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Biomedical subjects

J Shine

Publications and source records attributed to J Shine.

At least 19 recordsLinked to original sources
PubMed2003

Hyperalgesia and increased neuropathic pain-like response in mice lacking galanin receptor 1 receptors.

The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. The effect of galanin is mediated by at least three subtypes of receptors. In the present study, we assessed the nociceptive sensitivity in mice lacking the galanin receptor 1 gene (Galr1) and the development of neuropathic pain-like behaviours after photochemically induced partial sciatic nerve ischaemic injury. Under basal condition, Galr1 knock-out (Galr1(-/-)) mice had shortened response latency on the hot plate, but not tail flick and paw radiant heat, tests. The mechanical sensitivity was not different between Galr1(-/-) and wild type (Galr1(+/+)) mice, whereas the cold response was moderately enhanced in Galr1(-/-) mice. Both Galr1(-/-) mice and Galr1(+/+) controls developed mechanical and heat hypersensitivity after partial sciatic nerve injury. The duration of such pain-like behaviours was significantly increased in Galr1(-/-). The Galr1(-/-) mice and Galr1(+/+) mice did not differ in their recovery from deficits in toe-spread after sciatic nerve crush. The results provide some evidence for an inhibitory function for the neuropeptide galanin acting on galanin receptor 1 (GALR1) in nociception and neuropathic pain after peripheral nerve injury in mice.

Animals↗
PubMed2002

Molecular modelling and site-directed mutagenesis of human GALR1 galanin receptor defines determinants of receptor subtype specificity.

Human galanin is a 30 amino acid neuropeptide that elicits a range of biological activities by interaction with G protein-coupled receptors. We have generated a model of the human GALR1 galanin receptor subtype (hGALR1) based on the alpha carbon maps of frog rhodopsin and investigated the significance of potential contact residues suggested by the model using site-directed mutagenesis. Mutation of Phe186 within the second extracellular loop to Ala resulted in a 6-fold decrease in affinity for galanin, representing a change in free energy consistent with hydrophobic interaction. Our model suggests interaction between Phe186 of hGALR1 and Ala7 or Leu11 of galanin. Receptor subtype specificity was investigated by replacement of residues in hGALR1 with the corresponding residues in hGALR2 and use of the hGALR2-specific ligands hGalanin(2-30) and [D-Trp2]hGalanin(1-30). The His267Ile mutant receptor exhibited a pharmacological profile corresponding to that of hGALR1, suggesting that His267 is not involved in a receptor-ligand interaction. The mutation Phe115Ala resulted in a decreased binding affinity for hGalanin and for hGALR2-specific analogues, indicating Phe115 to be of structural importance to the ligand binding pocket of hGALR1 but not involved in direct ligand interaction. Analysis of Glu271Trp suggested that Glu271 of hGALR1 interacts with the N-terminus of galanin and that the Trp residue in the corresponding position in hGALR2 is involved in receptor subtype specificity of binding. Our model supports previous reports of Phe282 of hGALR1 interacting with Trp2 of galanin and His264 of hGALR1 interacting with Tyr9 of galanin.

Amino Acid Substitution↗
PubMed2000

Institutional behaviour and time in treatment among psychopaths admitted to a prison-based therapeutic community.

Previous research has indicated that psychopathy is associated with high levels of institutional misconduct and high attrition rates in therapeutic communities. However, most of this work has been conducted with North American populations. In the present study, data is presented on institutional behaviour and time in therapy for 104 inmates admitted to Grendon Therapeutic Prison. The results indicated that high scores on the Hare Psychopathy Checklist Revised were significantly associated with failure to progress from the assessment unit onto a therapy wing and the number of adjudications and security information reports. A trend was found for psychopathy to be associated with shorter periods in therapy, but this just failed to reach significance. The results confirm previous research on the association between psychopathy and institutional misconduct and provide some support for the association between psychopathy and early termination of treatment in therapeutic communities. A number of methodological issues are discussed.

Antisocial Personality Disorder↗
PubMed2000

Personality disorders and the interpersonal octagon.

The interpersonal octagon is a theoretical structure, similar to the interpersonal circle, within which a person's relating tendencies can be defined. It is constructed around a horizontal axis, concerning relating either closely or distantly, and a vertical one, concerning relating either downwardly or upwardly. The Person's Relating to Others Questionnaire--Revised Version (PROQ2) was designed to measure relating within the octagon. To test the validity of the proposed location of the 10 DSM-IV personality disorders within the octagon, the PROQ2 was administered, together with the DSM-IV version of the Personality Diagnostic Questionnaire (PDQ-IV), to a series of 107 men admitted to a therapeutic prison. The mean PROQ2 scores of the prisoners fell mid-way between those of male students and psychotherapy patients. High intercorrelations were found between the scale scores of both the PROQ2 and the PDQ, and there was a high correlation between total scores of the two instruments. All disorders were highly correlated with the lower close scale of the PROQ2. The locations of some disorders corresponded well with the pre-study predictions, and those of others came close. Those of a few came far from what was predicted, and some explanations for this are offered.

Adult↗
PubMed1999

Conservation of expression of neuropeptide Y5 receptor between human and rat hypothalamus and limbic regions suggests an integral role in central neuroendocrine control.

Neuropeptide Y receptors belong to the G-protein-coupled receptor superfamily and mediate a wide variety of physiological functions, including blood pressure regulation, hormone release, appetite control, seizure propensity, cognition, and emotion. The recent description of a new neuropeptide Y receptor, Y5, expressed in hypothalamic nuclei in rat brain, raised the possibility that Y5 was the receptor mediating the feeding and appetite-related functions of neuropeptide Y. This was supported by subsequent data showing a downregulation of this "feeding" receptor in the brain of the obese Zucker rat (Widdowson, 1997). We have performed a detailed analysis of Y5 expression in rat brain using in situ hybridization histochemistry with digoxygenin-labeled riboprobes and compared this to expression of Y5 in human brain regions. mRNA for the human Y5 receptor was highly expressed in human hypothalamic and thalamic nuclei. In particular, the arcuate and paraventricular nuclei of the hypothalamus, midline thalamic nuclei, and amygdala showed very high levels of expression with high levels in hippocampus. The striking conservation of expression of the rat and human Y5 receptors in relevant hypothalamic and other nuclei implies sharing of a major neuroendocrine functional role by this receptor.

Animals↗
PubMed1999

Galanin and galanin receptors.

The development of a strain of galanin knockout mice has provided confirmation of a neuroendocrine role for galanin, as well as supporting results of previous physiological investigations indicating a role for galanin in analgesia and neuropathic pain, and potentially in neuronal growth and regeneration processes. Whether elevation of galanin expression in neurodegenerative disorders such as Alzheimer's disease represents a survival response or exacerbates functional deficit in afflicted individuals remains to be determined. More detailed analysis of the phenotype of the galanin knockout mouse should provide insights into the physiological role of galanin in memory and learning processes, as well as in hypothalamic function and other aspects of neuroendocrine regulation. Biochemical and molecular cloning efforts have demonstrated that the multiplicity of actions of galanin is matched by complexity in the distribution and regulation of galanin and its receptors. A focus on characterisation of galanin receptors has resulted in the molecular cloning of three receptor subtypes to date. The distribution and functional properties of these receptors have not yet been fully elucidated, currently precluding assignment of discrete functions of galanin to any one receptor subtype. It is not currently possible to reconcile available pharmacological data using analogs of galanin and chimeric peptides in functional assay systems with the pharmacological properties of cloned receptor subtypes. This highlights the value of further knockout approaches targeting galanin receptor subtypes, but also raises the possibility of the existence of additional receptor subtypes that have yet to be cloned, or that receptor activity may be modulated by regulatory molecules that remain to be identified. The development of receptor subtype-specific compounds remains a high priority to advance work in this area. The ability to selectively modulate the many different actions of galanin, through a clearer understanding of receptor structure-function relationships and neuronal distribution, promises to provide important insights into the molecular and cellular basis of galanin action in normal physiology, and may provide lead compounds with therapeutic application in the prevention and treatment of a range of disorders.

Amino Acid Sequence↗
PubMed1998

Structural organization and chromosomal localization of three human galanin receptor genes.

Human galanin receptor subtypes GALR1, GALR2, and GALR3 are encoded by separate genes that are located on human chromosomes 18q23, 17q25.3, and 22q13.1, respectively. The exon:intron organization of the gene encoding GALR2 (GALNR2) and GALR3 (GALNR3) is conserved, with exon 1 encoding the NH2-terminus to the end of transmembrane domain 3 and exon 2 encoding the remainder of the receptor, from the second intracellular loop to the COOH-terminus. This conservation of structural organization is indicative of a common evolutionary origin for GALNR2 and GALNR3. The exon:intron organization of the gene encoding GALR1 (GALNR1) is different from that of GALNR2 and GALNR3, with exon 1 encoding the NH2-terminus to the end of transmembrane domain 5, exon 2 encoding the third intracellular loop, and exon 3 encoding the remainder of the receptor, from transmembrane domain 6 to the COOH-terminus. The structural organization of GALNR1 suggests convergent evolution for this gene and represents a structural organization that is unique among genes encoding G-protein-coupled receptors.

Amino Acid Sequence↗
PubMed1998

Distribution and characterization of the cell types expressing GALR2 mRNA in brain and pituitary gland.

The neuropeptide galanin mediates its activities through G-protein-coupled receptors, and three receptor subtypes have been described with distinctly different patterns of regional tissue expression. GALR1 is predominantly expressed in basal forebrain, hypothalamus, as well as spinal cord. GALR2 has a wider distribution in brain and is also present in the pituitary gland and peripheral tissues. GALR3 has been found to be widely distributed at low abundance. We examined the distribution of GALR2 in rat brain and pituitary by in situ hybridization histochemistry and found it abundant in regions of hippocampus, piriform and entorhinal cortex, basal nucleus of the accessory olfactory tract, amygdala, hypothalamic nuclei, Purkinje cells, and discrete brainstem nuclei. It is also highly expressed in the intermediate and anterior lobes of the pituitary. Using combined in situ hybridization immunohistochemistry we characterized the neurotransmitter and hormonal phenotype of cells expressing GALR2 mRNA in the hypothalamus and pituitary gland. Our findings suggest GALR2 is a receptor mediating important functions of galanin in the hypothalamic-pituitary axis and may also play a role in hippocampal and cerebellar function.

Animals↗
PubMed1998

Amplification, expression, and steroid regulation of the preprogalanin gene in human breast cancer.

The GALN gene encodes the preprogalanin protein that is cleaved to liberate the galanin peptide, a neuropeptide and tumor cell mitogen, and the galanin message-associated peptide, which is of unknown function. GALN is located at chromosome 11q13, a frequently amplified locus in diverse tumor types including breast cancer. To determine whether GALN may contribute to the tumor phenotype resulting from 11q13 amplification, we examined GALN amplification and preprogalanin mRNA levels in breast tumors and cell lines. GALN was amplified in a subset of breast tumors and cell lines that carried 11q13 amplifications. Preprogalanin mRNA was expressed in the majority of breast cancer cell lines, but Northern analysis failed to demonstrate a relationship between GALN amplification and preprogalanin mRNA levels. Eight of eight estrogen receptor-positive cell lines expressed detectable preprogalanin mRNA, and further investigation showed that preprogalanin mRNA was increased by treatment with estradiol and progestin and decreased by the removal of serum or treatment with antiestrogens. Thus, GALN amplification is unlikely to contribute to the phenotype conferred by 11q13 amplification in breast cancer, but preprogalanin mRNA is expressed by breast cancer cells and is under steroid hormone control in estrogen receptor-positive cells, opening the wider question of the role of this steroid-regulated neuropeptide in the normal and cancerous breast.

Blotting, Northern↗
PubMed1998

Ligament force and joint motion in the intact ankle: a cadaveric study.

The aims of this study were to measure the forces in the anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) and the motion in the tibiotalar and subtalar joints during simulated weight-bearing in eight cadaver ankle specimens. An MTS test machine was used to apply compressive loads to specimens held in a specially designed testing apparatus in which the ankle position (dorsiflexion-plantarflexion and supination-pronation) could be varied in a controlled manner. The forces in the ATFL and CFL were measured with buckle transducers. Tibiotalar motion and total ankle joint motion were measured with an instrumented spatial linkage. The specimens were positioned sequentially at 10 degrees dorsiflexion, neutral, and 10 degrees and 20 degrees plantarflexion, and this sequence was repeated at 15 degrees supination, neutral pronation/supination, and 15 degrees pronation. Force and motion measurements were recorded in each of these positions with and without a 375 N compressive load simulating weight-bearing. From 10 degrees dorsiflexion to 20 degrees plantarflexion, all motion occurred in the tibiotalar joint. In contrast, the ratio of subtalar motion to tibiotalar motion was 3:1 for supination-pronation and 4:1 for internal-external rotation. Inverse loading patterns were observed for the ATFL and CFL from plantarflexion to dorsiflexion. Compressive loading did not affect CFL tension, but it magnified the pattern of increasing ATFL tension with plantarflexion. The largest increase in ATFL force was observed in supination and plantarflexion with a compressive load (76 +/- 23 N), whereas CFL tension mainly increased in supination and dorsiflexion with a compressive load (109 +/- 28 N). In conclusion, the results showed that the ATFL acted as a primary restraint in inversion, where injuries typically occur (combined plantarflexion, supination and internal rotation). Also, the subtalar joint was of primary importance for normal supination-pronation and internal-external rotation.

Adult↗
PubMed1998

Interactions between metals and microbial communities in New Bedford Harbor, Massachusetts.

The fate of toxic metals in marine sediments depends on a combination of the physical, chemical, and biologic conditions encountered in any given environment. These conditions may vary dramatically, both spatially and temporally, in response to factors ranging from seasonal changes and storm events to human activities such as dredging or remediation efforts. This paper describes a program designed to evaluate the interrelationships between the microbial community and pollutants in the New Bedford Harbor, Massachusetts, area, a U.S. Environmental Protection Agency designated Superfund site. Research has focused on establishing distributional relationships between contaminant metals, fluxes of metals between sediments and the overlying water, changes in microbial diversity in response to metals, and potential use of the microbial community as a biomarker of contaminant availability. This research has shown that a significant flux of metals to the water column is mediated by benthic biologic activity, and that microbial communities may be a responsive marker of contaminant stress. A combination of biogeochemical studies and the use of molecular tools can be used to improve our understanding of the fate and effect of heavy metals released to aquatic systems.

Animals↗