Biomedical subjects

A J Fulford

Publications and source records attributed to A J Fulford.

At least 19 recordsLinked to original sources

PubMed2006

The nociceptin receptor antagonist [Nphe1,Arg14,Lys15]nociceptin/orphanin FQ-NH2 blocks the stimulatory effects of nociceptin/orphanin FQ on the HPA axis in rats.

Nociceptin/orphanin FQ (N/OFQ) is an opioid-related peptide that stimulates corticosterone release after i.c.v. administration in non-stressed rats. We employed in situ hybridization histochemistry to investigate N/OFQ-stimulated activation of the HPA axis at the hypothalamic and pituitary level. We have demonstrated that N/OFQ-induced activation of the HPA axis is mediated via the central N/OFQ peptide receptor (NOP) using the recently described selective NOP antagonist [Nphe(1),Arg(14),Lys(15)]nociceptin/orphanin FQ-NH(2) (UFP-101). We found that, at 30 min post-i.c.v. injection, N/OFQ dose-dependently increased plasma adrenocorticotrophin hormone and corticosterone compared with the vehicle-injected controls. N/OFQ (1.0 microg) significantly increased CRF mRNA but not AVP mRNA within the parvocellular hypothalamic paraventricular nucleus compared with the control group, and significantly increased pro-opiomelanocortin (POMC) mRNA in the anterior pituitary. While UFP-101 (1.0 microg) alone had no significant effect on plasma corticosterone concentration it blocked the effect of N/OFQ (1.0 microg) on plasma corticosterone levels when compared with N/OFQ administered alone. UFP-101 also blocked the N/OFQ-induced increase in CRF mRNA and POMC mRNA. These results demonstrate that centrally administered N/OFQ activates the HPA axis via up-regulation of CRF and POMC mRNA and stimulation of corticosterone release in rats. Further, we have demonstrated for the first time that the selective NOP receptor antagonist UFP-101 blocks these effects indicating that N/OFQ-induced HPA axis activation is mediated via central NOP receptors.

Adrenocorticotropic Hormone↗

PubMed2002

Isolation rearing in the rat disrupts the hippocampal response to stress.

Both human schizophrenia and the effects of isolation rearing in rats produce deficits in hippocampal and cortical functioning. This study was concerned with identifying changes associated with altered neuronal function in the rat hippocampus following isolation rearing. Rats were isolated from weaning at 21 days postnatal for 6 weeks and the hippocampal sensitivity to isolation rearing and stress were studied using c-fos immunohistochemistry and in vivo microdialysis. Isolation rearing altered neuronal activity measured by Fos-like immunoreactivity in the specific brain areas as measured by either increased or reduced expression. Basal neuronal activity in the ventral CA1 hippocampus in isolation-reared rats was notably higher compared to group-reared rats but markedly lower Fos-like immunoreactivity was found in the central and basolateral nuclei of the amygdala. Exposure to stress produced differential effects on neuronal activity in isolation-reared rats between the dorsal and ventral hippocampus, with increased Fos-like immunoreactivity in the dorsal hippocampus but lower Fos-like immunoreactivity in the ventral hippocampus compared to group-reared rats. These results indicate that isolation rearing may alter the relationship between hippocampal neuronal function in the dorsal and ventral hippocampus. An in vivo microdialysis study showed that systemically administered parachloroamphetamine (2.5 mg/kg, i.p.) enhanced extracellular 5-hydroxytryptamine (5-HT) in the dorsal hippocampus in group-reared but not in isolation-reared rats. Restraint stress had no effect on hippocampal extracellular 5-HT in group-reared rats but reduced levels in isolation-reared rats during the period of restraint. Inescapable mild footshock produced a marked increase in extracellular hippocampal 5-HT in group-reared but not isolation-reared rats. Overall the results provide extensive evidence that isolation rearing alters presynaptic 5-HT hippocampal function and that the neuronal response to stress is altered by isolation. Isolation rearing in the rat alters hippocampal function, including the serotonergic system, leading to changes in neurotransmitter systems in other brain areas. These changes may model aspects of human neurodevelopmental disorders such as schizophrenia.

Animal Husbandry↗

PubMed2000

Antisense inhibition of pro-opiomelanocortin and proenkephalin A messenger RNA translation alters rat immune cell function in vitro.

Pro-opiomelanocortin (POMC) and proenkephalin A (PEA) antisense oligodeoxynucleotides respectively reduced and enhanced proliferation of rat splenocytes incubated with concanavalin A in vitro. Nonsense base sequences used as controls were without effect. Coincubation with the exogenous synthetic opioid peptides, ACTH, beta-endorphin, met-enkephalin or [D-ala,D-leu]-enkephalin did not significantly alter either the POMC or PEA antisense response, indicating potential differences in bioactivity of immunocyte opioid peptides compared with synthetic equivalents. Levels of the POMC opioid products, ACTH and beta-endorphin, were significantly reduced in splenocytes incubated with POMC antisense probes. These data provide evidence for functional effects of endogenous opioid peptides on rat splenocyte proliferation in vitro.

Adrenocorticotropic Hormone↗

PubMed2000

Novel opioid peptides endomorphin-1 and endomorphin-2 are present in mammalian immune tissues.

Endomorphin (EM)-1 and EM-2 are opioid tetrapeptides, reported within the central nervous system, which have very high specificity and affinity for the mu-opioid receptor. We have used newly developed and well-characterised radioimmunoassays (RIAs) in combination with reversed-phase high-performance liquid chromatography (HPLC) to detect EM-1 and EM-2 immunoreactivity (ir) in rat immune tissues. Endomorphins were detectable in extracts of rat spleen (total EM-1-ir/spleen: 440+/-73 pg, mean+/-SEM, a=group of eight rats; EM-2-ir: 150+/-12 pg) and thymus (EM-1-ir: 152+/-18 pg, mean+/-SEM n=8; EM-2-ir: 156+/-28 pg). EM-2-ir was detectable in extracts of human spleen (338+/-196 pg/g tissue, n=3). Multiple peaks of EM-1-ir and EM-2-ir were observed in rat spleen and thymus extracts, and multiple peaks of EM-2-ir were observed in extracts of human spleen, following reversed-phase HPLC and RIAs. This is the first report of endomorphin immunoreactivity in tissues of the rat and human immune systems.

Adult↗

PubMed1999

Adult resistance to schistosomiasis mansoni: age-dependence of reinfection remains constant in communities with diverse exposure patterns.

In a fishing community on Lake Albert in Uganda the pattern of intensity of Schistosoma mansoni infection 6 months after treatment with praziquantel was found to be very similar to reinfection patterns seen in previously studied endemic communities: the profile peaks sharply at around the age of 10 years falling away rapidly to much lower levels in adults. This is in stark contrast to the patterns of water contact, which differ greatly between fishing and non-fishing communities. On Lake Albert, adults appear to be more heavily exposed than children. From these observations we conclude that adults are physiologically (perhaps immunologically) more resistant to infection after treatment than children.

Adolescent↗

PubMed1999

Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice.

The spontaneous development of insulin dependent diabetes mellitus in non-obese diabetic (NOD) mice has been shown to be mediated by a Th1 response against beta cell antigens. It is known that in murine models of Schistosoma mansoni infection, egg production is associated with a switch from a Th1 to Th2 response. This subsequent dominance of a Th2 response in S.mansoni infected mice has been shown to influence the response to other infectious agents or antigens. We therefore determined whether infection with S.mansoni could influence the spontaneous incidence of insulin dependent diabetes mellitus (IDDM) in NOD mice. Infection with this helminth significantly reduced the spontaneous incidence of IDDM. IDDM was also prevented by injecting parasite eggs alone. Because until relatively recently humans might expect to succumb to a variety of infectious agents, the current freedom from infection might permit the expression of a genetic predisposition to autoimmune pathology and be responsible for the increased incidence of IDDM.

Animals↗

PubMed1999

Development of antibody isotype responses to Schistosoma mansoni in an immunologically naive immigrant population: influence of infection duration, infection intensity, and host age.

We have identified the influence of host and parasite factors that give rise to characteristic antibody isotype profiles with age seen in human populations living in different areas of schistosomiasis endemicity. This is important in the immunobiology of this disease. It is also of interest in the context of human responses to chronic antigen stimulation, vaccines, allergens, and other pathogens. In populations exposed to endemic schistosomiasis, factors such as intensity and duration of infection are age dependent. They therefore confound the influence of host age on antiparasite responses. Here, we resolved these confounding factors by comparing the developing antibody responses of an immunologically naive immigrant population as they acquired the infection for the first time with those of chronically infected resident inhabitants of the same region of Schistosoma mansoni endemicity in Kenya. Recent arrival in the area strongly favored immunoglobulin G3 (IgG3) responses against the parasite. The antibody isotype responses associated with human susceptibility to reinfection after chemotherapy were elevated in those suffering high intensities of infection (IgG4 responses against worm and egg antigens) or were characteristic responses of young children irrespective of the intensity or duration of infection (IgG2 responses against egg antigen). IgE responses against the adult worm, a response associated with resistance to reinfection after chemotherapy, increased with the ages of infected individuals and were also favored in those currently suffering higher intensities of infection.

Adult↗

PubMed1998

High levels of TNF, soluble TNF receptors, soluble ICAM-1, and IFN-gamma, but low levels of IL-5, are associated with hepatosplenic disease in human schistosomiasis mansoni.

In a case-control study based in two areas of Kenya, hepatosplenic schistosomiasis mansoni was shown to be linked with low levels of IL-5 and with correspondingly high IFN-gamma, TNF, and circulating soluble TNF receptor I (sTNFR-I), sTNFR-II, and sICAM-1. PBMC from the hepatosplenic cases responded to in vitro Ag stimulation with significantly higher levels of IFN-gamma and TNF, but lower levels of IL-5, compared with nonhepatosplenic controls matched for age and infection intensity. Most of these correlations were confounded by differences between geographical areas. However, principle component analysis identified a high IFN-gamma and TNF, and low IL-5 axis in the data as the first principle component; this was significantly associated with hepatosplenomegaly (p < 0.0005) even after controlling for area. High plasma levels of sTNFR-I (p < 0.001), sTNFR-II, (p < 0.0001), and sICAM-1 (p < 0.009) were also significantly associated with hepatosplenomegaly, independently of area, in the case of the soluble forms of both TNF receptors. These parameters were negatively related to IL-5. These results suggest that proinflammatory cytokines are involved in the hepatosplenic disease process in infected individuals who have low anti-inflammatory Th2 responses and that sTNFR may be a useful circulating marker for this disease process, perhaps reflecting the level of TNF activity in hepatic tissues.

Adolescent↗

PubMed1998

Puberty and Age-related Changes in Susceptibility to Schistosome Infection.

Recent data from outbreaks of schistosomiasis in immunologically naive populations have refuelled the debate concerning the nature or existence of protective, acquired immunity to schistosomiasis in humans. Data from endemic communities provide some compelling evidence for an abrupt change in reinfection rates that coincides with puberty. We suggest that the hormonal changes of adrenarche may hold the key to understanding the relative resistance to infection found in adults.

Journal Article↗

PubMed1998

Conditioned release of 5-hydroxytryptamine in vivo in the nucleus accumbens following isolation-rearing in the rat.

This study examined the effect of isolation-rearing in the Lister hooded rat on extracellular 5-hydroxytryptamine in the medial nucleus accumbens following footshock and in relation to a conditioned emotional response. Inescapable mild footshock was associated with an immediate and prolonged increase in extracellular 5-hydroxytryptamine in the medial nucleus accumbens of isolation-reared rats. In group-reared rats (footshock-treated) and control groups (no footshock) there was no significant change in extracellular 5-hydroxytryptamine levels. When exposed to the contextual stimulus 140 min later (testing box without shock) there was an immediate and long-lasting increase in extracellular 5-hydroxytryptamine in the nucleus accumbens of the isolation-reared rats, however, the contextual stimulus did not significantly affect extracellular 5-hydroxytryptamine in the medial nucleus accumbens of group-reared rats. The results show that exposure to footshock and conditioning to context are not normally associated with a change in extracellular 5-hydroxytryptamine in the medial nucleus accumbens, however, in rats exposed to social isolation from weaning, both stimuli increase extracellular 5-hydroxytryptamine. The isolation-induced increase in presynaptic serotonergic function in the medial nucleus accumbens contrasts with previous reports of reduced 5-hydroxytryptamine release in the hippocampus and therefore suggests that isolation-rearing differentially affects the function of serotonergic neurons in the brain. The changes in 5-hydroxytryptamine function in the medial nucleus accumbens may represent physiological adaptations to stress or may occur secondary to changes in the function of another neurotransmitter, possibly dopamine.

Animals↗

PubMed1998

The development of schistosomiasis mansoni in an immunologically naive immigrant population in Masongaleni, Kenya.

The relocation of several thousand members of the Kamba tribe from the Kyulu Hills to the Thange valley near Masongaleni in Kenya provides an excellent opportunity to study the development of the immune response to schistosomiasis mansoni in a population with little or no previous experience of the infection. An adjacent, well-established Kamba community with similar patterns of water contact provides a suitable endemic control population. The immigrants were, uniquely, examined shortly after their arrival in the endemic area, while the prevalence of infection was still low. At this time faecal egg counts peaked atypically around 30 years of age. Over the next 12-18 months infection increased rapidly, especially among teenagers, producing a pattern of infection more typical of endemic communities. This substantially narrows estimates of the time required to develop the important determinants of the age-intensity profile, supporting the notion that changes related to age per se, rather than duration of infection, dominate. Age-dependent factors might include behaviour or physiology, including immune response. This paper provides the background for continuing longitudinal studies on the development of immunological responses to this parasite.

Adolescent↗

PubMed1998

Human IgE responses to rSm22.6 are associated with infection intensity rather than age per se, in a recently established focus of Schistomiasis mansoni.

In studies of schistosomasis mansoni-endemic communities, individuals with IgE responses to a 22 kD adult worm antigen (rSm22.6) suffered lower intensities of reinfection after treatment. It is of interest to define the factors that lead to the production of rSm22.6-specific IgE because it is a marker for resistant individuals and it may be involved in the development of resistance to reinfection. In endemic populations rSm22.6-specific IgE increases linearly with age. However, it is not possible to distinguish between age per se and 'history of infection' in endemic populations because individuals are exposed to the parasite at an early age. We have, therefore, quantified pre- and post-treatment isotype responses to rSm22.6 in a comparatively 'epidemic' Senegalese community where the patients were infected at different ages and where pre-treatment intensity of infection can be taken as a reasonable measure of antigen exposure. Post-treatment isotype responses to rSm22.6 correlated positively with pre-treatment intensities of infection but were not shown to be related to age. IgG1, IgG4 and IgE responses to rSm22.6 were significantly higher after treatment with the difference increasing with the pre-treatment level of infection. These results from a recently established focus of infection suggest that isotype responses to rSm22.6 are antigen-exposure dependent rather than dependent on age per se.

Adolescent↗

PubMed1998

Effect of isolation-rearing on conditioned dopamine release in vivo in the nucleus accumbens of the rat.

Intracerebral microdialysis in conjunction with HPLC coupled to electrochemical detection was used to investigate the effect of isolation-rearing in the rat on extracellular dopamine (DA) and its metabolites in vivo, in the shell region of the nucleus accumbens, in response to footshock and in relation to a conditioned emotional response. Male Lister hooded rats were reared from weaning for 6-8 weeks in either social isolation or groups of five. In the training phase, rats were exposed to a novel environment for 10 min where they experienced mild footshock. Footshock caused an immediate increase in basal extracellular DA levels in both rearing groups relative to control rats. However, the increase in extracellular DA was prolonged in the case of the isolation-reared rats and significantly greater than in group-reared rats. Exposure to the novel environment without shock (control groups) did not significantly alter basal extracellular DA in the nucleus accumbens shell; 140 min later rats were returned to the testing box (contextual stimulus) without receiving footshock. The contextual stimulus increased basal extracellular DA in the nucleus accumbens of both groups of rats with respect to controls; however, this increase was significantly greater and more prolonged in isolates. Extracellular levels of the metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid did not differ between isolation- and group-reared rats, and they were not significantly affected by either footshock or the contextual stimulus. These results suggest that exposure to footshock and a contextual stimulus are associated with increases in basal extracellular DA levels in the nucleus accumbens shell. The results also support evidence in favour of an isolation-induced enhancement in dopaminergic activity in the nucleus accumbens, which probably underlies aspects of the behavioural syndrome associated with isolation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

Effect of isolation-rearing on noradrenaline release in rat hypothalamus and hippocampus in vitro.

A fixed volume incubation method in conjunction with HPLC-ED analysis was employed to measure endogenous NA release in vitro in slices of hippocampus and hypothalamus from rats reared in either groups of five or in social isolation from weaning. NA in release supernatants from hippocampal slices was found to be increased in response to stimulation with high K+ (30 mM), an effect which was dependent on Ca2+. Basal NA release was also Ca2+ dependent. Isolation-rearing did not significantly alter either basal or K+-stimulated release. Clonidine (10 microM) caused an inhibition of basal NA release in both regions and in both rearing groups, however there was no significant effect of isolation-rearing for this response although the response tended to be greater in the hippocampus from isolates. Idazoxan (10 microM) significantly increased basal NA release in hippocampal and hypothalamic slices in both rearing groups, but this effect was significantly greater in the hippocampus from isolation-reared rats. These findings suggest there may be a region-specific change in the sensitivity of the alpha2-adrenoceptor in isolates. Taken together with previous findings, there is evidence to suggest that isolation-rearing alters the sensitivity of the presynaptic terminal alpha2-autoreceptor in the hippocampus.

Adrenergic alpha-Agonists↗

PubMed1997

Spatial patterns of human water contact and Schistosoma mansoni transmission and infection in four rural areas in Machakos District, Kenya.

This paper presents the results of microgeographical studies of human water contact behavior and Schistosoma mansoni transmission levels and intensity of infection in four rural areas in Machakos District, Kenya. The relationship between intensity of infection (geometric mean egg counts) in 3502 persons aggregated in 120 household clusters and eight independent variables was investigated using straight and stepwise linear regression and mapping techniques. Results indicate that the two water contact variables, mean frequency per person and mean duration per person, as well as mean number of sites used per person, a transmission index and mean distance to the most frequently used site were the strongest predictors of geometric mean egg counts. All three distance variables were usually negatively associated with infection although intensity of infection and water contact declined relatively slowly with distance from the streams. This pattern appears to be owing to a combination of the relatively short distances, a general lack of safe alternative water sources and the use of more distant water contact sites both inside and outside the study area during periods of drought. The study of snail-to-man transmission identified number of infected snails as the major transmission variable and number of contacts as the major predictor variable. Mapping of total egg counts at the household cluster level and total number of infected snails revealed spatial association with transmission sites. All results varied considerably between study areas, owing to differences in exposure levels, transmission patterns and environmental factors. Findings are discussed in relation to the epidemiology and control of schistosomiasis and suggestions are made for further spatial studies.

Adolescent↗

PubMed1997

Social isolation in the rat enhances alpha 2-autoreceptor function in the hippocampus in vivo.

This study investigated the effects of isolation rearing from weaning in rats on extracellular noradrenaline in the dorsal hippocampus in vivo, measured using microdialysis. Male Lister hooded rats were obtained at weaning and reared in social isolation or in groups for six to eight weeks. Basal noradrenaline efflux did not differ between isolation- and group-reared rats. Local K+ stimulation (50 and 100 mM) increased noradrenaline efflux in the hippocampus of both groups of rats; however, this effect was greater in group-reared rats (50 mM K+). The alpha 2-adrenoceptor agonist, clonidine (0.3 mg/kg, i.p.), reduced noradrenaline efflux in both groups of rats, but this decrease was greater in isolates. Systemic (1.0 mg/kg, i.p.) and local (via the probe; 100 microM) administration of the alpha 2-adrenoceptor antagonist, idazoxan, increased noradrenaline efflux, but these responses were also greater in isolation-reared rats. The magnitudes of the idazoxan-induced increases in noradrenaline efflux were similar for both systemic and local administration, indicating that presynaptic terminal alpha 2-adrenoceptors were predominantly involved. Furthermore, although tail pinch increased noradrenaline efflux in both isolation- and group-reared rats, there was a significant/attenuation in the response in the isolation- compared to group-reared rats. Taken together with previous findings, the present results provide evidence in favour of an isolation-induced enhancement in the function of the presynaptic terminal alpha 2-autoreceptor in the dorsal hippocampus in vivo, resulting in decreased functional responsiveness of hippocampal noradrenergic nerve terminals.

Adrenergic alpha-Agonists↗

PubMed1997

The influence of sex and age on antibody isotype responses to Schistosoma mansoni and Schistosoma japonicum in human populations in Kenya and the Philippines.

We have investigated the effects of host age and sex on human antibody isotype responses to Schistosoma mansoni and Schistosoma japonicum adult worm (AW) and soluble egg (SEA) antigens, using sera from subjects in Kenya and the Philippines. Similar trends with age were observed between the two populations despite host, parasite and environmental differences between the two geographical locations. IgE to AW increased with age, whereas most isotype responses to SEA decreased with age. IgG1, IgG3 and IgG4 subclass responses to adult worm, however, did not show a broadly rising or falling pattern with age. Males were found to have higher IgG1, IgG4 and IgE to AW in both populations. This sex difference remained significant in the Kenyan population even after controlling statistically for confounding factors such as age and differences in intensity of infection. Analysis of S. mansoni and S. japonicum adult worm antigens reactive with IgE revealed a predominant 22 kDa band in both parasites. Only those individuals with relatively high IgE titres specifically reactive with S. mansoni or S. japonicum AW had detectable IgE against Sj22 or Sm22.

Adolescent↗

PubMed1997

The isolation of a 22 kDa band after SDS-PAGE of Schistosoma mansoni adult worms and its use to demonstrate that IgE responses against the antigen(s) it contains are associated with human resistance to reinfection.

In schistosomiasis endemic areas, intensities of reinfection after treatment are greater amongst young children than amongst adults, and high levels of parasite-specific IgE are associated with resistance to reinfection in an age-dependent manner. Previously we have reported that, in Western blots, a 22 kDa band was recognized by human IgE and that the incidence and intensity of S. mansoni reinfection were significantly lower amongst individuals who had IgE against this band, compared with those who did not (Dunne et al. 1992). Here we report the isolation of a 22 kDa SDS-PAGE band, its incorporation into ELISA and the demonstration that levels of human anti-22 kDa IgE had a significant negative correlation with intensities of subsequent reinfection. Rabbit anti-22 kDa band serum recognized the outer tegument, gut tegument, and the collecting ducts and flame cells of adult worms. The 22 kDa band antigen(s) was also present in "lung'- and "post-lung' schistosomula stages of S. mansoni, and in S. haematobium, S. bovis and S. japonicum adult worms. Metabolic labelling of schistosomula and worms demonstrated the in vitro synthesis and release of 22 kDa antigens.

Animals↗