Biomedical subjects

X M Gao

Publications and source records attributed to X M Gao.

At least 19 recordsLinked to original sources

PubMed2005

T cell vaccination in systemic lupus erythematosus with autologous activated T cells.

Systemic lupus erythematosus (SLE) is an autoreactive T cell mediated autoimmune disease. Immunization with inactivated autoreactive T cells may induce idiotype anti-idiotypic reaction to deplete specific subsets of autoreactive T cells involved in SLE. Six SLE patients unsuitable or refused to use immunosuppressants were treated with T cell vaccination. Their clinical manifestations and laboratory parameters including mixed lymphocyte reactions were evaluated. Autoreactive T cell clones were derived from peripheral blood mononuclear cells of the patients and 1 X 10(7) irradiated T cells were inoculated subcutaneously at 0, two, six and eight weeks, respectively. The enrolled patients were followed up for 32-40 months at an interval of three to six months. The clinical characteristics and laboratory abnormalities improved after inoculation without increasing the dose of corticosteroids and immunosuppressants in most patients. SLE disease activity index (SLEDAI) scores decreased. Proliferative responses against the T cell vaccine were observed in four of six patients. At the time of this report, the six patients remain in clinical remission. No significant side effect from the vaccination was noticed during the follow-up period. The results of this pilot study indicate that T cell vaccination is a safe and effective treatment in SLE.

Adolescent↗

PubMed2001

Scopolamine fails to diminish chronic haloperidol-induced purposeless chewing in rats.

Chronic haloperidol treatment for 4-12 months gradually induces spontaneous, irregular, purposeless oral chewing movements (CMs), apparently involuntary, in some but not all treated rats. Based on phenomenologic and pharmacologic similarities, this laboratory preparation has been used as an animal model of tardive dyskinesia (TD), which is the human hyperkinetic motor syndrome associated with chronic antipsychotic administration. This putative animal model has received the most severe challenge to its validity by claims that its oral movements can be suppressed by anticholinergic treatments, since resistance to anticholinergic suppression is an accepted pharmacologic feature of TD. In this experiment, we challenged a group of haloperidol-treated rats with CMs using three doses of scopolamine (0.1, 0.3, 1.0 mg/kg) and placebo and rated the change in dyskinetic movements. Each scopolamine dose reduced CMs by a similar magnitude, without any dose effect; the saline dose also reduced CMs to an equivalent degree. Therefore, we concluded that some component of the experiment, not the scopolamine, reduced the CMs. The handling component of the procedure was identified as a likely confound, and we tested this further. Rats with CMs were handled at several levels of "severity"; and the dyskinesias were rated at 1 and 3 h later. CMs were reduced by the experimental handling, in relation to the strength of the handling. Minimal handling produced modest CM reductions with quick recovery; whereas, the "strongest" handling plus the placebo injection produced the greatest CM reduction, evident over 3 h, resembling the CM reductions seen in the scopolamine and placebo experiment. Overall, these results suggest that anticholinergic drugs do not suppress chronic haloperidol-induced rat CMs. However, the movements are sensitive to stressful handling situations, and diminish with stress. In both of these characteristics, rat CMs resemble human TD, further supporting a role for this model in studies of human TD.

Animals↗

PubMed2001

Traditional and new antipsychotic drugs differentially alter neurotransmission markers in basal ganglia-thalamocortical neural pathways.

The effects of three chronically administered antipsychotic drugs on selected neurochemical markers of dopaminergic and GABAergic transmission were compared within the cerebral regions making up the basal ganglia-thalamocortical parallel processing neuronal pathways. All three drugs reduce psychosis in humans, whereas only haloperidol, but not olanzapine or sertindole, induce purposeless oral chewing movements (CMs) in rats or cause high rates of parkinsonism or tardive dyskinesia in humans. Male Sprague Dawley rats were treated with haloperidol, sertindole, or olanzapine delivered in drinking water for 6 months at doses which produce drug plasma levels in rat in the human therapeutic range. Results show the expected dopamine D2 receptor upregulation in striatum predominantly with haloperidol, although mild D2 upregulation was apparent in striatum after olanzapine. GAD67 mRNA was increased in striatum and decreased in globus pallidus by haloperidol and sertindole, but not by olanzapine. In the substantia nigra pars reticulata (SNR), both olanzapine and sertindole failed to induce GABA(A) receptor upregulation or D1 receptor downregulation, but haloperidol did both, confirming a previous report. In thalamus, all three drugs increased GAD expression in the reticular nucleus, whereas only haloperidol decreased GABA(A) binding in the mediodorsal nucleus, actions consistent with a reduction in nigrothalamic, GABA-mediated neural transmission. These results are consistent with the idea that the two new antipsychotics tested have mild and regionally restricted actions within the basal ganglia nuclei and a common action on increasing GAD expression in the reticular nucleus of the thalamus (RtN). Haloperidol, in contrast, has a broad and potent action in basal ganglia, causing changes in SNR and in the mediodorsal nucleus, while also altering GAD mRNA in RtN, potentially reflective of its dyskinetic and antipsychotic actions.

Animals↗

PubMed2001

Reperfusion-induced Ins(1,4,5)P(3) generation and arrhythmogenesis require activation of the Na(+)/Ca(2+) exchanger.

Reperfusion of globally ischemic rat hearts causes rapid generation of inositol(1,4,5) trisphosphate [Ins(1,4,5)P(3)] and the development of arrhythmias, following stimulation of alpha(1)-adrenergic receptors by norepinephrine released from the cardiac sympathetic nerves. The heightened inositol phosphate response in reperfusion depends on the activation of the Na(+)/H(+) exchanger, which might reflect a central role for increased Ca(2+)following reverse mode activation of the Na(+)/Ca(2+) exchanger (NCX). Isolated, perfused rat hearts were subjected to 20 min ischemia followed by 2 min reperfusion and the content of Ins(1,4,5)P(3) measured by mass analysis or by anion-exchange high performance liquid chromatography (HPLC) following [(3)H]inositol labeling. Reperfusion caused generation of Ins(1,4,5)P(3) (1266+/-401 to 3387+/-256 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01) and the development of arrhythmias. Inhibition of NCX either by reperfusion at low Ca(2+) (1133+/-173 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01 relative to reperfusion control) or by adding 10 microm KB-R7943, an inhibitor of reverse mode Na(+)/Ca(2+) exchange, prevented the Ins(1,4,5)P(3) response (1151+/-243 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01 relative to reperfusion control) and the development of ventricular fibrillation. Lower concentrations of KB-R7943 were less effective. Reverse mode activation of NCX is therefore required for the enhanced Ins(1,4,5)P(3) response in early reperfusion, and inhibitors of this transporter may be useful in the prevention of arrhythmias under such conditions.

Animals↗

PubMed2000

Serial echocardiographic assessment of left ventricular dimensions and function after myocardial infarction in mice.

OBJECTIVE: To test the usage of serial echocardiography in mice with induced myocardial infarct (MI) and to characterize the mouse model of MI. METHODS: C57 mice underwent open-chest surgery to induce left coronary artery occlusion or sham-operation (SH). Echocardiography was performed before and at 1, 2.5, 6 and 9 weeks after surgery. Left ventricular end diastolic and end systolic dimensions (LVEDd, LVESd) and fractional shortening (FS) were measured. Haemodynamics was determined at week 9 by LV catheterization and hearts were examined morphologically. RESULTS: Post-infarct mortality was 46% (10/22), of which, 70% died of acute heart failure or LV rupture within the first week. LV dimensions and FS remained stable in SH group (n = 10) during the study period. In surviving MI mice (n = 12), there was modest LV dilatation and fall in FS at week 1. Compared with week 0 values, there were progressive increase in LVEDd (+50(-)+66%) and LVESd (+124(-)+171%), and decline in FS (-53(-)-73%) during the 2.5-9 week period. Infarcted mice also had lower LV systolic pressure (LVSP), dP/dtmax and dP/dtmin (all P < 0.01 vs. SH group). Infarct size, LVSP and dP/dt significantly correlated with FS and LV dimensions (r = 0.61-0.80, all P < 0.01). CONCLUSIONS: LV remodeling and dysfunction in mice with MI are time-dependent processes and early remodeling seems associated with high risk of rupture and acute pump failure. Our findings provide a baseline description of this murine model and confirm echocardiography as a reliable means to serially assess changes of cardiac structure and function after MI.

Animals↗

PubMed2000

Expression of active alpha(1B)-adrenergic receptors in the heart does not alleviate ischemic reperfusion injury.

Ischemic preconditioning reduces infarct size and improves cardiac function in various species, including mice. The mechanism for ischemic preconditioning protection is not entirely clear and activation of alpha(1B)-adrenergic receptors (AR) is believed to be involved. Transgenic mice expressing constitutively active mutant alpha(1B)-AR in the heart have enhanced alpha(1B)-AR activity and therefore can be used to test the role of alpha(1B)-AR in ischemic preconditioning. Wild-type and transgenic mice were subjected to 30- or 40-min periods of left coronary artery occlusion followed by 60-min reperfusion, or ischemic preconditioning prior to sustained ischemia-reperfusion. Risk and infarct zones were determined by staining with Evans blue and triphenyltetrazolium, respectively, and quantitated digitally. Infarct zone and infarct size were not different between wild-type and transgenic mice, nor was the extent of reduction in infarct size by preconditioning ischemia (wild-type mice: 45+/-3 to 18+/-3%, transgenic mice: 46+/-3 to 19+/-2% of the left ventricle, both P<0.01). Ventricular function was similar between wild-type and transgenic mice with or without ischemia-reperfusion injury. In conclusion, enhanced alpha(1B)-AR activity by cardiac-specific expression of constitutively active mutant alpha(1B)-AR in mice does not mimic ischemic preconditioning to protect against ischemia-reperfusion injury.

Animals↗

PubMed2000

Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing beta(2)-adrenergic receptors in the heart.

OBJECTIVE: To explore long-term cardiac phenotype in transgenic (TG) mice with 300-fold overexpression of beta(2)-adrenergic receptors (AR). METHODS: Echocardiography was performed serially on a cohort of wild-type and TG mice (n=26 each) between 4 and 15 months of age. Survival was monitored and autopsy and histological examinations were performed. RESULTS: Heart rate was higher in TG than in wild-type mice throughout the study period. The left ventricular dimensions and fractional shortening were similar between TG and wild-type groups during 4-6 months. Starting at 9 months, however, TG mice showed progressive reduction in fractional shortening and systolic wall thickening, and increase in left ventricular dimensions and left ventricular mass, indicating onset of heart failure, left ventricular hypertrophy and remodeling. Abnormal waveforms in the electrocardiogram and episodes of ventricular ectopic beats were also observed in TG mice. Death of TG mice started at 8.5 months, and the cumulative mortality was 81% by 15 months (P<0.0001 vs. 4% in wild-type mice). The majority of deaths were due to severe heart failure, indicated by cardiac dilatation, lung congestion, pleural effusion and atrial thrombus. Left ventricular sections showed widespread interstitial fibrosis, loss of myocytes and myocyte hypertrophy in TG mice. CONCLUSIONS: A high level of beta(2)AR overexpression results in cardiomyopathy and heart failure. The onset was slower and the expression levels of receptors required are much higher than previously described for the beta(1)AR overexpression.

Aging↗

PubMed2000

Characterisation of Candida albicans infections of haematogenous and mucosal origin in mice lacking the interferon gamma receptor protein.

Mice harbouring a null deletion mutation in the IFNgamma receptor gene were used to study the role of IFNgamma responsiveness during experimental systemic candidiasis of mucosal or haematogenous origin. After intravenous (i.v.) or intranasal (i.n.) challenge with Candida albicans the progression of infection and concomitant cellular and antibody anti-C. albicans immune responses were analysed. During the week following i.v. challenge, the rate of C. albicans multiplication in kidneys, liver and spleen was faster in IFNgammaR (-/-) than IFNgammaR (+/+) mice. As a result, IFNgammaR (-/-) mice perished earlier than IFNgammaR (+/+) mice when challenged with equal numbers of live yeast cells. However, the overall susceptibility of the two mouse strains, in terms of survival against different C. albicans challenge doses over a 60-day period, was similar. No differences were found in the cellular anti-C. albicans response generated by i.v. challenge in both mouse strains. In contrast the kinetics and strength of the serum anti-C. albicans antibody responses were markedly different. Significantly stronger, predominantly IgG2a antibody responses accompanied the eventual control of C. albicans infection in IFNgammaR (-/-) mice. Following intranasal challenge, there was no difference in the rate of C. albicans clearance from the lungs of IFNgammaR (-/-) and IFNgammaR (+/+) mice. However, 48 h after challenge, large, conspicuous abscesses appeared in the lungs, liver, kidneys and spleen of IFNgammaR (-/-) mice. These abscesses were characterised by the presence of C. albicans and abundant neutrophilic infiltrates, but very few macrophages. No such abscesses developed in i.n. challenged IFNgammaR (+/+) mice. In both mouse strains, i.n. challenge induced strong systemic anti-C. albicans cellular responses, but relatively low titre systemic antibody responses. Mucosal anti-C. albicans antibody responses were detected in IFNgammaR (+/+), but not IFNgammaR (-/-) mice. Splenic adherent macrophages obtained from IFNgammaR (-/-) mice exhibited a significantly lower candidacidal activity than those of IFNgammaR (+/+) mice, and as expected, were not responsive to IFNgamma. In summary, these data suggest that IFNgamma has a role in limiting C. albicans multiplication during the early stages of infection, as well as in preventing the development of C. albicans-associated abscesses. Activation of macrophages by IFNgamma might be pivotal in mediating this role.

Animals↗

PubMed2000

Preserved ventricular contractility in infarcted mouse heart overexpressing beta(2)-adrenergic receptors.

Effects of cardiac specific overexpression of beta(2)-adrenergic receptors (beta(2)-AR) on the development of heart failure (HF) were studied in wild-type (WT) and transgenic (TG) mice following myocardial infarction (MI) by coronary artery occlusion. Animals were studied by echocardiography at weeks 7 to 8 and by catheterization at week 9 after surgery. Post-infarct mortality, due to HF or cardiac rupture, was not different among WT mice, and there was no difference in infarct size (IS). Compared with the sham-operated group (all P < 0.01), WT mice with moderate (<36%) and large (>36%) IS developed lung congestion, cardiac hypertrophy, left ventricular (LV) dilatation, elevated LV end-diastolic pressure (LVEDP), and suppressed maximal rate of increase of LV pressure (LV dP/dt(max)) and fractional shortening (FS). Whereas changes in organ weights and echo parameters were similar to those in infarcted WT groups, TG mice had significantly higher levels of LV contractility in both moderate (dP/dt(max) 4,862 +/- 133 vs. 3,694 +/- 191 mmHg/s) and large IS groups (dP/dt(max) 4,556 +/- 252 vs. 3,145 +/- 312 mmHg/s, both P < 0.01). Incidence of pleural effusion (36% vs. 85%, P < 0.05) and LVEDP levels (6 +/- 0.3 vs. 9 +/- 0.8 mmHg, P < 0.05) were also lower in TG than in WT mice with large IS. Thus beta(2)-AR overexpression preserved LV contractility following MI without adverse consequence.

Adrenergic beta-Agonists↗

PubMed2000

Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia.

OBJECTIVE: Multiple quantifiable biologic abnormalities have been localized to the hippocampus in schizophrenia. Alterations in glutamate-mediated transmission at N-methyl-D-aspartic acid (NMDA)-sensitive receptors in hippocampus have been implicated in the pathophysiology of the illness. The authors tested the hypothesis that glutamatergic transmission within and efferent from hippocampus is altered in schizophrenia. METHOD: The authors analyzed postmortem hippocampal tissue from individuals with schizophrenia and from healthy individuals. The tissue samples had been collected by two brain tissue banks, one in Maryland and the other in Melbourne, Australia. lonotropic receptor binding for the NMDA, kainate, and (3)H-amino-3-hydroxy-5-methylisoxazol-4-propionate (AMPA) receptors was quantified by using usual radioligand techniques. In situ hybridization autoradiography was used to quantify mRNA for the NMDA receptor subunits NR1, NR2A, and NR2B. RESULTS: Ligand binding to the ionotropic glutamate receptors (NMDA, kainate, and AMPA) did not differ significantly overall or in any subregion between the schizophrenia tissue and the healthy comparison tissue. The only exception was AMPA receptor binding in hippocampal subregion CA2, which was slightly but significantly less in schizophrenia. However, the level of mRNA for the NMDA receptor subunits NR1 and NR2B was significantly different between groups; in several hippocampal subregions, the level of NR1 mRNA was lower and the level of NR2B mRNA higher in schizophrenia. CONCLUSIONS: Because the NR1 subunit of the NMDA receptor is critical to full receptor activity, a reduction of NR1 in hippocampus in schizophrenia suggests a functional impairment in glutamatergic transmission at the NMDA receptor, resulting in reduced glutamatergic transmission within and possibly efferent from the hippocampus in schizophrenia. This defect could underlie a hypoglutamatergic state in regions of limbic cortex, consistent with published results from other lines of research in schizophrenia.

Adult↗

PubMed1999

Magnetic resonance imaging of the upper airway in obstructive sleep apnea before and after oral appliance therapy.

OBJECTIVE: To determine the mechanism by which an oral appliance may be used to treat obstructive sleep apnea syndrome (OSAS). METHODS: Eleven OSAS patients (8 males and 3 females) were involved in the study. Mean age was 52.2 +/- 10.6 years; height was 166.6 +/- 7.2 cm, and weight was 75.6 +/- 9.3 kg; body mass index (BMI) was 27.2 +/- 2.9 kg/m2. Each patient underwent magnetic resonance imaging (MRI) and polysomnography before and after oral appliance therapy. Pharyngeal changes were measured and compared with the variation in sleep parameters. Also, Pearson's correlation and multiple linear regression were performed to investigate the relationship of sleep parameters and MRI items. RESULTS: Through oral appliance therapy, the sleep disorder decreased. Apnea/hypopnea index (AHI) decreased from 44.6 +/- 21.5 to 9.6 +/- 6.3 per hour of sleep. Lowest oxygen desaturation rose from 71.4 +/- 15.0% to 82.0 +/- 7.7%. Meanwhile, the upper airway increased at most levels, and especially at oropharynx. As measured by the correlation and regression analysis, the AHI changes had a negative association with tongue volume (R = -0.5730) and a positive association with the area alternation of high oropharynx (R = 0.5823); the change of the lowest oxygen desaturation (SaO2%) was positively associated with whole airway volume (R = 0.6554). CONCLUSION: The oral appliance works by enlarging the upper airway morphology and keeping the airway open, mainly at the back of soft palate. The effect of the oral appliance is associated with the degree of enlargement of the high oropharynx. Those who have a small tongue and a large pharynx may expect to have good results with the use of the oral appliance.

Female↗

PubMed1998

TCR usage by homocysteine-specific human CTL.

We have recently demonstrated that homocysteine can modify HLA class I Ags and induce homocysteine-specific CTL (Hom-CTL) responses in humans. Here, we have investigated TCR usage by Hom-CTL from five patients with ankylosing spondylitis or reactive arthritis. TCR of HLA-A68-restricted Hom-CTL from two unrelated donors share the same TCR Valpha, Vbeta, and Jbeta gene segments (AV4, BV23, and BJ2S1, respectively) with similar third complementarity determining regions (CDR3) of the beta-chains. Interestingly, the Va and Vbeta gene segments employed by an HLA-B27-restricted Hom-CTL clone are also closely related to AV4 and BV23, indicating strong selection pressure for AV4, BV23, and related gene products in the homocysteine-specific TCR. An arginine or lysine residue frequently appeared at position alpha93 in the CDR3 of the TCR alpha-chains from Hom-CTL restricted by HLA-A68 or -B8. This may suggest a potential salt bridge between the carboxyl group of homocysteine and specific TCR. TCR usage by HLA-B27-restricted Hom-CTL from unrelated individuals appears to be less conserved, although two T cell clones from one individual rearranged the same V gene segments with identical lengths of CDR3. Implications of these data for the molecular mechanisms for homocysteine modification of HLA Ags are also discussed.

Amino Acid Sequence↗

PubMed1998

Phencyclidine (PCP) and dizocilpine (MK801) exert time-dependent effects on the expression of immediate early genes in rat brain.

The mRNA expression pattern for four different immediate early genes was examined dynamically in rat brain after administration of phencyclidine (PCP; 0.86 or 8.6 mg/kg) or MK801 (0.1 or 1.0 mg/kg). Following each treatment, the expression of cfos, cjun, junB, and zif268 mRNA changed distinctively and dynamically between 1 and 48 hours. cfos mRNA was induced in cortical areas at early times after either dose of PCP or of MK801; the change was especially prominent in cingulate and auditory cortices. zif268 mRNA showed an early (1 hour) activation and a delayed (24-48 hour) suppression after PCP and MK801 in neocortical areas. PCP also caused cjun and junB mRNA induction in cortical areas at early times, with a distribution and time course similar to its effects on cfos mRNA. No alterations in cfos, cjun, or junB mRNA were found in neocortical or hippocampal areas at any delayed time (>6 hours) after PCP treatment, whereas suppression of zif268 expression was prominent even at 48 hours post-treatment. CPP, a competitive NMDA antagonist, showed a similar pattern of effects on cfos and zif268 mRNA expression. These functional consequences of a PCP- or MK801-induced reduction in NMDA-sensitive glutamate transmission may be relevant to an understanding of animal NMDA pharmacology and/or to clinical psychotomimetic side effects of antiglutamatergic treatments.

Animals↗

PubMed1998

Mixture in the distribution of haloperidol-induced oral dyskinesias in the rat supports an animal model of tardive dyskinesia.

Spontaneous adventitious oral movements which are produced in rats by very chronic (6-month) neuroleptic treatment have some phenomenologic and pharmacologic characteristics in common with tardive dyskinesia in humans. However, since not all of the features match, this putative model has been questioned and further support is warranted. Data from several laboratories support dichotomizing these neuroleptic-induced rat oral movements into "low" or "not TD-like" movements and "high" or "TD-like" movements, similar to the division of neuroleptic-induced involuntary movements in humans. Here, we have used mixture analysis to test this proposal statistically in 185 haloperidol-treated and 127 water-treated animals. Rats from several different studies were grouped together to form these two cohorts. The haloperidol dose, route of administration, rating technique, and balanced experimental groups were held constant across all experiments. Results show that two distinct groups of rat movements are induced by very chronic haloperidol treatment (1.5 mg/kg per day). The "low" vacuous chewing movement (VCM) group of rats had an average of 3.6 VCMs/5 min, and the "high" VCM group had an average of 16.1 VCMs/5 min; the control group, with a median VCM rate of 2.0 VCMs/5 min, demonstrated a single distribution. These data suggest that rats, like humans, dichotomize into two groups either expressing or not expressing "high" VCM dyskinesias with very chronic haloperidol treatment.

Animals↗

PubMed1998

Chronic olanzapine or sertindole treatment results in reduced oral chewing movements in rats compared to haloperidol.

Chronic haloperidol treatment typically produces late-onset, purposeless oral chewing movements in laboratory rats with a prevalence of 40 to 60%. Chronic clozapine does not produce these movements. Based on the phenomenologic and pharmacologic similarities between these rat chewing movements and human tardive dyskinesia (TD), the animal movements are often used as a model of tardive dyskinesia (TD). Here we report results of the association of oral chewing movements in rats with chronic administration of two new antipsychotic drugs, olanzapine and sertindole. Because each of these antipsychotic drugs has a very low incidence of acute Parkinsonism in human studies, they are candidates for showing a low tardive dyskinesia risk. Neither new drug produced a significant incidence of haloperidol-like chewing in rats, nor did movement ratings after their chronic administration differ from placebo; whereas, haloperidol produced a 60% prevalence of purposeless chewing and a prevalence significantly increased from placebo. This low rate of oral dyskinesias in rats is consistent with several of the preclinical characteristics of the drugs and correlates with their low acute motor side effects in clinical trials. We propose, although have not yet tested in humans, that these animal results will predict low TD liability of these drugs.

Animals↗

PubMed1997

The effect of chronic haloperidol treatment on dendritic spines in the rat striatum.

Previous studies have shown that schizophrenics, in comparison to controls, have reduced cortical spine density and smaller striatal spines. The current study in the rat was conducted to determine whether such differences could result from chronic neuroleptic treatment and whether they are correlated with neuroleptic-induced oral dyskinesias. Rats administered 1.5 mg/kg/day of haloperidol (HA) (n = 28) or water (n = 10) were tested for vacuous chewing movements (VCMs). After 6 months, rats were divided into low and high VCM groups; all but seven high VCM rats were sacrificed. These rats (withdrawn group) were withdrawn from HA for 4 weeks. Random electron micrographs of the striatum were analyzed for spine changes. Spine size was not significantly affected by HA (0.193 vs 0.174 microm2, HA and control, respectively) nor correlated with oral dyskinesias (0.191 vs 0.196 microm2, low and high VCM groups, respectively). These results suggest that smaller spines in schizophrenic striatum may be correlated with the disease rather than caused by neuroleptic treatment. Spine density decreased in the HA-treated group (32.7 +/- 9.5) in comparison to controls (53.7 +/- 7.3, P < 0.001) and remained low in the withdrawn group (35.0 +/- 4.2, P < 0.01). Spine density also decreased in both the low (37.3 +/- 9.9, P < 0.01) and the high (28.0 +/- 7.0, P < 0.000) VCM groups in comparison to controls. However, there was no significant difference between high and low VCM groups, suggesting that decreased spine density is independent of oral dyskinesias. These results suggest that the decreased spine density observed in schizophrenic cortex may be a result of neuroleptic treatment.

Animals↗

PubMed1997

The dose-response characteristics of rat oral dyskinesias with chronic haloperidol or clozapine administration.

Whether the pathophysiology and treatment of neuroleptic-induced oral dyskinesias in rats parallel that for tardive dyskinesia in humans remains a question. To address the issue further, Sprague Dawley rats were treated for 6 months with multiple oral doses of haloperidol (1.5 and 3.0 mg/ kg/day) or clozapine (10, 20, and 30 mg/kg/day) and compared with water treated animals. The rate of oral dyskinesias was monitored at study start and monthly by trained raters who were blind to treatment group. All haloperidol-treated rats developed oral dyskinesias at a significantly higher rate than rats treated with water (p = 0.0007) or those treated with clozapine (p = 0.0017). Each dose of haloperidol produced significantly higher rates of oral dyskinesias than did any dose of clozapine and did so in an apparent dose-sensitive manner. Clozapine lacked a dose-sensitive relationship with the oral dyskinesias, and failed to show a significant difference in rate from control rats at any dose. Plasma levels of haloperidol with these doses were in the human therapeutic range; with clozapine only the highest dose produced plasma levels in the human therapeutic range. These data show little association between rat oral dyskinesias and clozapine treatment, whereas a strong association is present with haloperidol. The data are, thereby, consistent with the clinical association of tardive dyskinesia with typical neuroleptics like haloperidol but not with the atypical neuroleptic clozapine.

Administration, Oral↗

PubMed1997

Immunization of mice with DNA encoding fragment C of tetanus toxin.

Immunization of mice with Fragment C protein, the non-toxic C-terminal domain of tetanus toxin, will protect mice against lethal challenge with tetanus toxin. A plasmid, pcDNA3/tetC, which encodes a synthetic tetC gene expressed under the control of the human cytomegalovirus major intermediate early promoter/enhancer region, was constructed. Fragment C expression was observed in Chinese hamster ovary cells following transfection with pcDNA3/tetC. The immune response induced by intramuscular immunization with pure pcDNA3/tetC DNA was evaluated in a murine model. Anti-Fragment C serum immunoglobulin and proliferative responses in splenocytes were observed following two immunizations with pcDNA3/tetC. The major IgG subclass that recognized Fragment C was IgG2a and the stimulated splenocytes secreted high levels of interferon-gamma. Sufficient anti-Fragment C serum immunoglobulins were induced by DNA-mediated immunization to protect mice against lethal challenge with tetanus toxin.

Animals↗