Diastolic function in children and adolescents on dialysis and after kidney transplantation: an echocardiographic assessment

Thirty-seven children and adolescents on renal replacement therapy (11 on haemodialysis, 14 on continuous ambulatory peritoneal dialysis and 12 after renal transplantation) were studied by echocardiography, echo-Doppler and phonocardiography. Right and left ventricular (R/L V) diastolic functions were measured by transmitral and transtricuspid flow velocities and by LV isovolumic relaxation time (LVIRT). Thirty-seven age- and sex-matched healthy subjects served as controls. R/L V diastolic dysfunction was only observed in the dialysis patients. In these patients LVIRT was prolonged. LV and RV peak inflow velocities were increased both in early (E) and late (A) diastole with a reduction in the E/A ratios. This pattern of diastolic dysfunction is compatible with the combined effects of a hypercirculatory state (volume overload, anaemia, arteriovenous fistula) and an abnormality of cardiac relaxation. The transplant patients showed no major cardiac abnormalities.     

Facilitation of discrimination transfers under amphetamine: the relative control by S+ and S− and general transfer effects

Rats were trained in a Y-maze on a two-choice simultaneous black-white discrimination with either black or white as S⁺. Animals were then transferred to one of three discrimination tasks. In task 1 (New S^–), a new stimulus, either vertical or horizontal stripes, was substituted for the original S^–. In task 2 (New S⁺), a new stimulus, either vertical or horizontal stripes as in task 1, was substituted for the original S⁺. In task 3 (New S⁺/S^–) animals were trained on horizontal-vertical discrimination. The pre-trial administration of 1 mg/kg d-amphetamine facilitated the acquisition of the original black-white discrimination with both black as S⁺ and white as S⁺. Likewise, the drug improved performance in all three transfer conditions. However, the course of learning in the three transfer tasks was different in the placebo- and amphetamine-treated animals. Amphetamine-treated animals were disrupted more by a change in S⁺ than by a change in S^–, whereas the opposite pattern was evident in the placebo controls. When both discriminative stimuli were changed, placebo animals exhibited pronounced decrement in performance, whereas amphetamine animals exhibited excellent learning. The implications of these findings for the effects of amphetamine on discrimination learning are discussed.     

Deprivation of parenting disrupts development of homeostatic and reward systems in marmoset monkey offspring.

BACKGROUND: Early environment is a major determinant of long-term mental health, evidenced by the relationship between early-life neglect or abuse and chronically increased vulnerability to developmental psychopathology, including major depressive disorder (MDD). Animal studies can increase understanding of environmentally mediated causal risk processes. We describe how daily deprivation of biological parenting in primate infants disrupts development of homeostatic and reward systems central to MDD. METHODS: Nine breeding pairs of marmoset monkeys provided control twins (CON) and early-deprived twins (ED); the latter were socially isolated for 30-120 min/day on days 2-28. During the first year of life, basal urinary norepinephrine (NE) titers and cardiophysiologic activity were measured. At the end of year 1 (adolescence), automated neuropsychologic tests were conducted to measure responsiveness to changes in stimulus-reward association (simple/reversed visual discrimination learning) and to reward per se (progressive ratio [PR] reinforcement schedule). RESULTS: The ED monkeys exhibited increased basal urinary NE titers and increased systolic blood pressure relative to CON siblings. The ED monkeys required more sessions to reinstate stimulus-oriented behavior following reversal, suggesting increased vulnerability to perceived loss of environmental control; ED monkeys also performed less PR operant responses, indicating that reward was less of an incentive and that they were mildly anhedonic relative to CON. CONCLUSIONS: In marmoset monkeys, neglect-like manipulation of ED leads to chronic changes in homeostatic systems, similar to those in children and adolescents exposed to early-life adversity and in MDD, and to responses to environmental stimuli similar to those that characterize MDD.     

Effects of haloperidol on the multitrial partial reinforcement extinction effect (PREE): evidence for neuroleptic drug action on nonreinforcement but not on reinforcement

Two experiments investigated the effects of haloperidol (0.1 mg/kg) on the partial reinforcement extinction effect (PREE). In experiment 1 two groups of rats were trained to run in a straight alley using six trials/day with an intertrial interval (ITI) of 5–8 min. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Haloperidol was administered in a 2 × 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. In experiment 2 two groups of rats were trained to press a lever in an operant chamber using a discrete trial procedure of ten trials/day with an ITI of 60 s. The CRF group was rewarded on each trial and the PRF group was rewarded on a quasi-random 50% schedule. Haloperidol was administered for 22 days prior to the start of the PREE procedure as well as throughout acquisition and extinction. The PREE, i.e., increased resistance to extinction of PRF as compared to CRF animals, was obtained in both experiments in all drug conditions. In both experiments haloperidol increased the rate of extinction. Experiment 1 revealed that this effect was entirely dur to the administration of the drug in extinction, independently of the drug condition in acquisition. In contrast to previous results in a one trial/day procedure, the administration of haloperidol to CRF animals did not increase resistance to extinction, failing to support the notion that neuroleptics attenuate the rewarding properties of reinforcement.     

Anterior ischemic optic neuropathy: Classification of field defects by Octopus™ automated static perimetry

Visual fields of patients with anterior ischemic optic neuropathy (AION) were classified according to quantitative criteria, using the Octopus perimeter. Although a significant altitudinal pattern of field loss was found in 55% of perimetric examinations, the "spared" hemifields routinely showed some loss of sensitivity. This finding, along with the diffuse loss of sensitivity in a high percentage of visual fields, indicates more extensive involvement of the circulation of the anterior optic nerve head than has previously been suggested. Furthermore, patients with diabetes mellitus alone were found to have a statistically separable pattern of visual field loss. The pathophysiologic implications of the visual fields in AION and their relationship to the clinical findings were investigated.     

The ventral hippocampus and fear conditioning in rats. Different anterograde amnesias of fear after tetrodotoxin inactivation and infusion of the GABA(A) agonist muscimol

Studies on the involvement of the rat hippocampus in classical fear conditioning have focused mainly on the dorsal hippocampus and conditioning to a context. However, the ventral hippocampus has intimate connections with the amygdala and the nucleus accumbens, which are involved in classical fear conditioning to explicit and contextual cues. Consistently, a few recent lesion studies have indicated a role for the ventral hippocampus in classical fear conditioning to explicit and contextual cues. The present study examined whether neuronal activity within the ventral hippocampus is important for the formation of fear memory to explicit and contextual cues by classical fear conditioning. Tetrodotoxin (TTX; 10 ng/side), which completely blocks neuronal activity, or muscimol (1 microg/side), which increases GABA(A) receptor-mediated inhibition, were bilaterally infused into the ventral hippocampus of Wistar rats before the conditioning session of a classical fear-conditioning experiment. Conditioning to a tone and the context were assessed using freezing as a measure of conditioned fear. TTX blocked fear conditioning to both tone and context. Muscimol only blocked fear conditioning to the context. The data of the present study indicate that activity of neurons in the ventral hippocampus is necessary for the formation of fear memory to both explicit and contextual cues and that neurons in the ventral hippocampus that bear the GABA(A) receptor are important for the formation of fear conditioning to a context. In addition, both bilateral muscimol (0.5 microg/side and 1 microg/side) and TTX (5 ng/side and 10 ng/side) infusion into the ventral hippocampus dose-dependently decreased locomotor activity in an open-field experiment.     

Microinfusion of the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of wistar rats does not affect latent inhibition and prepulse inhibition, but increases startle reaction and locomotor activity

Latent inhibition (the retarded conditioning to a stimulus following its repeated non-reinforced pre-exposure) and prepulse inhibition (the reduction in the startle response to an intense acoustic stimulus when this stimulus is immediately preceded by a prepulse) reflect cognitive and sensorimotor gating processes, respectively, and are deficient in schizophrenic patients. The disruption of latent inhibition and prepulse inhibition in the rat is used as an animal model for the attentional deficits associated with schizophrenia. The present study tested the extent to which latent inhibition and prepulse inhibition, startle reaction and locomotor activity in the open field were affected by infusing the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats. We used the same dose of MK-801 (6.25microg/0.5microl per side) previously found to be effective in the disruption of prepulse inhibition when infused into the dorsal hippocampus of Sprague-Dawley rats [Bakshi V. P. and Geyer M. A. (1998) J. Neurosci. 18, 8394-8401; Bakshi V. P. and Geyer M. A. (1999) Neuroscience 92, 113-121]. Bilateral infusion of MK-801 into the dorsal hippocampus did not disrupt latent inhibition. Furthermore, in contrast to previous studies, we failed to find a significant disruption of prepulse inhibition after MK-801 infusion into the dorsal hippocampus, although MK-801 infusion was effective in increasing the startle amplitude as well as locomotor activity in an open field.From our results, we suggest that N-methyl-D-aspartate receptor-mediated processes within the dorsal hippocampus are not necessary for the normal maintenance of the attentional processes reflected by latent inhibition and prepulse inhibition.     

Circadian‐ and temperature‐specific effects of early deprivation on rat maternal care and pup development: Short‐term markers for long‐term effects?

We compare the effects on pup body weight and on maternal care of 4-hr separation from dam and littermates on postnatal Days 1 to 14 (early deprivation, ED) under different thermal and circadian conditions. ED was performed at either 21 degrees C (Cold), or 32 degrees C (Warm), and either during the light or dark phase. The comparison group was nonhandling (NH), either under a nonreversed (Light) or reversed (Dark) cycle. At weaning, Cold ED pups were of lower body weight than Warm ED pups, and Warm ED pups were of lower body weight than NH pups. Light and Dark ED pups received high care at reunion relative to NH, and Cold ED pups received higher care at several hours postreunion relative to Warm ED and NH pups. We propose that reduced pup weight and increased maternal care are short-term markers for the severity of Cold ED, and that this manipulation could therefore impact negatively on emotionality and cognition in adulthood.     

A novel ELISpot method for adherent cells

The purpose of this study was to develop an enzyme-linked immunospot assay (ELISpot assay) that can be used with human adherent cells. While standard enzyme-linked immunosorbent assays (ELISAs) are available and widely used and ELISpot assays are used for nonadherent lymphocytes, no ELISpot assay has been developed for adherent cells. We used primary human fibroblasts from four different tissues (myometrium, lung, gingiva, and orbit), either unstimulated or interleukin (IL)-1beta-activated, to evaluate an ELISpot assay. Antibody pairs for IL-6 and IL-8 were used and results were compared to a standard ELISA. We found that we could reliably detect IL-6 and IL-8 spots with as few as 10 fibroblasts. Optimal cell numbers were 50 cells per well incubated for 8 h, although spots appeared as early as 2 h after incubation. Spots were absent when cells, primary, or secondary anti-cytokine antibodies were omitted from the protocol. Spot number and size can be ascertained using current automated ELISpot reader technology. The frequency of IL-6 and IL-8-producing human fibroblasts could also be determined. For example, 60% of the lung fibroblasts express IL-6, but IL-8 can be detected from only 40% of the cells. Approximately 80% of the human orbital fibroblasts make IL-6, whereas approximately 50% generate IL-8 following IL-1beta stimulation. These new findings show that fibroblasts from different human tissues display different frequencies of cytokine production and this further supports the concept of fibroblast diversity. The sensitivity of this new ELISpot assay is adequate for cytokine detection in just a few cells, unlike the standard ELISA. It should permit ascertaining the frequency of fibroblasts and other adherent cells that produce cytokines and, if desired, can be used in tandem with a standard ELISA to determine total cytokine produced. Moreover, the assay is suitable for normal human adherent cells that are often short-lived and difficult to cultivate.     

Amphetamine does not affect the partial punishment effect (PPE)

The effects of amphetamine on the partial punishment effect (PPE) at one trial per day, were examined. Two groups of animals were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially punished (PP) group received food reward on every trial but in addition, received footshocks of a gradually increasing intensity in the goal box on a random 50% of the trials. In the test stage, all animals received both food and footshock on each trial. dl-Amphetamine 1.5 mg/kg was administered in a 2 × 2 design, i.e. drug-no drug in training and drug-no drug in test. The partially punished animals exhibited increased persitence in running to the goal box during test, and this partial punishment effect was unaffected by amphetamine.