Biomedical subjects

J R Martin

Publications and source records attributed to J R Martin.

At least 73 records · Page 4Linked to original sources

PubMed1995

The sensitive individual and the indoor environment: case study.

This case study describes an indoor environment investigation initiated in response to numerous health and comfort complaints suspected of being associated with a two-story office building. Conventional indoor environment investigation techniques were applied in an attempt to identify one or several contributing factors, such as inadequate outdoor air ventilation and the presence of a respiratory irritant. The air quality satisfaction percentage in the building was well above 80%; however, at least one individual was experiencing a fairly severe reaction only upon entering the subject building. Evaluating the building indoor conditions as acceptable without attempting to address all possible building-related causes and communicating findings to interested occupants would likely have resulted in more occupant complaints and increased the potential for hysteria conditions. This investigation necessarily addressed a sensitive individual and involved an occupational physician as a constructive participant in the investigation.

Air Pollutants↗

PubMed1995

Familial hypertryptophanemia in two siblings.

Mild and moderate mental retardation with exaggerated affective responses, periodic mood swings, and apparent hypersexual behavior were present in two siblings with hypertryptophanemia and tryptophanuria. In addition, the male had severe myopia, a speech impediment, musculoskeletal abnormalities and perceptual hypersensitivity. His sister was deaf, which was ascribed to antenatal rubella. The occurrence in siblings and the presence of abnormal urinary tryptophan metabolite in the mother and a half-sibling suggest that the condition results from an autosomal recessive gene with minor expression in some heterozygotes.

Adult↗

PubMed1995

Targeting and gene expression in spinal cord motor neurons following intramuscular inoculation of an HSV-1 vector.

One problem in devising strategies of gene transfer to the nervous system is targeting specific neuronal populations. To evaluate the potential for using herpes simplex virus (HSV) as a vector for gene transfer to spinal cord motor neurons, the HSV-1 mutant LAT-LTR in which the E. coli beta-galactosidase gene is expressed under control of the HSV LAT core promoter (LAT) and the Moloney murine leukemia virus long terminal repeat (LTR) was inoculated unilaterally into the gastrocnemius muscle. Infectious virus was isolated from the spinal cord on days 3-7 post inoculation (PI). Immunocytochemical labeling of HSV antigen was detected in ipsilateral ventral horn neurons in the spinal cord at day 3 PI and had spread to contiguous spinal cord regions by day 6 PI. No viral antigen was detected at 14 or 28 DPI. beta-galactosidase expression (driven by the LAT-LTR promoter) was detected in neurons of the ventral horn on days 3, 6, 14, and 28 PI. Histological analysis showed mild lesions in the ventral horn on day 3 PI which progressed through days 6, 14 and 28 PI. This study demonstrates the feasibility of gene delivery into spinal motor neurons after injection of an HSV vector at a peripheral muscular site. This approach should prove useful in neurobiological investigations and it suggests a possible application to development of gene therapy for heritable diseases affecting motor neurons.

Animals↗

PubMed1995

Comparison of benzodiazepine receptor ligands with partial agonistic, antagonistic or partial inverse agonistic properties in precipitating withdrawal in squirrel monkeys.

Benzodiazepine receptor (BZR) ligands previously characterized as differing in intrinsic efficacy were evaluated first for potency in antagonizing flunitrazepam-induced sleep in monkeys. Data from these experiments were used to define approximately equieffective doses for subsequent use in precipitating withdrawal in diazepam-treated monkeys. It was shown that partial agonists with intermediate intrinsic efficacy (bretazenil, Ro 41-7812) were relatively ineffective in precipitating withdrawal reactions in diazepam-treated squirrel monkeys. The potent and specific BZR antagonist flumazenil, which possesses weak intrinsic efficacy, was more effective in precipitating a withdrawal reaction in diazepam-treated monkeys. In contrast, the highest dose of the BZR antagonist ZK 93426 that could be administered failed to precipitate withdrawal under the same experimental conditions. Finally, the BZR partial inverse agonist sarmazenil was the most effective of these BZR ligands in eliciting a precipitated withdrawal reaction. Thus, the results of the present investigation strongly suggest that BZR ligands differing in intrinsic efficacy differentially precipitate withdrawal in squirrel monkeys treated chronically with diazepam.

Animals↗

PubMed1994

Structural characterisation of human stefin A in solution and implications for binding to cysteine proteinases.

Stefin A is a member of the cystatin superfamily of proteins which are tight and reversibly binding inhibitors of the papain-like cysteine proteinases. The 1H-NMR and 15N-NMR resonances of human stefin A have been sequentially assigned using two-dimensional homonuclear and heteronuclear NMR techniques in conjunction with three-dimensional heteronuclear methods. Characteristic sequential and medium range NOE contacts, J constants and hydrogen exchange data have been used to identify the secondary structural elements of the protein which consists of five anti-parallel beta-strands and a single alpha-helix. There is much similarity between the secondary structural features of stefin A and the homologous protein stefin B in its complex with papain [Stubbs, M. T., Laber, B., Bode, W., Huber, R., Jerala, R., Lenarcic, B. & Turk, V. (1990) EMBO. J. 9. 1939-1947] but also some important differences in regions which are fundamental to the binding event. The principal difference is the presence of two conformationally unrestricted regions in stefin A that form two of the components of the tripartite wedge which docks into the active site of the target proteinase. Specifically, these regions are the five N-terminal residues and the second binding loop, which form a turn and a short helix respectively, in the bound conformation of stefin B.

Amino Acid Sequence↗

PubMed1994

Terminal pattern elements in Drosophila embryo induced by the torso-like protein.

The genes torso (tor) and torso-like (tsl) are two of the Drosophila maternal group genes implicated in a receptor tyrosine kinase signalling pathway that specifies terminal cell fate (reviewed in ref. 3). Loss-of-function mutations in these loci cause an identical phenotype in which pattern elements from the anterior (acron) and posterior (telson) ends have been deleted. We have cloned the tsl gene and demonstrate here that, in agreement with previous genetic data, it encodes a protein that is secreted and whose transcription is restricted to specialized categories of follicle cells localized at the poles of the egg chamber. At early blastoderm stage, tsl protein forms a symmetrical concentration gradient at the poles on the surface of the devitellinized embryo. Unrestricted expression of the tsl protein in tsl female mutants induces terminal pattern elements and suppresses the formation of abdomen in embryos. These results suggest that the tsl protein is the ligand that binds to the torso receptor.

Amino Acid Sequence↗

PubMed1994

Investigating the genetic basis for ankylosing spondylitis. Linkage studies with the major histocompatibility complex region.

OBJECTIVE: To assess the hypothesis that B27 or a gene(s) in close proximity (e.g., within or near the major histocompatibility complex [MHC]) represents a disease-causing ankylosing spondylitis (AS) gene, and therefore contributes directly to the pathogenesis of this disorder. METHODS: MHC haplotypes were determined by both serologic and molecular analyses in 15 multiple-case AS families from Toronto and Newfoundland. Segregation of MHC haplotypes with AS within these families was examined by linkage and identity-by-descent analyses. Attributable risk estimates for various genetic markers and for sex were calculated. RESULTS: Linkage analyses established significant linkage between AS and the MHC, the maximal logarithm of odds (LOD) score being 3.48 at a recombination frequency (O) of 0.05. In a second analysis in which the population association of the MHC gene HLA-B27 with AS was taken into account, the maximal LOD score was 7.5 at O = 0.05. Identity-by-descent analyses showed a significant departure from random segregation among affected avuncular (P < 0.05) and cousin (P < 0.01) pairs. The presence of HLA-B40 in HLA-B27 positive individuals increased the risk for disease more than 3-fold, confirming previous reports. Disease susceptibility modeling suggested an autosomal dominant pattern of inheritance, with penetrance of approximately 20%. CONCLUSION: These data provide the first conclusive demonstration of linkage between the MHC region and AS, and confirm that genes within this region contribute directly to the genetic susceptibility for AS.

Adolescent↗

PubMed1994

Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents.

This study investigated behavioural effects of very potent 5-HT reuptake inhibitors after acute treatment (cianopramine and citalopram), as well as after chronic treatment (cianopramine), in two behavioural models of anxiety: 1) the light/dark choice procedure in mice and 2) the elevated plus-maze test in rats. In addition, the responses of mice to novelty in a free exploration paradigm were assessed after acute administration of both drugs. A single injection of cianopramine or citalopram increased neophobic reactions in the free exploration test. Furthermore, these drugs increased the avoidance reaction to a brightly illuminated chamber in the light/dark choice procedure as well as to open arms in the elevated plus-maze test. In contrast, after chronic treatment (10 mg/kg IP, once daily for 21 days) of cianopramine, anxiogenic-like effects were no longer produced in the light/dark choice paradigm whereas in the elevated plus-maze test, anxiolytic-like effects appeared. These results shed more light on the 5-HT hypothesis of anxiety, insofar as the increased availability of 5-HT resulting here from reuptake inhibition seems to initially result in an increased emotional reactivity which, however, subsequently disappears during chronic treatment.

Animals↗

PubMed1994

In situ polymerase chain reaction: localization of HSV-2 DNA sequences in infections of the nervous system.

To detect and localize a herpes simplex virus type 2 (HSV-2) thymidine kinase gene sequence in paraffin sections of brains and trigeminal ganglia of infected mice, an in situ polymerase chain reaction (ISPCR) protocol was developed. Using a single pair of primers, a 110 base pair DNA target sequence, and incorporation of a digoxigenin-labelled nucleotide during amplification, this procedure permitted rapid, specific, reproducible detection of infected cells. During acute brain infection, cells labelled by ISPCR were in the same infected foci that, in adjacent sections, contained viral antigen. This, together with controls, gave evidence of method specificity. In mice surviving acute infection, latently infected cells were labelled by ISPCR. In brains, focal areas contained labelled cell nuclei, and in trigeminal ganglia, neuronal nuclei were likewise labelled. Latent infection was confirmed by several methods, including identification of an HSV-specific sequence in DNA extracts of brains and ganglia, virus isolation from explanted ganglia, and HSV-2 latency-associated transcript (LAT) RNA localization in ganglionic neurons by in situ hybridization. Evidence in brains of ISPCR-labelled cells in regions where HSV-2 LAT-positive cells were not detected, and in ganglia of more ISPCR-labelled neurons than were LAT-positive, indicated that ISPCR is more sensitive in detecting latently infected cells than previous methods.

Acute Disease↗

PubMed1994

Brain 5-HT1C receptors and antidepressants.

A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HT1C receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine, oxaprotiline) and two atypical antidepressants (mianserin and trazodone) were found to display affinity for 5-HT1C receptors in the nanomolar range. Antidepressants of other chemical classes and mechanisms of action (serotonin uptake inhibitors: fluoxetine, citalopram, sertraline, fluvoxamine; noradrenaline-dopamine uptake inhibitors: nomifensine, bupropion, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had affinities in the micromolar range for 5-HT1C receptors, except fluoxetine. When tested in an in vivo functional model revealing agonistic or antagonistic properties at 5-HT1C receptors, all antidepressants displaying high affinity for this receptor type (except fluoxetine, clomipramine, trimipramine and oxaprotiline) were antagonists at 5-HT1C receptors. Antidepressants with lower 5-HT1C receptor affinity (except nomifensine) were inactive in this functional in vivo model. Antagonism at brain 5-HT1C receptors is a component of the antiserotonergic properties of a number of established antidepressants, especially of the tricyclic class.

Animals↗

PubMed1994

HSV-2 DNA persistence in astrocytes of the trigeminal root entry zone: double labeling by in situ PCR and immunohistochemistry.

A previous study using an in situ polymerase chain reaction (PCR) amplification method showed persistent herpes simplex virus type 2 (HSV-2) DNA sequences in brains of experimentally infected mice, particularly in cells of the pons near the trigeminal root entry zone. The present study was undertaken to identify the CNS cell type(s) that persistently harbor HSV DNA and to define the associated pathology. Tissue sections including the trigeminal root were immunoreacted to detect cellular antigens, then an HSV sequence was amplified in situ. During acute infection, the CNS portion of the trigeminal root was focally demyelinated and contained viral antigen and HSV DNA in glial cells. Following acute infection, no infectious virus of HSV antigen was detected. Demyelinated root lesions contained cells whose nuclei were similar in size to those of astrocytes and contained HSV-2 DNA by in situ PCR. With double labeling techniques, HSV DNA-containing nuclei were often associated with glial fibrillary acidic protein immunoreactivity, but not with that of neuron-specific enolase and only rarely with galactocerebroside or transferrin immunostaining. Thus, at least some of the cells containing persistent HSV DNA are astrocytes. Since HSV DNA is detected when no infectious virus can be isolated and no HSV antigen is found, we conclude that this astrocytic infection is non-productive. While in situ hybridization methods show HSV latency-associated transcript (LAT) RNA in neuronal nuclei during latent infections in trigeminal ganglia and, occasionally, in brain, we were unable to detect HSV-2 LAT RNA in astrocytes in these lesions, which suggests that persistent HSV infection of astrocytes may differ from neuronal latency.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

In situ PCR localization of herpes simplex virus DNA sequences in disseminated neonatal herpes encephalitis.

To more precisely define the role of herpes simplex virus (HSV) in development of nervous system disease in neonates with disseminated infection, an in situ polymerase chain reaction (ISPCR) method was used to detect and localize HSV DNA sequences in paraffin sections of neural and non-neural autopsy tissues. In subregions of adjacent sections corresponding to ISPCR-labeled and unlabeled areas, HSV specificity was verified using solution PCR and Southern blots. In serial sections, ISPCR results were compared to lesions, HSV antigen and, in selected samples, to viral sequence detection by in situ hybridization. By ISPCR, HSV-specific labeling was limited to HSV-infected neonates and experimentally infected mouse controls. ISPCR-labeled cells corresponded to regions that were histologically abnormal and contained HSV antigen or in situ hybridization signal in some foci; in others, labeled cells were in areas with no evident lesions or antigen. Results suggest two routes of HSV spread to the CNS: (i) blood-borne infection, with HSV DNA in splenic lymphocytes, circulating cells, meningeal vessel walls and cells in intraventricular hemorrhage, and (ii) neural spread, with HSV detected in brain stem sensory neurons. In the brain of one neonate surviving acute infection, detection of HSV nucleic acid sequences suggests a latent or persistent viral genome. With other methods, this highly sensitive ISPCR technique permits a more complete definition of HSV infection in these infants and provides new insights into disease mechanisms. Fuller understanding of HSV persistence and recurrent neurological disease in survivors will require further studies using these and other techniques in human tissues and in animal models.

Animals↗

PubMed1994

Herpes simplex virus type 1 DNA persistence, progressive disease and transgenic immediate early gene promoter activity in chronic corneal infections in mice.

We have used a mouse model system and the corneal route of inoculation to examine the issue of extra-neuronal persistence of herpes simplex virus type 1 (HSV-1). HSV-1 strain F DNA and inflammatory lesions were detected in corneal tissue of mice at 5, 11, 23, 37 and 60 days post-infection (p.i.) Viral DNA was localized by in situ PCR to epithelial cells and less frequently to cells in the stroma of the cornea. Viral proteins were not detected in the cornea and virus could not be isolated from tissue homogenates after 11 days p.i. even though histopathological lesions became progressively more severe at 37 and 60 days p.i. The DNA-containing cells were usually adjacent to the sites of inflammation or within these sites in the chronic stage (23, 37 and 60 days p.i.). In contrast to strain F, persistence of HSV-1 strain KOS DNA and inflammatory lesions were not detected after 11 days p.i.; this result suggests that the long-term persistence of HSV-1 DNA and the development of inflammatory lesions are virus strain-dependent. We tested for the possibility of transgenic HSV-1 immediate early gene (ICP4) promoter activity in chronically infected corneas of transgenic mice containing the ICP4 promoter fused to the bacterial beta-galactosidase coding sequence. Our results indicated that the chimeric transgene was expressed in the cornea at 5, 11, 23, 37 and 41 days p.i. Possible explanations for these results and mechanisms for the generation of the chronic inflammatory lesions are discussed. The properties of chronic HSV infections in the cornea may be similar to those which have been described for persistent or defective viral infections in other systems.

Animals↗

PubMed1994

Curative effects of the atypical antidepressant mianserin in the chronic mild stress-induced anhedonia model of depression.

This study was designed to validate a novel animal model of depression by testing the curative effects of the atypical antidepressant mianserin. In this paradigm, the hedonic state of rats was assessed using an intracranial self-stimulation (ICSS) procedure. The ICSS threshold was determined before, during and after a 38-day period of exposure to a variety of intermittent, unpredictable, mild stressors. After 11 days of this regimen, the ICSS threshold was significantly higher in the stressed rats, suggesting a gradual decrease of sensitivity to reward. This "anhedonia" lasted throughout the stress regimen and progressively diminished over a 20-day period after stress was terminated. When stressed animals exhibiting anhedonia were treated with mianserin, the stress-induced increase in the ICSS threshold was gradually reversed over ten days of treatment. These results provide further support for the value of this anhedonia paradigm in modelling an important aspect of human depressive disorders.

Animals↗

PubMed1993

Involvement of amyloid precursor protein in memory formation in the rat: an indirect antibody approach.

The potential role of different isoforms of amyloid precursor proteins (APPs) in memory and learning processes was investigated in rats using antibodies differentiating between APP isoforms containing or lacking the Kunitz protease inhibitor (KPI) domain. Rats received intracerebroventricular injection of control immunoglobulins (IgGs), anti-KPI-APP (= anti-P3) or anti-N-terminus-APP (= anti-P4). No immediate effects on learning of a passive avoidance task were observed; however, performance evaluated 1 day later was somewhat impaired by the anti-P3 antibody (reacting with APPKPI) and even more markedly impaired by the anti-P4 antibody (reacting with both APP695 and APPKPI) relative to control antibody. The antibodies did not affect performance of an active avoidance task acquired prior to the experimental treatment or active avoidance learning 8 days post-treatment. These results suggest that blockade of APP by an antibody injected intracerebroventricularly impairs the consolidation and/or retrieval of memory in rats.

Amyloid beta-Protein Precursor↗

PubMed1993

Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs.

A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HT1C receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine) as well as mianserin and trazodone were found to display high to low nanomolar affinity for 5-HT1C receptors. Antidepressants of other chemical classes and with other mechanisms of action (affecting amine uptake systems: fluoxetine, citalopram, sertraline, fluvoxamine, nomifensine, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had negligible affinities (micromolar range) for 5-HT1C receptors, except fluoxetine. When tested in an in vivo rat model thought to reveal functional agonistic or antagonistic properties at 5-HT1C receptors, all antidepressants displaying high affinity for this receptor type (except clomipramine and trimipramine) were antagonists at 5-HT1C receptors. Antidepressants with a lower affinity for 5-HT1C receptors (except nomifensine) were inactive in this functional in vivo model. Taken together, these results suggest that antagonism at brain 5-HT1C receptors is a component of the antiserotonergic properties of a number of established antidepressants. In addition, the study confirmed that 5-HT1A receptors functionally interact with 5-HT1C receptors, which suggests that some degree of activity at 5-HT1A receptors may also be an important property for antidepressant activity.

Animals↗

PubMed1993

Neural antigen detection in mouse tissues is not impaired by decalcification.

We examined whether EDTA decalcification decreases the sensitivity of antigen detection of formalin-fixed paraffin-embedded neural tissues. In undissected decalcified tissues, the immunoreactivities of select neural antigens were quantitatively compared with those in dissected sensory ganglia. Decalcification does not reduce either the numbers or staining intensities of antigen-positive neural cells. Tissues are well preserved and complex anatomical relationships are maintained.

Animals↗

PubMed1993

Effects of repeated mild stress and two antidepressant treatments on the behavioral response to 5HT1C receptor activation in rats.

This study investigated the possible involvement of 5HT1C receptors in the development of depressive states and in the mode of action of antidepressants. The effects of repeated unpredictable mild stress (a regimen known to induce an anhedonic state in the rat) and of chronic administration of either of two recognized antidepressant treatments (sleep deprivation or inhibition of monoamine oxidase type A) in rats were studied on a 5HT1C receptor initiated response, i.e. mCPP-induced penile erection. A 3-week period of repeated, but unpredictable exposure to mild stressors induced a shift to the left of the dose-response curve for mCPP-induced penile erection. In contrast, 72-h REM sleep deprivation resulted in a shift to the right of the mCPP dose-response curve and 10-day administration of the monoamine oxidase type A inhibitor moclobemide (20 mg/kg IP bid) also resulted in a decreased number of mCPP-induced penile erections. These findings support the hypothesis that neuronal activities initiated via 5HT1C receptor stimulation may play a role in the pathophysiology and treatment of depression.

Animals↗