we developed a reverse genetics system based on the neurovirulent Snyder Hill (SH) strain of CDV (CDV(SH)) and show that this virus rapidly circumvents the blood-brain and blood-cerebrospinal fluid (CSF) barriers to spread into the subarachnoid space to induce dramatic viral meningoencephalitis. The use of recombinant CDV(SH) (rCDV(SH)) expressing enhanced green fluorescent protein (EGFP) or red fluorescent protein (dTomato) facilitated the sensitive pathological assessment of routes of virus spread in vivo. Infection of ferrets with these viruses led to the full spectrum of clinical signs typically associated with distemper in dogs during a rapid, fatal disease course of approximately 2 weeks. Comparison with the ferret-adapted CDV(5804P) and the prototypic wild-type CDV(R252) showed that hematogenous infection of the choroid plexus is not a significant route of virus spread into the CSF. Instead, viral spread into the subarachnoid space in rCDV(SH)-infected animals was triggered by infection of vascular endothelial cells and the hematogenous spread of virus-infected leukocytes from meningeal blood vessels into the subarachnoid space. This resulted in widespread infection of cells of the pia and arachnoid mater of the leptomeninges over large areas of the cerebral hemispheres. The ability to sensitively assess the in vivo spread of a neurovirulent strain of CDV provides a novel model system to study the mechanisms of virus spread into the CSF and the pathogenesis of acute viral meningitis.

Behavior, pain perception, and the extremely low-birth weight survivor

This article explores the literature concerning responses to pain of both premature and term-born newborn infants, the evidence for short-term and long-term effects of pain, and behavioral sequelae in individuals who have experienced repeated early pain in neonatal life as they mature. There is no doubt that pain causes stress in babies and this in turn may adversely affect long-term neurodevelopmental outcome. Although there are methods for assessing dimensions of acute reactivity to pain in an experimental setting, there are no very good measures available at the present time that can be used clinically. In the clinical setting repeated or chronic pain is more likely the norm rather than infrequent discrete noxious stimuli of the sort that can be readily studied. The wind-up phenomenon suggests that, exposed to a cascade of procedures as happens with clustering of care in the clinical setting in an attempt to provide periods of rest for stressed babies, an infant may in fact perceive procedures that are not normally viewed as noxious, as pain. Pain exposure during lifesaving intensive medical care of ELBW neonates may also affect subsequent reactivity to pain in the neonatal period, but behavioral differences are probably not likely to be clinically significant in the long term. Prolonged and repeated untreated pain in the newborn period, however, may produce a relatively permanent shift in basal autonomic arousal related to prior NICU pain experience, which may have long-term sequelae. In the long run, the most significant clinical effects of early pain exposure may be on neurodevelopment, contributing to later attention, learning, and behavior problems in these vulnerable children. Although there is considerable evidence to support a variety of adverse effects of early pain, there is less information about the long-term effects of opiates and benzodiazepines on the developing central nervous system. Current evidence reviewed suggests that judicious use of morphine for adjustment to mechanical ventilation may ameliorate the altered autonomic response. It may be very important, however, to distinguish stress from pain. Animal evidence suggests that the neonatal brain is affected differently when exposed to morphine administered in the absence of pain than in the presence of pain. Pain control may be important for many reasons but overuse of morphine or benzodiazepines may have undesirable long-term effects. This is a rapidly evolving area of knowledge of clear relevance to clinical management likely to affect long-term outcomes of high-risk children.

Wild-type Measles Virus Infection Upregulates Poliovirus Receptor-Related 4 and Causes Apoptosis in Brain Endothelial Cells by Induction of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

Small numbers of brain endothelial cells (BECs) are infected in children with neurologic complications of measles virus (MV) infection. This may provide a mechanism for virus entry into the central nervous system, but the mechanisms are unclear. Both in vitro culture systems and animal models are required to elucidate events in the endothelium. We compared the ability of wild-type (WT), vaccine, and rodent-adapted MV strains to infect, replicate, and induce apoptosis in human and murine brain endothelial cells (HBECs and MBECs, respectively). Mice also were infected intracerebrally. All MV stains productively infected HBECs and induced the MV receptor PVRL4. Efficient WT MV production also occurred in MBECs. Extensive monolayer destruction associated with activated caspase 3 staining was observed in HBECs and MBECs, most markedly with WT MV. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), but not Fas ligand, was induced by MV infection. Treatment of MBECs with supernatants from MV-infected MBEC cultures with an anti-TRAIL antibody blocked caspase 3 expression and monolayer destruction. TRAIL was also expressed in the endothelium and other cell types in infected murine brains. This is the first demonstration that infection of low numbers of BECs with WT MV allows efficient virus production, induction of TRAIL, and subsequent widespread apoptosis.

Bilateral non-contiguous atypical papillary glioneuronal tumor:case report

Papillary glioneuronal tumor (PGNT) was first described as a distinct clinic-pathological entity by Komori et al. in 1998. Since then it has been included as a mixed neuronal-glial tumor in the revised WHO (2007) classification of central nervous system tumors. On brain imaging, it appears as a demarcated, solid to cystic, contrast-enhancing mass usually located in the temporal lobe. Histologically, it is considered a biphasic tumor characterized by small cuboidal GFAP-positive astrocytes around hyalinised blood vessels and synaptophysin-positive interpapillary collections of neurocytes, large neurons and intermediate-sized "ganglioid cells". Although they are generally regarded as benign WHO Grade I tumors, recent reports have described more pathologically aggressive features. To date, these reports have all been single lesions.

Bilateral non-contiguous atypical papillary glioneuronal tumor: case report

Papillary glioneuronal tumor (PGNT) was first described as a distinct clinic-pathological entity by Komori et al. in 1998. Since then it has been included as a mixed neuronal-glial tumor in the revised WHO (2007) classification of central nervous system tumors. On brain imaging, it appears as a demarcated, solid to cystic, contrast-enhancing mass usually located in the temporal lobe. Histologically, it is considered a biphasic tumor characterized by small cuboidal GFAP-positive astrocytes around hyalinised blood vessels and synaptophysin-positive interpapillary collections of neurocytes, large neurons and intermediate-sized "ganglioid cells". Although they are generally regarded as benign WHO Grade I tumors, recent reports have described more pathologically aggressive features. To date, these reports have all been single lesions.

Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response

Multiple sclerosis is considered a disease of complex autoimmune etiology, yet there remains a lack of consensus as to specific immune effector mechanisms. Recent analyses of experimental autoimmune encephalomyelitis, the common mouse model of multiple sclerosis, have investigated the relative contribution of Th1 and Th17 CD4 T cell subsets to initial autoimmune central nervous system (CNS) damage. However, inherent in these studies are biases influenced by the adjuvant and toxin needed to break self-tolerance. We investigated spontaneous CNS disease in a clinically relevant, humanized, T cell receptor transgenic mouse model. Mice develop spontaneous, ascending paralysis, allowing unbiased characterization of T cell immunity in an HLA-DR15-restricted T cell repertoire. Analysis of naturally progressing disease shows that IFN?(+) cells dominate disease initiation with IL-17(+) cells apparent in affected tissue only once disease is established. Tregs accumulate in the CNS but are ultimately ineffective at halting disease progression. However, ablation of Tregs causes profound acceleration of disease, with uncontrolled infiltration of lymphocytes into the CNS. This synchronous, severe disease allows characterization of the responses that are deregulated in exacerbated disease: the correlation is with increased CNS CD4 and CD8 IFN? responses. Recovery of the ablated Treg population halts ongoing disease progression and Tregs extracted from the central nervous system at peak disease are functionally competent to regulate myelin specific T cell responses. Thus, in a clinically relevant mouse model of MS, initial disease is IFN? driven and the enhanced central nervous system responses unleashed through Treg ablation comprise IFN? cytokine production by CD4 and CD8 cells, but not IL-17 responses.

Pharmacological studies of 8-OH-DPAT-induced pupillary dilation in anesthetized rats

Serotonin (5-HT) receptor agonists have been reported to produce mydriasis in mice, and miosis in rabbits and humans. However, the underlying mechanisms for this action are unclear. This study was undertaken in an attempt to explore the mechanism by which 5-HT receptors are involved in the modulation of pupillary size in pentobarbital-anesthetized rats. Intravenous administration of the 5-HT receptor agonist, (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 0.003-3 mg/kg), elicited dose-dependent pupillary dilation, which was not affected by section of the preganglionic cervical sympathetic nerve. 8-OH-DPAT-elicited mydriatic responses were attenuated by the selective 5-HT receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2- pyridinylcyclohexanecarboxamide maleate (WAY 100635; 0.3-1 mg/kg, i.v.), as well as by the selective a -adrenoceptor antagonist, (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a-dechydro-3-methoxy-12- (ethylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridine hydrochloride (RS 79948; 0.3 mg/kg, i.v.), but not by the selective a -adrenoceptor antagonist, prazosin (0.3 mg/kg, i.v.). Mydriatic responses elicited by the a -adrenoceptor agonist, guanabenz (0.003-0.3 mg/kg, i.v.), were not antagonized by WAY 100635 (0.3-1 mg/kg, i.v.). To determine whether central nervous system (CNS) 5-HT receptors, like a -adrenoceptors, are involved in reflex mydriasis, voltage response curves of pupillary dilation were constructed by stimulation of the sciatic nerve in anesthetized rats. WAY 100635 (1 mg/kg, i.v.) did not antagonize the evoked reflex mydriasis, which, however, was blocked by RS 79948 (0.3 mg/kg, i.v.). Taken together, these results suggest that 8-OH-DPAT produces pupillary dilation in anesthetized rats by stimulating CNS 5-HT receptors, which in turn trigger the release of norepinephrine, presumably from the locus coeruleus. The latter reduces parasympathetic neuronal tone to the iris sphincter muscle by stimulation of postsynaptic a - adrenoceptors within the Edinger-Westphal nucleus. Unlike a - adrenoceptors, 5-HT receptors in the CNS do not mediate reflex mydriasis evoked by sciatic nerve stimulation. © 2004 Elsevier B.V. All rights reserved.

What the newspapers say about medication adherence: a content analysis

Background: This study investigates the coverage of adherence to medicine by the UK and US newsprint media. Adherence to medicine is recognised as an important issue facing healthcare professionals and the newsprint media is a key source of health information, however, little is known about newspaper coverage of medication adherence.

Methods. A search of the newspaper database Nexis®UK from 2004-2011 was performed. Content analysis of newspaper articles which referenced medication adherence from the twelve highest circulating UK and US daily newspapers and their Sunday equivalents was carried out. A second researcher coded a 15% sample of newspaper articles to establish the inter-rater reliability of coding.

Results: Searches of newspaper coverage of medication adherence in the UK and US yielded 181 relevant articles for each country. There was a large increase in the number of scientific articles on medication adherence in PubMed® over the study period, however, this was not reflected in the frequency of newspaper articles published on medication adherence. UK newspaper articles were significantly more likely to report the benefits of adherence (p = 0.005), whereas US newspaper articles were significantly more likely to report adherence issues in the elderly population (p = 0.004) and adherence associated with diseases of the central nervous system (p = 0.046). The most commonly reported barriers to adherence were patient factors e.g. poor memory, beliefs and age, whereas, the most commonly reported facilitators to adherence were medication factors including simplified regimens, shorter treatment duration and combination tablets. HIV/AIDS was the single most frequently cited disease (reported in 20% of newspaper articles). Poor quality reporting of medication adherence was identified in 62% of newspaper articles.

Conclusion: Adherence is not well covered in the newspaper media despite a significant presence in the medical literature. The mass media have the potential to help educate and shape the public's knowledge regarding the importance of medication adherence; this potential is not being realised at present. © 2013 Goodfellow et al.; licensee BioMed Central Ltd.

Lamina propria: The functional center of the bladder?

The bladder mucosa consists of the urothelium, basement membrane, and lamina propria (LP). Although the urothelium has been given much attention, it may be regarded as one part of a signaling system involving another equally important component of the bladder mucosa, namely, the LP. The LP lies between the basement membrane of the mucosa and the detrusor muscle and is composed of an extracellular matrix containing several types of cells, including fibroblasts, adipocytes, interstitial cells, and afferent and efferent nerve endings. In addition, the LP contains a rich vascular network, lymphatic vessels, elastic fibers, and smooth muscle fascicles (muscularis mucosae). The roles of the LP and its components in bladder function have not been definitively established, though it has been suggested to be the capacitance layer of the bladder, determining bladder compliance and enabling adaptive changes to increasing volumes. However, the bladder LP may also serve as a communication center, with an important integrative role in signal transduction to the central nervous system (nociception, mechanosensation). The LP may also, by means of its different components, make it possible for the urothelium to transmit information to other components of the bladder wall, contributing to activation of the detrusor muscle. In addition, the LP may serve as a source for production of factors influencing the growth of both the overlying urothelium and the underlying detrusor muscle.