Role of brain nitric oxide in the thermoregulation of broiler chicks

Nitric oxide (NO) plays a key role in body temperature (Tb) regulation of mammals, acting on the brain to stimulate heat loss. Regarding birds, the putative participation of NO in the maintenance of Tb in thermoneutrality or during heat stress and the site of its action (periphery or brain) is unknown. Thus, we tested if NO participates in the maintenance of chicks` Tb in those conditions. We investigated the effect of intramuscular (im; 25, 50, 100 mg/kg) or intracerebroventricular (icv; 22.5, 45, 90, 180 mu g/animal) injections of the non selective NO synthase inhibitor L-NAME on Tb of 5-day-old chicks at thermoneutral zone (TNZ; 31-32 degrees C) and under heat stress (37 degrees C for 5-6 h). We also verified plasma and diencephalic nitrite/nitrate levels in non-injected chicks under both conditions. At TNZ, 100 mg/kg (im) or 45,90,180 mu g (icv) of L-NAME decreased Tb. A significant correlation between Tb and diencephalic, but not plasma, nitrite/nitrate levels was observed. Heat stress-induced hyperthermia was inhibited by all tested doses of L-NAME (im and icv). Tb was correlated neither with plasma nor with diencephalic nitrite/nitrate levels during heat stress. These results indicate the involvement of brain NO in the maintenance of Tb of chicks, an opposite action of that observed in mammals, and may modulate hyperthermia. (C) 2009 Elsevier Inc. All rights reserved.

Vibratory noise to the fingertip enhances balance improvement associated with light touch

Light touch of a fingertip on an external stable surface greatly improves the postural stability of standing subjects. The hypothesis of the present work was that a vibrating surface could increase the effectiveness of fingertip signaling to the central nervous system (e.g., by a stochastic resonance mechanism) and hence improve postural stability beyond that achieved by light touch. Subjects stood quietly over a force plate while touching with their right index fingertip a surface that could be either quiescent or randomly vibrated at two low-level noise intensities. The vibratory noise of the contact surface caused a significant decrease in postural sway, as assessed by center of pressure measures in both time and frequency domains. Complementary experiments were designed to test whether postural control improvements were associated with a stochastic resonance mechanism or whether attentional mechanisms could be contributing. A full curve relating body sway parameters and different levels of vibratory noise resulted in a U-like function, suggesting that the improvement in sway relied on a stochastic resonance mechanism. Additionally, no decrease in postural sway was observed when the vibrating contact surface was attached to the subject`s body, suggesting that no attentional mechanisms were involved. These results indicate that sensory cues obtained from the fingertip need not necessarily be associated with static contact surfaces to cause improvement in postural stability. A low-level noisy vibration applied to the contact surface could lead to a better performance of the postural control system.

Brain nitric oxide production by a proline-rich decapeptide from Bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats

Baroreflex sensitivity is disturbed in many people with cardiovascular diseases such as hypertension. Brain deficiency of nitric oxide (NO), which is synthesized by NO synthase (NOS) in the citrulline-NO cycle (with argininosuccinate synthase (ASS) activity being the rate-limiting step), contributes to impaired baroreflex. We recently showed that a decapeptide isolated from Bothrops jararaca snake venom, denoted Bj-PRO-10c, exerts powerful and sustained antihypertensive activity. Bj-PRO-10c promoted vasodilatation dependent on the positive modulation of ASS activity and NO production in the endothelium, and also acted on the central nervous system, inducing the release of GABA and glutamate, two important neurotransmitters in the regulation of autonomic systems. We evaluated baroreflex function using the regression line obtained by the best-fit points of measured heart rate (HR) and mean arterial pressure (MAP) data from spontaneously hypertensive rats (SHRs) treated with Bj-PRO-10c. We also investigated molecular mechanisms involved in this effect, both in vitro and in vivo. Bj-PRO-10c mediated an increase in baroreflex sensitivity and a decrease in MAP and HR. The effects exerted by the peptide include an increase in the gene expression of endothelial NOS and ASS. Bj-PRO-10c-induced NO production depended on intracellular calcium fluxes and the activation of a G(i/o)-protein-coupled metabotropic receptor. Bj-PRO-10c induced NO production and the gene expression of ASS and endothelial NOS in the brains of SHRs, thereby improving baroreflex sensitivity. Bj-PRO-10c may reveal novel approaches for treating diseases with impaired baroreflex function. Hypertension Research (2010) 33, 1283-1288; doi: 10.1038/hr.2010.208

Neuropharmacological effects in mice of Lychnophora species (Vernonieae, Asteraceae) and anticonvulsant activity of 4,5-di-O-[E]-caffeoylquinic acid isolated from the stem of L-rupestris and L-staavioides

Aiming at contributing with the search for neuroactive substances from natural sources, we report for the first time antinociceptive and anticonvulsant effects of some Lychnophora species. We verify the protective effects of polar extracts (600 mg/kg, intraperitoneally), and methanolic fractions of L. staavioides and L. rupestris (100 mg/kg, intraperitoneally) in pentylenetetrazole-induced seizures on mice. Previously, a screening was accomplished, evaluating the antinociceptive central activity (hot plate test), with different extracts of L. rupestris, L. staavioides and L. diamantinana. It was possible to select the possible extracts of Lychnophora with central nervous system activity. Some of the active extracts were submitted to fractionation and purification process and the methanolic fractions of L. rupestris (stem) and L. staavioides (stem), with anticonvulsant properties (100 mg/kg, intraperitoneally), yielded 4,5-di-O-[E]-caffeoylquinic acid. This substance was injected intraperitoneally in mice and showed anticonvulsant effect against pentylenetetrazole-induced seizures at doses of 25 and 50 mg/kg. It has often been shown that seizures induced by pentylenetetrazole are involved in inhibition and/or attenuation of GABAergic neurotransmission. However, other systems of the central nervous system such as adenosinergic and glutamatergic could be involved in the caffeoylquinic acid effects. Further studies should be conducted to verify that the target receptor could be participating in this anticonvulsant property. Although other investigations have reported a series of biological activities from Lychnophora species, this is the first report of central analgesic and anticonvulsant activity in species of this genus.

Increase of core temperature induced by corticotropin-releasing factor and urocortin: A comparative study

This study compared the ability of CRF and UCN1 to induce a thermoregulatory response when centrally injected into rats. The effects of antipyretic drugs and CRF receptor antagonists (CRF(1) and CRF(2)) on the temperature (T) changes induced by these peptides were also investigated. Rectal (rT) and tail skin (T(sk)) temperatures were measured with a thermistor probe while body (bT) temperature was measured with a battery-operated biotelemetry transmitter in male Wistar rats (200 g) every 30 min over a period of 6 h, after intracerebroventricular (i.c.v.) injection of 1 nmol of either CRF or UCN1. Rats were pre-treated with indomethacin (2 mg kg(-1), i.p.) or celecoxib (5 mg kg(-1), p.o.), dexamethasone (0.5 mg kg(-1), s.c.), astressin (a CRF(1)/CRF(2) antagonist, 7 nmol, icy.) or antalarmin (a CRF(1) antagonist, 20 mg kg 1, i.p.). The increase in body temperature induced by CRF was accompanied by a reduction in T(sk) while the response induced by UCN1 was accompanied by an elevation in T(sk). Indomethacin or celecoxib did not change the increases in rT caused by either CRF or UCN1. Although dexamethasone attenuated the increase in rectal temperature in response to CRF, dexamethasone did not modify the response induced by UCN1. Astressin blocked the UCN1-induced hyperthermia and reduced CRF-induced fever. Antalarmin did not modify the hyperthermia in response to UCN1, but reduced the fever evoked by CRF. This study demonstrated that CRF by acting on the CRF(1) receptor induces a prostaglandin-independent fever which seems to depend, at least in part, on the synthesis of other mediators while UCN1 acts on the CRF(2) receptor, promoting a hyperthermic response which seems to be independent on synthesis/release of any mediator. (C) 2010 Elsevier B.V. All rights reserved.

Measurement of functional ability following traumatic brain injury using the Clinical Outcomes Variable Scale: A reliability study

This study determined the inter-tester and intra-tester reliability of physiotherapists measuring functional motor ability of traumatic brain injury clients using the Clinical Outcomes Variable Scale (COVS). To test inter-tester reliability, 14 physiotherapists scored the ability of 16 videotaped patients to execute the items that comprise the COVS. Intra-tester reliability was determined by four physiotherapists repeating their assessments after one week, and three months later. The intra-class correlation coefficients (ICC) were very high for both inter-tester reliability (ICC > 0.97 for total COVS scores, ICC > 0.93 for individual COVS items) and intra-tester reliability (ICC > 0.97). This study demonstrates that physiotherapists are reliable in the administration of the COVS.

Does anticipation of back pain predispose to back trouble?

Limb movement imparts a perturbation to the body. The impact of that perturbation is limited via anticipatory postural adjustments. The strategy by which the CNS controls anticipatory postural adjustments of the trunk muscles during limb movement is altered during acute back pain and in people with recurrent back pain, even when they are pain free. The altered postural strategy probably serves to protect the spine in the short term, but it is associated with a cost and is thought to predispose spinal structures to injury in the long term. It is not known why this protective strategy might occur even when people are pain free, but one possibility is that it is caused by the anticipation of back pain. In eight healthy subjects, recordings of intramuscular EMG were made from the trunk muscles during single and repetitive arm movements. Anticipation of experimental back pain and anticipation of experimental elbow pain were elicited by the threat of painful cutaneous stimulation. There was no effect of anticipated experimental elbow pain on postural adjustments. During anticipated experimental back pain, for single arm movements there was delayed activation of the deep trunk muscles and augmentation of at least one superficial trunk muscle. For repetitive arm movements, there was decreased activity and a shift from biphasic to monophasic activation of the deep trunk muscles and increased activity of superficial trunk muscles during anticipation of back pain. In both instances, the changes were consistent with adoption of an altered strategy for postural control and were similar to those observed in patients with recurrent back pain. We conclude that anticipation of experimental back pain evokes a protective postural strategy that stiffens the spine. This protective strategy is associated with compressive cost and is thought to predispose to spinal injury if maintained long term. © Guarantors of Brain 2004; all rights reserved

Allelic Variation Investigation of the Estrogen Receptor Within an Australian Multiple Sclerosis Population

Multiple Sclerosis (MS) is a central nervous system (CNS) chronic inflammatory demyelinating disease leading to various neurological disabilities. The disorder is more prevalent for women with a ratio of 3:2 female to male. Objectives: To investigate variation within the estrogen receptor 1 (ESR1) polymorphism gene in an Australian MS case-control population using two intragenic restriction fragment length polymorphisms; the G594A located in exon 8 detected with the BtgI restriction enzyme and T938C located in intron 1, detected with PvuII. One hundred and ten Australian MS patients were studied, with patients classified clinically as Relapsing Remitting MS (RR-MS), Secondary Progressive MS (SP-MS) or Primary Progressive MS (PP-MS). Also, 110 age, sex and ethnicity matched controls were investigated as a comparative group. No significant difference in the allelic distribution frequency was found between the case and control groups for the ESR1 PvuII (P = 0.50) and Btg1 (P = 0.45) marker. Our results do not support a role for these two ESR1 markers in multiple sclerosis susceptibility, however other markers within ESR1 should not be excluded for potential involvement in the disorder.

No Association Between MTHFR A1298C and MTRR A66G Polymorphisms, and MS in an Australian Cohort

Multiple sclerosis (MS) is a complex neurological disease that affects the central nervous system (CNS) resulting in debilitating neuropathology. Pathogenesis is primarily defined by CNS inflammation and demyelination of nerve axons. Methionine synthase reductase (MTRR) is an enzyme that catalyzes the remethylation of homocysteine (Hcy) to methionine via cobalamin and folate dependant reactions. Cobalamin acts as an intermediate methyl carrier between methylenetetrahydrofolate reductase (MTHFR) and Hcy. MTRR plays a critical role in maintaining cobalamin in an active form and is consequently an important determinant of total plasma Hcy (pHcy) concentrations. Elevated intracellular pHcy levels have been suggested to play a role in CNS dysfunction, neurodegenerative, and cerebrovascular diseases. Our investigation entailed the genotyping of a cohort of 140 cases and matched controls for MTRR and MTHFR, by restriction length polymorphism (RFLP) techniques. Two polymorphisms: MTRR A66G and MTHFR A1298C were investigated in an Australian age and gender matched case-control study. No significant allelic frequency difference was observed between cases and controls at the α = 0.05 level (MTRR χ^2 = 0.005, P = 0.95, MTHFR χ^2 = 1.15, P = 0.28). Our preliminary findings suggest no association between the MTRR A66G and MTHFR A1298C polymorphisms and MS.

The prospects for immunotherapy in smoking cessation

Context Smoking is a major preventable cause of death and disability that is maintained by dependence on nicotine. Smoking cessation reduces mortality and morbidity. Although existing pharmacological aids to smoking cessation and relapse prevention (nicotine replacement therapy and bupropion) improve on unassisted quitting and behavioural methods, they are only modestly effective. More effective pharmacological methods are required that improve compliance, reduce side-effects, and can be used in combination with existing cessation methods. Starting point A nicotine vaccine is a promising immunotherapeutic approach to smoking cessation and relapse prevention. Such a vaccine would induce the immune system to form specific antibodies to nicotine to prevent it from crossing the blood-brain barrier to act on receptor sites in the central nervous system. Recent studies in rats provide proof of principle by showing that nicotine-specific antibodies can prevent the reinstatement of nicotine self-administration (N Lindblom et al, Respiration 2002; 69: 254–60) and block dopamine release in the shell of the nucleus accumbens (Sde Villiers et al, Respiration 2002; 69: 247–53). A phase 1 trial of a human cocaine vaccine has also recently been successfully completed (T Kosten et al, Vaccine 2002; 20: 1196–204). A safe and effective human nicotine vaccine would potentially have fewer side-effects and better compliance than existing smoking-cessation pharmacotherapies. It could also be used in combination with some of them (eg, bupropion). Where next? The most promising clinical application of a human nicotine vaccine is likely to be in relapse prevention in abstinent smokers. A vaccine may also have a role in preparing smokers to quit. Clinical trials of safety and efficacy in human smokers and ex-smokers are warranted. If a nicotine vaccine proves to be safe and effective, the health-care system will need to ensure that it is registered for clinical use and that the poorer members of the community (among whom smoking prevalence is now highest in developed countries) have access to the vaccine. The community will need to be appropriately informed about the role of a nicotine vaccine to ensure that it is not prematurely used for preventive purposes in children and adolescents.

Governing coordination: Behavioural principles and neural correlates

The coordination of movement is governed by a coalition of constraints. The expression of these constraints ranges from the concrete—the restricted range of motion offered by the mechanical configuration of our muscles and joints; to the abstract—the difficulty that we experience in combining simple movements into complex rhythms. We seek to illustrate that the various constraints on coordination are complementary and inclusive, and the means by which their expression and interaction are mediated systematically by the integrative action of the central nervous system (CNS). Beyond identifying the general principles at the behavioural level that govern the mutual interplay of constraints, we attempt to demonstrate that these principles have as their foundation specific functional properties of the cortical motor systems. We propose that regions of the brain upstream of the motor cortex may play a significant role in mediating interactions between the functional representations of muscles engaged in sensorimotor coordination tasks. We also argue that activity in these ldquosupramotorrdquo regions may mediate the stabilising role of augmented sensory feedback.

Immunology of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) leading to demyelination, axonal damage, and progressive neurologic disability. The development of MS is influenced by environmental factors, particularly the Epstein-Barr virus (EBV), and genetic factors, which include specific HLA types, particularly DRB1*1501-DQA1*0102-DQB1*0602, and a predisposition to autoimmunity in general. MS patients have increased circulating T-cell and antibody reactivity to myelin proteins and gangliosides. It is proposed that the role of EBV is to infect autoreactive B cells that then seed the CNS and promote the survival of autoreactive T cells there. It is also proposed that the clinical attacks of relapsing-remitting MS are orchestrated by myelin-reactive T cells entering the white matter of the CNS from the blood, and that the progressive disability in primary and secondary progressive MS is caused by the action of autoantibodies produced in the CNS by ­meningeal lymphoid follicles with germinal centers.

Immunopathology and Pathophysiology of Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS), and is widely studied as an animal model of the human CNS demyelinating diseases, including multiple sclerosis (Raine, 1984). EAE can be induced by inoculation with whole CNS tissue, purified myelin basic protein (MBP) or myelin proteolipid protein (PLP), together with adjuvants. It may also be induced by the passive transfer of T cells specifically reactive to these myelin antigens. EAE may have either an acute or a chronic relapsing course. Acute EAE closely resembles the human disease acute disseminated encephalomyelitis, while chronic relapsing EAE resembles multiple sclerosis. EAE is also the prototype for T-cell-mediated autoimmune disease in general. This chapter will focus on the immunopathology and pathophysiology of EAE, which are the subjects of investigation in my laboratory.

Transformation of external sensilla to chordotonal sensilla in the cut mutant of Drosophila assessed by single-cell marking in the embryo and larva

The cut gene of Drosophila melanogaster is an identity selector gene that establishes the program of development and differentiation of external sense organs. Mutations in the cut gene cause a transformation of the external sense organs into chordotonal organs, originally assessed by the use of immunostaining methods [Bodmer et al. (1987): Cell, 51:293-307]. Because of evidence that axonal projections of the transformed neurons within the central nervous system are not completely switched in cut mutants, the transformation of the four cells making up a sense organ was reassessed using single-cell staining with fluorescent dye and differential interface contrast (DIC) microscopy of the embryo and larva. The results provide strong evidence that all cells of the sense organs are completely transformed, exhibiting the morphologies and organelles characteristic of chordotonal sense organs. A comparison of the structures of external sense organs and chordotonal organs indicates that a number of the differences could be due to the degree of development of common structures, and that cut or downstream genes modulate effector genes that are normally utilized in both receptor types. The possible derivation of insect chordotonal and external sense organs from a receptor type found in crustaceans is discussed in the light of arthropod phylogenetics and the molecular genetics of sense organ development. (C) 1997 Wiley-Liss, Inc.

hnRNP A2 selectively binds the cytoplasmic transport sequence of myelin basic protein mRNA

Segregation of mRNAs in the cytoplasm of polar cells has been demonstrated for proteins involved in Xenopus and Drosophila oogenesis, and for some proteins in somatic cells. It is assumed that vectorial transport of the messages is generally responsible for this localization. The mRNA encoding the basic protein of central nervous system myelin is selectively transported to the distal ends of the processes of oligodendrocytes, where it is anchored to the myelin membrane and translated. This transport is dependent on a 21-nucleotide cis-acting segment of the 3'-untranslated region (RTS). Proteins that bind to this cis-acting segment have now been isolated from extracts of rat brain. A group of six 35-42-kDa proteins bind to a 35-base oligoribonucleotide incorporating the RTS, but not to several oligoribonucleotides with the same composition but randomized sequences, thus establishing specificity for the base sequence in the RTS. The most abundant of these proteins has been identified, by Edman sequencing of tryptic peptides and mass spectroscopy, as heterogeneous nuclear ribonucleoprotein (hnRNP) A2, a 36-kDa member of a family of proteins that are primarily, but not solely, intranuclear. This protein was most abundant in samples from rat brain and testis, with lower amounts in other tissues. It was separated from the other polypeptides by using reverse-phase HPLC and shown to retain preferential association with the RTS. In cultured oligodendrocytes, hnRNP A2 was demonstrated by confocal microscopy to be distributed throughout the nucleus, cell soma, and processes.