Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease

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Lesions of the entorhinal cortex disrupt behavioral and neuronal responses to context change during extinction of discriminative avoidance behavior

 Rabbits given either electrolytic lesions of the entorhinal cortex or sham-lesions were trained to prevent a foot-shock by stepping in an activity wheel after one tone, a positive conditioned stimulus (CS+), and to ignore a different tone, a negative conditioned stimulus (CS–). Neuronal activity was recorded simultaneously in the basolateral nucleus of the amygdala, the CA1 cell field of hippocampus, anterior cingulate cortical area 24b and posterior cingulate cortical area 29c/d. The activity of neurons in the entorhinal cortex was recorded in the controls. Acquisition of conditioned avoidance responses (CRs) was not affected by lesions of the entorhinal cortex. Discriminative neuronal activity (greater neuronal responses to the CS+ than to the CS–) during CR acquisition was significantly enhanced in hippocampal area CA1 and attenuated in the basolateral amygdala in rabbits with lesions. Following acquisition to a criterion, two counterbalanced extinction tests were administered, one in the original context and the other in the presence of novel contextual stimuli. CR frequency was significantly reduced in controls but not in rabbits with lesions, during extinction with novel contextual stimuli, relative to performance in the original context. The rabbits with lesions also showed fewer inter-trial responses than controls during extinction in the original context but inter-trial response frequency in rabbits with lesions did not differ from the frequency in controls during extinction in the novel context. Neurons in the basolateral amygdala in controls showed discriminative activity during extinction in the original context but not in the novel context. Amygdalar neurons in the rabbits with lesions did not show discriminative activity during extinction in either context. Posterior cingulate cortical neurons in control rabbits did not show discriminative activity during extinction in the original context but these neurons exhibited robust discriminative activity in the novel context. Posterior cingulate cortical neurons in rabbits with lesions showed discriminative activity in both extinction sessions. The results indicated that the entorhinal cortex does not play a significant role in the acquisition of discriminative avoidance behavior, under the employed conditions of training. However, the interactions of neurons in the entorhinal cortex, amygdala and cingulate cortex are essential for contextual modulation of CRs during extinction. Received: 17 September 1996 / Accepted: 14 January 1997     

Patterns of Drop-Outs from a Methadone Program for Narcotic Addicts

The relationships of conduct problems, attention deficit hyperactivity disorder (ADHD) signs, and depression to substance use were examined between 1994 and 1999 among 900 incarcerated young offenders in South Australia, 206 of whom were reassessed when later readmitted to secure care. At the first and second assessments, conduct problems, ADHD signs, and depression scores all had significant concurrent associations with a measure of recent substance use. Prospectively, there were no significant associations between depression and substance use. At the zero-order level, both ADHD signs and conduct problems predicted future substance use. ADHD signs remained significantly predictive after controlling for concurrent associations. The results lend support to the view that substance use is related to general deviance and that the arousal needs associated with increased ADHD signs increase the risk of substance use. There was no support for the view that substance use in this population is self-medication in response to internalizing problems.     

Magnetic resonance spectroscopy of memory and frontal brain region in early multiple sclerosis

In vivo proton magnetic resonance spectroscopy (1H-MRS) has been used to assess biochemical changes that occur in demyelinating lesions and in normal appearing white matter (NAWM) in multiple sclerosis (MS) patients. N-acetylaspartate (NAA) levels in MS patients may indicate neural viability. In early stages of MS, patients may suffer from slight cognitive impairment. The objective of this study was to investigate memory function in relation to biochemical properties of frontal brain areas of MS patients. Twenty-one patients with relapsing-remitting MS and 21 healthy comparison subjects were examined psychometrically using the Wechsler Memory Scale (WMS) and the Multiple Sclerosis Functional Composite (MSFC) scale, and (1H-MRS) was used to examine frontal deep white matter (left hemisphere) and the frontal cingulate gyrus (Brodmann areas 24/32, bihemispheric). A significant reduction of the NAA/Creatine (Cr) ratio in the frontal cingulate gyrus among the MS patient group was detected when compared to healthy subjects. A significant decrease in the NAA/Cr ratio was also found in volumes of cerebral deep white matter, including plaques, in the MS patients. No NAA/Cr ratio changes were found in NAWM. Differences in MSFC results did not reach statistical significance, but the WMS general memory score showed a significant statistical difference between the patient group and healthy subjects. Regression analysis showed the gray matter NAA/Cr ratio of the frontal cingulate gyrus to be significantly related to distinct memory functions. The authors conclude that (1H-MRS) of gray matter in early stages of MS may be pertinent in the detections of early metabolic disturbances, particularly in subjects with or without minor neurological impairment. Findings suggest a general relationship between the metabolic status of the frontal cortices and memory function.     

Comparison of nerve terminal events in vivo effecting retrograde transport of vesicles containing neurotrophins or synaptic vesicle components

Although vesicular retrograde transport of neurotrophins in vivo is well established, relatively little is known about the mechanisms that underlie vesicle endocytosis and formation before transport. We demonstrate that in vivo not all retrograde transport vesicles are alike, nor are they all formed using identical mechanisms. As characterized by density, there are at least two populations of vesicles present in the synaptic terminal that are retrogradely transported along the axon: those containing neurotrophins (NTs) and those resulting from synaptic vesicle recycling. Vesicles containing nerve growth factor (NGF), NT-3, or NT-4 had similar densities with peak values at about 1.05 g/ml. Synaptic-derived vesicles, labeled with anti-dopamine beta-hydroxylase (DBH), had densities with peak values at about 1.16 g/ml. We assayed the effects of pharmacologic agents in vivo on retrograde transport from the anterior eye chamber to the superior cervical ganglion. Inhibitors of phosphatidylinositol-3-OH (PI-3) kinase and actin function blocked transport of both anti-DBH and NGF, demonstrating an essential role for these molecules in retrograde transport of both vesicle types. Dynamin, a key element in synaptic vesicle recycling, was axonally transported in retrograde and anterograde directions, and compounds able to interfere with dynamin function had a differential effect on retrograde transport of NTs and anti-DBH. Okadaic acid significantly decreased retrograde axonal transport of anti-DBH and increased NGF retrograde transport. We conclude that there are both different and common proteins involved in endocytosis and targeting of retrograde transport of these two populations of vesicles.     

Connections of the caudal anterior cingulate cortex in rabbit: neural circuitry participating in the acquisition of trace eyeblink conditioning

The caudal anterior cingulate cortex (cAC) is an essential component of the circuitry involved in acquisition of forebrain-dependent trace eyeblink conditioning. Lesions of the cAC prevent trace eyeblink conditioning [Weible AP, McEchron MD, Disterhoft JF (2000) Cortical involvement in acquisition and extinction of trace eyeblink conditioning. Behav Neurosci 114(6):1058-1067]. The patterns of activation of cAC neurons recorded in vivo suggest an attentional role for this structure early in training [Weible AP, Weiss C, Disterhoft JF (2003) Activity profiles of single neurons in caudal anterior cingulate cortex during trace eyeblink conditioning in the rabbit. J Neurophysiol 90(2):599-612]. The goal of the present study was to identify connections of the portion of the rabbit cAC previously demonstrated to be involved in trace eyeblink conditioning, using the neuronal tract tracer wheat germ agglutinin conjugated to horseradish peroxidase, to better understand how the cAC contributes to the process of associative learning. Reciprocal connections with the claustrum provide a route for the transfer of sensory information between the cAC and neocortical and allocortical regions also involved in learning. Connections with components of the basal forebrain cholinergic system are described, with relevance to the proposed attentional role of the cAC. Reciprocal and unidirectional connections were in evidence in multiple thalamic regions, including the medial dorsal nucleus, which have been implicated in a variety of conditioning paradigms. Anterograde connections with the caudate and lateral pontine nuclei provide access to forebrain motor and brainstem sensory circuitry, respectively. The relevance of these connections to acquisition of the trace conditioned reflex is discussed.     

Transport of transforming growth factor-beta 2 across the blood-brain barrier

The blood-brain barrier acts as an interface between the brain and body through a combination of restrictive mechanisms and transport processes. Substances essential for brain function pass through the barrier either by passive diffusion or by active transport. We report here that [125I]-transforming growth factor-beta2 (TGF-beta2) passes through the blood-brain barrier and blood-nerve barriers, after intravenous, intraperitoneal or intramuscular injections. The entry of the [125I]-TGF-beta2 to the brain was rapid, saturable and inhibited by co-injection of unlabelled TGF-beta2. In contrast, co-injection of unlabelled TGF-beta2 increased the retention of [125I]-TGF-beta2 in the blood. The [125I]-TGF-beta2 transported into the brain was localised by autoradiography to the extracellular space, and was intact as judged by SDS-PAGE. The [125I]-TGF-beta2 was widely distributed throughout the brain, with the highest concentrations in the hypothalamus and nerves and the lowest in the cerebral hemispheres. The [125I]-TGF-beta2 had a half-life of 4 h in the brain. These results indicate that therapeutically relevant levels of TGF-beta2 reach the brain after peripheral administration of TGF-beta2.