Lamotrigine for generalised epilepsies.
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Adult↗
Biomedical subjects
J Stewart
Publications and source records attributed to J Stewart.
The stimulation of central kappa opioid receptors decreases male sexual behavior and locomotor activity.
Systemic injections of the kappa (kappa) opioid receptor agonist U-50,488H decreased male sexual behavior, locomotor activity, body temperature and bodily grooming, and induced body flattening. The U-50,488H-induced inhibitions of male sexual behavior were prevented by systemic injections of naloxone and by intra-cranial injections of the kappa opioid antagonist nor-binaltorphimine (NBNI). Injections of NBNI to either the ventral tegmental area (VTA) or the nucleus accumbens septi (NAS) increased female-directed behavior, and prevented the U-50,488H-induced decreases in female-directed behavior. Intra-VTA NBNI prevented U-50,488H-induced decreases in the mean number of ejaculations, intra-NAS NBNI prevented U-50,488H-induced increases in copulation latencies. Intra-medial preoptic area (mPOA) injections of NBNI increased female-directed behavior, and attenuated U-50,488H-induced decreases in female-directed behavior as well as U-50,488H-induced increases in both copulation and ejaculation latencies. Injections of NBNI dorsal to the mPOA were ineffective. Two of 26 days following the central injection of NBNI, systemic injections of U-50,488H remained behaviorally ineffective, leaving both sexual behavior and locomotor activity undiminished. These results suggest that the stimulation of central kappa opioid receptors inhibits sexual behavior in the male rat; perhaps endogenous kappa opioid agonists induce sexual refractory periods.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Selective activation of p42 mitogen-activated protein (MAP) kinase in murine B lymphoma cell lines by membrane immunoglobulin cross-linking. Evidence for protein kinase C-independent and -dependent mechanisms of activation.
Cross-linking of membrane immunoglobulin (mIg), the B lymphocyte antigen receptor, with anti-receptor antibodies stimulates tyrosine phosphorylation of a number of proteins, including one of 42 kDa. Proteins with a similar molecular mass are tyrosine-phosphorylated in response to receptor stimulation in other cell types and have been identified as serine/threonine kinases, termed mitogen-activated protein (MAP) kinases or extracellular signal-regulated kinases (ERKs). The MAP kinases constitute a family of related kinases, at least three of which have molecular masses of 40-45 kDa. In this paper we show that mIg cross-linking stimulated the myelin basic protein phosphotransferase activity characteristic of MAP kinase in both mature and immature murine B cell lines. This enzyme activity co-purified on three different columns with a 42 kDa protein that was tyrosine-phosphorylated (pp42) in response to mIg cross-linking and which reacted with a panel of anti-(MAP kinase) antibodies. Although immunoblotting with the anti-(MAP kinase) antibodies showed that these B cell lines expressed both 42 kDa and 44 kDa forms of MAP kinase, only the 42 kDa form was activated and tyrosine-phosphorylated to a significant extent. Activation of protein kinase C (PKC) with phorbol esters also resulted in selective tyrosine phosphorylation and activation of the 42 kDa MAP kinase. This suggested that mIg-induced MAP kinase activation could be due to stimulation of PKC by mIg. However, mIg-stimulated MAP kinase activation and pp42 tyrosine phosphorylation was only partially blocked by a PKC inhibitor, the staurosporine analogue Compound 3. In contrast, Compound 3 completely blocked the ability of phorbol esters to stimulate MAP kinase activity and induce tyrosine phosphorylation of pp42. Thus mIg may activate MAP kinase by both PKC-dependent and -independent mechanisms.
Amino Acid Sequence↗
Neurobiology of conditioning to drugs of abuse.
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Animals↗
The effects of lesions of the habenular nuclei on the development of sensitization to the behavioral activational effects of repeatedly administered morphine in the rat.
The effects of lesions of the habenular nuclei on the development of sensitization to the behavioral activational effects of morphine (MOR), administered repeatedly either systemically or directly into the ventral tegmental area (VTA) were examined. Lesions of the habenular nuclei blocked the early-appearing sedative effects and enhanced the later-appearing locomotor activational effects seen after systemic injections of MOR (10 mg/kg, i.p.). Habenular lesions did not potentiate the development of sensitization to the locomotor-activational effects seen with the repeated, systemic administration of MOR. The bilateral injection of MOR (5.0 micrograms/0.5 microliter/side) directly into the VTA of animals with habenular lesions resulted in the performance of stereotyped behaviors that appeared as early as the second MOR exposure and remained at high levels with repeated MOR treatment. The stereotyped behavior shown by lesioned animals did not appear to interfere with the acute locomotor activational effects of intra-VTA MOR nor the development of sensitization to these effects when it was administered repeatedly. These results are in agreement with previous research suggesting that by disinhibiting the dopamine (DA) systems, habenular lesions enhance the acute behavioral activational effects of MOR. The results also suggest that the habenular nuclei do not control the changes in the response of the DA systems underlying the development of sensitization to the locomotor-activating effects of MOR when administered repeatedly.
Analysis of Variance↗
"We have to go back to healing the traditional way," native speakers tell Manitoba MDs.
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Canada↗
The kappa-opioid U-50,488H suppresses the initiation of nocturnal spontaneous drinking in normally hydrated rats.
The effect of a systemic (IP) treatment with 1.0, 3.0 and 9.0 mg/kg U-50,488H (U50), a highly selective kappa-agonist, on spontaneous, nocturnal ingestive behavior of the rat was studied using a microcomputer controlled data acquisition system. The latency to initiate drinking was increased and drinking behavior was suppressed in the first hour after injection in a dose-dependent manner. The consummatory indices of drinking were not affected. After this period of adipsia, a phase of polydipsia, that was probably due to the diuretic effect of U50, was evident. This prophagic effect of U50 was evident only at the dose of 3 mg/kg and was accompanied by an increased duration of feeding episodes but not by a reduced latency to feed. These results suggest that kappa-receptors play a pivotal role in modulating spontaneous drinking in the normally hydrated rat and that this control is mainly exerted on the motivational aspect of drinking.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Reinstatement of heroin self-administration habits: morphine prompts and naltrexone discourages renewed responding after extinction.
The effects of morphine, naltrexone, and nalorphine were studied in rats trained to lever-press for intravenous heroin and then tested under conditions of non-reinforcement. Animals were reinforced for lever-pressing on a continuous reinforcement schedule (100 micrograms/kg per infusion) for 2-3 h each day following which reinforcement was terminated and animals were studied under extinction conditions for the remainder of the session. Each day following the termination of responding under extinction conditions, animals were given a single injection of saline, morphine, nalorphine, or naltrexone; lever-pressing under the extinction conditions was then observed for several hours. When animals adapted to this regimen, very low levels of responding were seen following saline injections; morphine (2 or 10 mg/kg) reinstated vigorous responding that lasted 1-4 h. Naltrexone (2 mg/kg) suppressed responding below the levels seen after saline, and nalorphine (10 mg/kg) had the same effect as saline. These observations support the view that opioid-seeking behavior is primed by the proponent or opioid-like actions of opioids and not by the opponent or drug-opposite effects associated with opioid withdrawal.
Animals↗
Naloxone-induced hypoalgesia: lack of involvement of the GABA-benzodiazepine receptor complex.
Previous evidence has demonstrated that repeated daily administration of the opiate receptor antagonist naloxone prior to assessment of pain sensitivity provokes the development of a nonopioid form of hypoalgesia. The present experiments assessed whether the GABA-benzodiazepine receptor complex may be involved in the mediation of this effect. Male Wistar rats were administered 10 mg/kg naloxone prior to hot-plate tests (48.5 degrees C) for pain sensitivity for 8 consecutive days. Control animals were administered saline prior to, and naloxone 2-4 h after, assessment of pain reactivity. Beginning on the fourth or fifth day of this regimen, animals tested under the influence of naloxone displayed longer paw-lick latencies than controls. Preadministration of the GABAA agonist muscimol (1.0-5.0 mg/kg) and GABAA antagonist bicuculline (0.25-1.0 mg/kg) failed to affect paw-lick latencies in naloxone-tested and control rats. The GABAB receptor agonist baclofen (1.0-5.0 mg/kg) and the benzodiazepine receptor agonist diazepam (1.0-5.0 mg/kg) both elevated paw-lick latencies to the same degree in both groups of animals. These results suggest that the GABA-benzodiazepine receptor complex is not involved in the mediation of naloxone-induced hypoalgesia.
Analgesia↗
Immunoglobulins did not arise in evolution to fight infection.
The complex interactions between B and T cells in response to external antigens are the major focus of contemporary immunology. Here, John Stewart argues that they may be relatively late evolutionary developments, due to the redeployment of a system invented for other reasons. He suggests that the system of variable region molecules (VRM) arose, at the time of the first vertebrates, by an endogenous, self-organizing process; this primordial VRM system instituted a molecular ecology, a function so important that from then on no vertebrate has been able to do without it.
Animals↗
Secretor status and humoral immune responses to Neisseria lactamica and Neisseria meningitidis.
Non-secretors of ABO blood group antigens are over-represented among patients with meningococcal diseases. Lower levels of secretory IgA reported for non-secretors have been suggested to compromise mucosal defences. Total serum and salivary IgG, IgA and IgM and levels of these isotypes specific for Neisseria lactamica and five isolates of meningococci were determined by ELISA for 357 pupils and staff of a secondary school in which an outbreak of meningitis occurred. There were no differences in total or specific levels of serum IgG, IgA or IgM or salivary IgG or IgA of secretors compared with non-secretors. Non-secretors had significantly lower levels of salivary IgM (P = 0.022). A similar pattern was observed for levels of IgM specific for N. lactamica and five meningococcal isolates. The significance of these results is discussed with reference to the role of secretory IgM in protection of mucosal surfaces in infants.
Adolescent↗
Comparative evaluation of supplemental hepatitis C virus antibody test systems.
Implementation of routine blood donor screening using anti-hepatitis C virus (HCV) enzyme immunoassay (EIA) has resulted in an urgent need for well-characterized supplemental assays to confirm the presence of HCV antibodies. A comparative study of four commercially available supplemental assays is reported here: first- and second-generation versions of a strip recombinant immunoblot assay (RIBA-1 and RIBA-2), an HCV neutralization EIA, and HCV neutralization plus synthetic peptide EIA. Three hundred sixty-seven blood donor specimens that were repeatedly reactive on HCV EIA were studied. Most specimens (93%) were also evaluated by radioimmunoassay (RIA) with a six-antigen panel, and 60 selected specimens were tested for HCV RNA by the polymerase chain reaction (PCR). RIBA-1 and RIBA-2 gave concordant results with 86 percent of specimens, while an additional 13 percent were correctly classified by RIBA-2 but not RIBA-1. Neutralization EIA alone correctly identified 94 percent of the study group, while the remaining 6 percent required the peptide EIA or the combined neutralization-peptide assay system for correct classification. The RIBA-2 and neutralization-peptide assay system for correct classification. The RIBA-2 and neutralization-peptide assay systems yielded identical results for 86 percent of specimens, and these results were supported by RIA and selected PCR testing. Only 2 specimens (0.5%) were frankly discrepant, while 51 specimens were indeterminate on either (47) or both (4) assays. When either the RIBA-2 or neutralization-peptide assay yielded an indeterminate interpretation, the other system correctly classified the specimen (based on concordance with RIA and PCR data) in a high proportion (92%) of cases.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibodies, Viral↗
U-50,488H into A10 reduces haloperidol-induced elevations of accumbens dopamine.
Injections of kappa (k) opioid agonists into the A10 ventral tegmental area (VTA) induce behavioral inhibitions and decreased interest in incentive stimuli, behavioral changes indicative of decreased mesolimbic dopamine (DA) transmission. In seeming contrast, three separate laboratories have recently reported that intra-VTA injections of k agonists do not affect nucleus accumbens septi (NAS) basal levels of extracellular DA. In the present experiment, we investigated whether intra-VTA injections of a k agonist would decrease pharmacologically-stimulated increased levels of extracellular NAS DA. It was found that intra-VTA injections of the k agonist U-50,488H significantly attenuated haloperidol-induced elevations of DA, as measured by in vivo microdialysis.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Drinking context and other influences on the drinking of 15-year-old New Zealanders.
This study investigated the influence of the situational characteristics of the drinking setting and a number of parental, personal and demographic variables on adolescents' alcohol use. The sample were 15-year-old participants in a multidisciplinary longitudinal study carried out in New Zealand. Measures of alcohol consumption were self reported amount of alcohol consumed on the most recent drinking occasion and amount usually consumed. All of the situational variables investigated had an effect on the amount of alcohol consumed on the most recent occasion. Greater amounts of alcohol were consumed if the alcohol was obtained from peers or by the 15-year-olds themselves, if the drink was consumed away from their own home, in the presence of peers only, and during the evening. More money to spend each week and lower SES were also associated with reports of greater alcohol consumption on the most recent drinking occasion. Adolescents with female friends who approved of drinking reported greater amounts of alcohol, the effect of female friends was most marked in the lower amounts reported by males who had female friends that disapproved of drinking. For amount of alcohol usually consumed, reports of larger amounts of alcohol were associated with more money available to spend each week and with lower SES. Furthermore, both males and females reported greater usual amounts if their male friends approved of drinking; female friends' approval was associated with greater amounts of alcohol usually being consumed, this effect was strongest for males. Sixty-eight per cent of the 15-year-olds indicated that they thought they definitely or probably would get drunk in the future.
Adolescent↗
New Pathways of Phagocyte Activation. 4th Phagocyte Discussion Meeting. Edinburgh, United Kingdom, May 1992.
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Humans↗
Peripheral vascular disease in patients with systemic lupus erythematosus.
Patients with systemic lupus erythematosus may develop premature atherosclerosis, notably coronary artery disease. A group of 10 patients with peripheral vascular disease presenting with intermittent claudication or gangrene were studied from a group of 563 patients followed prospectively at the Wellesley Hospital Lupus Clinic. These 10 patients were compared with the next lupus clinic patient matched for age and sex, with respect to demographic characteristics and risk factors. The patients and controls did not differ significantly in lupus activity criteria count, partial thromboplastin time, the number with antibody to cardiolipin, number receiving steroids or mean steroid dose, family history of atherosclerosis, hyperlipidaemia, smoking, hypertension or use of oral contraceptives. The risk factors for developing peripheral vascular disease were a longer duration of systemic lupus erythematosus and a longer duration of use of steroids. Eight of the 10 patients had coexistent coronary artery disease or transient ischaemic attack.
Adult↗
Genetics and biology: a comment on the significance of the Elston-Stewart algorithm.
This article recounts the background to the development of the Elston-Stewart algorithm for the genetic analysis of pedigree data. The algorithm can be used in the context of two contrasting research programmes. The first approach is analytical and reductionist. Traditional biological disciplines, such as physiology, embryology and comparative biology, describe phenomenological domains in which biological organisms are treated as complex systems with emergent properties. In the reductionist approach, these biological domains are largely abandoned in favour of descriptions in the domain of the component elements of these systems, resulting in a concentration on molecular genetics as the central object of biological science. In the second approach, it is explicitly recognized that genes and molecules, per se, cannot be explanatory with respect to emergent systemic properties. However, since the genetic variation which occurs in natural populations can influence virtually every aspect and level of biological organization, from cell lineages to ecology, the study of such variation opens new possibilities for establishing meaningful articulations between the various biological disciplines. The author's expressed preference is for the second alternative.
Algorithms↗
Effect of radiation dose on the development of mixed haemopoietic chimerism following T cell-depleted allogeneic bone marrow transplantation.
The presence of mixed haemopoietic chimerism (MXC) was evaluated by cytogenetic and molecular analysis in 48 patients undergoing T cell-depleted BMT. The dose of total body irradiation (TBI) prescribed to all patients (14.4 Gy) was calculated to compensate for the absence of T cells in the graft. The actual midline dose of TBI received, however, differed significantly depending on the method of TBI administration. Thus, 35 adult patients received an average midline dose of 14.3 Gy, while 13 children received a lower dose of 13 Gy. The incidence of MXC in the adult group, who had received very close to 14.4 Gy to the midline, was 34% (12/35), which is lower than in most reported T cell-depleted series. During follow-up, chimerism remained relatively stable with time but varied between haemopoietic lineages. There was no relationship with relapse. MXC in the 13 children who had received a lower midline TBI dose was significantly higher at 69% (9/13) (p < 0.05) and increased to 90% (9/10) if patients who received additional chemotherapy in their conditioning were excluded (p = 0.001). This suggests that, in terms of marrow ablation, relatively small changes in the dose of TBI may be biologically significant, at least at this dose range. Again, in the lower TBI group MXC was not predictive of relapse.
Adolescent↗