Biomedical subjects

R Lalonde

Publications and source records attributed to R Lalonde.

At least 19 recordsLinked to original sources

PubMed1998

Brain dopamine and amino acid concentrations in Lurcher mutant mice.

Lurcher mutant mice are characterized by massive degeneration of the cerebellum, including Purkinje cells and granule cells, as well as for the loss of neurons from the inferior olive. Concentrations of dopamine and two of its metabolites and of several amino acid neurotransmitters were determined in the cerebellum and in other brain regions of these mutants. By comparison to wild-type mice of the same background strain, glutamate and taurine concentrations were reduced in the Lurcher cerebellum. No decrease was found for aspartate, gamma-aminobutyric acid (GABA), glycine, as well as dopamine and its metabolites. Moreover, no neurochemical alterations occurred in the brain stem, thalamus, or neostriatum of Lurcher mutants. A selective reduction of glutamate concentration was found in the hippocampus, while all amino acids measured were decreased in the entorhinal-piriform areas. These results indicate region-selective reductions of neurotransmitter concentrations in a mouse mutant with a defined cerebellar cortical pathology.

Amino Acids↗

PubMed1998

Emergence and prevalence of cytomegalovirus UL97 mutations associated with ganciclovir resistance in AIDS patients.

OBJECTIVES: To evaluate the prevalence of the most common cytomegalovirus (CMV) UL97 mutations associated with ganciclovir resistance directly in polymorphonuclear leukocytes (PMNL) of patients with AIDS and CMV retinitis. Also to correlate the presence (or absence) of these mutations with the systemic CMV viral load and the ophthalmologic outcome of these subjects. METHODS: Monthly blood samples were obtained from 19 patients with AIDS and CMV retinitis who had been treated with systemic ganciclovir for > or = 2 months. Detection of CMV UL97 mutations was done using nested PCR amplification followed by restriction enzyme analysis. The viral load was assessed with a polymerase chain reaction-based assay and non-isotopic hybridization detection. RESULTS: CMV UL97 mutations were detected in PMNL of four of 13 (30.8%) patients who had been treated with ganciclovir for > or = 3 months but in none of six patients who had been treated for < 3 months. All four patients with detectable UL97 mutations were presenting evidence of retinitis progression at the time those mutations were first detected (mean, 145.7 days of ganciclovir) and three of four patients had a viral DNA load > 10000 copies per 10(5) PMNL contrasting with the copy numbers in the 15 subjects without mutations (mean, 492.9 copies per 10(5) PMNL after a mean of 146.8 days of ganciclovir). CONCLUSIONS: The prevalence of the most common CMV UL97 mutations associated with ganciclovir resistance in PMNL of patients with AIDS treated for > or = 3 months (30.8%) appears to be higher than the rate of emergence of ganciclovir-resistant CMV isolates as previously reported using phenotypic assays (about 8%). Moreover, the detection of these mutations is associated with a considerable increase in the CMV DNA load in the blood as well as with progression of CMV retinitis during ganciclovir therapy.

AIDS-Related Opportunistic Infections↗

PubMed1998

Regional brain variations of cytochrome oxidase activity and motor coordination in Lurcher mutant mice.

Lurcher mutant mice are characterized by massive degeneration of cerebellar Purkinje cells and granule cells and by deficits in motor coordination. Regional brain variations of cytochrome oxidase (CO) activity were analyzed to identify those brain regions with abnormal metabolic activity as a secondary consequence of the cerebellar atrophy and to establish the relationship between CO activity and motor deficits. Lurcher mutants had higher CO activity in all three cerebellar deep nuclei than normal littermate controls of the same background strain. Higher CO activity was also found in Lurcher mutants in brain regions directly connected to the cerebellum, such as the lateral vestibular nucleus, the cochlear nucleus, the red nucleus, the ventrolateral thalamus, the dorsal raphe, the interpeduncular nucleus, and the inferior colliculus. By contrast, there was a sharp decrease in CO activity in the inferior olive. As for brain regions not directly connected to the cerebellum, higher CO activity was observed in the trigeminal motor nucleus and the CA1 molecular layer of the hippocampus, which highlights probable transsynaptic alterations as a secondary consequence of cerebellar atrophy. A positive correlation between CO activity in the red nucleus and latencies before falling in two motor-coordination tests indicates that a compensatory increase of metabolic activity in a cerebellar efferent region is associated with improved behavior.

Animals↗

PubMed1998

Grooming in Lurcher mutant mice.

Lurcher mutant mice, characterized by degeneration of cerebellar Purkinje cells and granule cells, were compared to normal littermate controls for different facets of grooming and nongrooming behaviors after a brief period of water immersion. By comparison to normal controls, the number and the duration of several grooming components were decreased in Lurcher mutant mice, namely, licking the forelimb, the abdomen, the back, and the hindlimb. By contrast, the number and duration of body-shaking episodes were not reduced. Lurcher mutants had fewer grooming elements for bouts with at least five elements. However, the serial organization of grooming, as determined by the order of appearance of grooming elements, was maintained in Lurcher mutants. These results indicate that the cerebellar cortex is involved in the appearance of various grooming elements but not in the organization of the cephalocaudal sequence.

Analysis of Variance↗

PubMed1998

Timed active avoidance learning in lurcher mutant mice.

Lurcher mutant mice (+/Lc) which exhibit a massive loss of neurons in the cerebellar cortex and in the inferior olivary nuclei were subjected to an active avoidance learning task; the animals' avoidance response must occur within a small time window after a short or a long delay. The control mice needed a mean of 8.3 sessions of 10 trials (short delay group) and of 11.8 sessions (long delay group) and showed good retention after a 24 h interval. When subjected to the same number of sessions, the +/Lc mice were unable to learn the timing task. However, a subgroup of lurcher mutants was able to learn after a high number of sessions (25.4 sessions as a mean). There was no intergroup difference in the standard version of one-way active avoidance. These results indicate that the cerebellar cortex is involved in time processing during active avoidance. The cerebellum may be part of a loop including the cerebral cortex known to be involved in time perception. An alternative explanation is that the cerebellar mutant animals had persevering tendencies acquired during performance of the one-way avoidance task.

Animals↗

PubMed1998

Early development of synchronized walking on the rotorod in rats. Effects of training and handling.

There is considerable improvement of motor coordination on the rotorod during the first 3 weeks of development in rats. The purpose of the present study was to determine some factors implicated in this improvement. From days 15-22 of age, rats were: (1) extensively trained on the rotorod; (2) minimally trained on the rotorod; (3) handled daily but not trained on the rotorod; and (4) neither handled nor trained. All animals were tested on the rotorod on day 23, with separate groups of the naive rats also being tested on days, 19, 20, 21 or 22. Latencies before falling and the percentage of time spent walking in time to the movement of the rotating rod were recorded. There was a close correspondence between these two scores during ontogeny. The percentage of time spent walking was similar among extensively trained, minimally trained, and handled rats and significantly higher than that measured in rats tested only on 1 day. These results indicate that the emergence of this postural sensorimotor skill is more dependent on the maturation of sensorimotor brain region than on previous training on the apparatus.

Aging↗

PubMed1998

The cerebellum and postural sensorimotor learning in mice and rats.

Animals with cerebellar damage caused by gene mutations, surgical ablations and irradiation by X-rays during developmental stages are impaired in maintaining posture and equilibrium. For most tests, even in animals with total cerebellectomy, postural sensorimotor learning is not abolished. Simpler compensatory movements may be adopted. The acquisition of simple sensorimotor skills occurring after massive damage of the cerebellar cortex may be explained by the modulatory role of the cerebellar deep nuclei during learning processes or by the influence of extracerebellar regions taking over lost cerebellar function.

Animals↗

PubMed1998

Distribution of dopamine transporters in basal ganglia of cerebellar ataxic mice by [125I]RTI-121 quantitative autoradiography.

Dopamine (DA) uptake sites, or transporters, were examined with [125I]RTI-121 in mutant mice that exhibit motor control deficits, namely weaver, lurcher and dystonia musculorum. In lurcher mice, the distribution of [125I]RTI-121 binding was similar to controls, except for a decrease in the subthalamic nucleus. For dystonia musculorum mice, the labelling presented no differences between controls and mutants, except for decreases in the dorsal half of caudal neostriatum and in the ventral tegmental area. Moreover, in this mutant the left rostral neostriatum DA transporters were reduced, when compared to the right counterpart. In weaver heterozygote (wv/+) mice, the distribution and density gradients of [125I]RTI-121 labelling were similar as in their controls, except in caudal neostriatum, where binding was slightly higher. In contrast, the weaver homozygote (wv/wv) showed important decreases in labelling of the dorsal quadrant of rostral neostriatum as well as of the dorsal half of caudal neostriatum, where the reductions of binding densities were of 65% to 70%, respectively. There were also slight decreases in [125I]RTI-121 binding in olfactory tubercles as well as in subthalamic nucleus, but only in wv/wv mice. In substantia nigra pars compacta and ventral tegmental area of wv/wv mice the labelling was lower; however, while the 60% decrease in labelling in substantia nigra was highly significant, the 30% reduction in ventral tegmental area did not attain statistical significance. In summary, in the ataxic neurological mutant mice studied, important reductions of DA transporters were documented only for the weaver mice, the cerebellar mutant presenting, besides its cerebellar pathology, a known degeneration of mesencephalic dopaminergic neurons. The results rule out major alterations of the central DA systems in lurcher and dystonia musculorum, and are compatible with the hypothesis that the dopaminergic abnormalities of weaver mutants are not secondary to cerebellar atrophy, but may be a direct consequence of the abnormal weaver gene expressed by DA neurons leading to their apoptotic death.

Animals↗

PubMed1998

Treadmill performance of mice with cerebellar lesions: 1. Purkinje cell degeneration mutant mice.

The purpose of this study was to evaluate the sensorimotor skills of a spontaneous mouse mutant, Purkinje cell degeneration (PCD), marked by selective cerebellar cortical atrophy on a treadmill activated at 1 of 2 speeds and at 1 of 3 slopes, requiring forward movements to avoid footshocks. There was no difference in latencies before falling from the belt between PCD mutants and controls during acquisition. However, PCD mutants were impaired on the fast treadmill during retention, implicating the cerebellum in the memory of a motor skill. During acquisition of the slow treadmill task at the 2 lowest slopes of inclination, PCD mutants spent more time walking than controls, an indication of a decreased ability of coordinating whole body movements. The same pattern of higher walking time on the slow treadmill in PCD mutants was evident during retention. These results indicate that the cerebellar cortex is involved in the acquisition and the retention of a task requiring equilibrium.

Animals↗

PubMed1998

Comparative evaluation of the cytomegalovirus DNA load in polymorphonuclear leukocytes and plasma of human immunodeficiency virus-infected subjects.

The cytomegalovirus (CMV) DNA load was determined in polymorphonuclear leukocytes (PMNL) and plasma samples from 106 human immunodeficiency virus-infected subjects at risk of developing CMV disease (group 1) and from 27 AIDS patients with documented CMV disease (group 2). For both groups, the number of CMV copies in PMNL was significantly higher than in plasma when results were derived from an equivalent blood volume (P < .001, PMNL vs. plasma). Additionally, group 2 (symptomatic) patients had a greater viral DNA load than group 1 (asymptomatic) subjects (P < .001 for both PMNL and plasma). The sensitivity, specificity, and positive and negative predictive values of qualitative polymerase chain reaction using PMNL (PCR-PMNL) for the presence of CMV disease were 100%, 58%, 38%, and 100%, respectively, compared with 70%, 93%, 74%, and 92% for qualitative PCR-plasma and 93%, 92%, 76%, and 98% for quantitative PCR-PMNL using a cutoff of 16,000 copies/mL. Thus, the best strategy for diagnosing CMV disease in these individuals relies on quantitative assessment of the viral DNA load in PMNL.

AIDS-Related Opportunistic Infections↗

PubMed1998

Clindamycin with primaquine vs. Trimethoprim-sulfamethoxazole therapy for mild and moderately severe Pneumocystis carinii pneumonia in patients with AIDS: a multicenter, double-blind, randomized trial (CTN 004). CTN-PCP Study Group.

This double-blind, randomized, multicenter trial compared clindamycin/primaquine (Cm/Prq) with trimethoprim-sulfamethoxazole (TMP-SMZ) as therapy for AIDS-related Pneumocystis carinii pneumonia (PCP). Forty-five patients received clindamycin (450 mg four times daily [q.i.d.]) and primaquine (15 mg of base/d); 42 received TMP-SMZ (320 mg/1,600 mg q.i.d. if weight of > or = 60 kg or 240 mg/1,200 mg q.i.d. if weight of < 60 kg) plus placebo primaquine. Overall, the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 76% vs. 79%, respectively); Cm/Prq was associated with fewer adverse events (P = .04), less steroid use (P = .18), and more rashes (P = .07). These differences were even greater for patients with PaO2 of > 70 mm Hg (P = .02, P = .04, and P = .02, respectively). For patients with PaO2 of < or = 70 mm Hg (23 Cm/Prq recipients and 21 TMP-SMZ recipients), the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 74% vs. 76%, respectively); Cm/Prq was associated with similar adverse events (P = .57), steroid use (P = .74), and rashes (P = .78). This trial confirms that Cm/Prq is a reasonable alternative therapy for mild and moderately severe PCP.

AIDS-Related Opportunistic Infections↗

PubMed1998

Regional brain variations of cytochrome oxidase activity and motor coordination in hot-foot mutant mice.

Hot-foot mutant mice are characterized by defective arborization of Purkinje cell dendrites, resulting in ataxia of gait and deficits of equilibrium. Regional brain variations of cytochrome oxidase (CO) activity were analysed for the purpose of identifying those brain regions with abnormal metabolic activity as a secondary consequence to the cerebellar alteration. In addition, the possible relation between CO activity and motor deficits was evaluated. By comparison to normal littermate controls of the same background strain, hot-foot mutants had higher CO activity in the molecular layer of the cerebellum, the ventrolateral and midline thalamic nuclei, as well as in the frontal eye field. There was no other alteration of CO activity in the hot-foot brain. No linear correlation was discerned between CO activity in the molecular layer of the cerebellum and the ventrolateral and midline nuclei on one hand, and motor coordination performance on the other. These results indicate regionally selective abnormalities of metabolic activity in a cerebellar mutant with defective dendritic arborization of the Purkinje cell.

Anatomy, Cross-Sectional↗

PubMed1998

Evaluation of the AMPLICOR cytomegalovirus test with specimens from human immunodeficiency virus-infected subjects.

The AMPLICOR cytomegalovirus (CMV) test, a new qualitative assay for the detection of CMV DNA in plasma, was compared to conventional methods and quantitative PCR (Q-PCR) assays by using leukocytes and plasma from 179 blood samples from subjects with AIDS. For the diagnosis of CMV disease, cell-based assays such as a Q-PCR with polymorphonuclear leukocytes (Q-PCR-PMNL) and a pp65 antigenemia assay had the highest sensitivities but suffered from a lack of specificity. The best agreement between the results of the Q-PCR-PMNL assay and those of the AMPLICOR test was found when a threshold diagnostic value of 690 copies per 10(5) cells was selected for the Q-PCR-PMNL assay. In that context, the AMPLICOR CMV test had a sensitivity of 96.4% and a specificity of 95.3% when results were compared to results of the cell-based PCR assay. This threshold was close to the one described as associated with the best sensitivity and specificity for the diagnosis of CMV disease in a recently published study (4). Blood samples that tested positive by the Q-PCR-PMNL assay but negative by the AMPLICOR CMV test were associated with viral loads (mean, 785 copies, median, 96 copies per 10(5) leukocytes) lower than the viral loads of blood samples that tested positive by both assays (mean, 21,452 copies; median, 9,784 copies per 10(5) leukocytes) (P = 0.003). The AMPLICOR CMV test gave positive results at least 48 days before the development of symptomatic CMV disease in a longitudinal analysis of a limited subset of patients (n = 6) from whom sequential specimens were available for testing. In conclusion, the AMPLICOR CMV test is a very convenient assay combining rapidity, simplicity, and the possibility of batch testing. A positive result by this test seems particularly important since this implies, in most instances, the presence or the imminence of CMV disease, although a negative test result does not rule out disease.

AIDS-Related Opportunistic Infections↗

PubMed1997

Sensorimotor learning and retention during equilibrium tests in Purkinje cell degeneration mutant mice.

In order to determine the consequences of atrophy to the cerebellar cortex on postural sensorimotor learning and performance, a natural mutation, Purkinje cell degeneration (pcd), was used. The homozygous mutants were compared to heterozygous non-ataxic controls on three static beams, two grids (vertical and tilted), a mobile beam (accelerating rotorod), and a coat-hanger. Although their posture was less stable than that of controls, the pcd mutants were not impaired in distance travelled or in latencies before falling on the static beams. Mutant performance on the grids was not impaired in comparison to controls, while a reduction of latencies before falling on the coat-hanger occurred only during the early part of training. On the accelerating rotorod, pcd mutants fell far sooner than controls and spent more time in passive rotation. By contrast to controls, pcd mutants were not able to improve with practice. Both mutants and controls were deficient during a retention test conducted 8 days after acquisition. The cerebellar cortex is critically involved in timing whole body movements during postural adjustments to a mobile beam but not to four types of immobile apparatus.

Analysis of Variance↗

PubMed1997

Neurobehavioral evaluation of lurcher mutant mice during ontogeny.

Lurcher mutant mice were compared to normal littermate controls for body weight, body righting, negative geotropism, sensorimotor coordination (rotating grid, wire suspension, rotorod), and visuomotor coordination requiring swimming toward a pole during postnatal (P) days 0-30. Lurcher mutants had a lower body weight on P20-P30 and were slower before performing the complete body righting response on P13-P30. Because of postural instability during the negative geotropism test, lurcher mutants turned quicker up the slope than normal mice. The mutants fell sooner from the rotating grid on P11-P14, from the horizontal wire on P15-P16, and from the rotorod on P14-P30. Lurcher mutants were also slower before swimming to the pole or climbing to the top of the pole and were inferior in pole climbing height on P22-P30. These results indicate test-selective and time-selective neurobehavioral deficits during ontogeny in a spontaneous cerebellar mutant.

Aging↗

PubMed1997

A revolving food pellet test for measuring sensorimotor performance in rats.

A revolving food pellet (RFP) test is presented, measuring the ability of rats to eat food pellets suspended from a horizontal bar in their home cage. This easy to make and economical device evaluates the efficiency of bilateral front paw coordination while standing. During the beginning of a ten day testing period, rats exposed to the RFP chamber had a lower intake of food and decreased body weight than rats housed in a standard home cage. With continued practice, the experimental group increased their food intake and body weight. During this time, the rats learned to control the revolving pellets by stabilizing them with their front paws and chewing on them. This apparatus is suitable for assessing a form of sensorimotor learning, involving the efficiency of front paw reaching, grasping, and holding movements, together with appropriate postural adjustments and biting movements. This test was sensitive to brain lesioning, as rats with bilateral lesions of the cerebellar fastigial nucleus were impaired.

Animals↗

PubMed1997

Impaired motor skills on static and mobile beams in lurcher mutant mice.

The cerebellum plays a role in various sensorimotor learning tasks. The purpose of the present studies was to evaluate sensorimotor skills in a spontaneous mouse mutant with cerebellar cortical atrophy. Lurcher mutant mice, characterized by massive losses of cerebellar granule cells and Purkinje cells, were assessed on two static beams varying in width and on an accelerating rotorod. On the static beams, lurcher mutants were deficient in stable positioning while immobile. Contrary to normal mice, they retreated backwards involuntarily and clung off-balance to the side of the beams. However, lurcher mutants were not deficient in segment crossings, body turns, latencies before crossing the first segment, and time spent in motion. There was an improvement over days in static stable positioning on both beams. On the rotorod, although lurcher mutants fell sooner and were inferior to controls in maximal speed of rotation achieved, there was an improvement on both measures across days. Moreover, retention of this motor skill was normal. These results indicate that, although lurcher mutants are limited in their capacity to execute motor coordination tasks, postural sensorimotor learning is not abolished in the absence of cerebellar cortical output neurons.

Animals↗

PubMed1997

Visuospatial abilities.

The importance of the hippocampus and its anatomical connections, including the medial septum, thalamic nuclei, and neocortical regions in many spatial tasks including the Morris water maze, has been emphasized. Studies in mutant mice with cerebellar atrophy and in rats with electrolytic lesions of the cerebellum have indicated that the cerebellum has a role in visuospatial and visuomotor processes in the Morris maze. Directional deficits in the water have also been noted in rats whose cerebellum was exposed to X-rays during different developmental stages. Cerebellar interactions with the superior colliculus, the hippocampus, and the neocortex via thalamic nuclei are suggested to be the basis of the cerebellar modulation of directional sense in maze tests.

Animals↗