Childhood-Onset Non-Infectious Uveitis in the "Biologic Era". Results From Spanish Multicenter Multidisciplinary Real-World Clinical Settings.

OBJECTIVE: To characterize and describe clinical experience with childhood-onset non-infectious uveitis. STUDY DESIGN: A multicenter retrospective multidisciplinary national web-based registry of 507 patients from 21 hospitals was analyzed. Cases were grouped as immune disease-associated (IMDu), idiopathic (IDIu) or ophthalmologically distinct. Characteristics of juvenile idiopathic arthritis-associated (non-HLA-B27-related) uveitis (JIAu), IDIu, and pars planitis (PP) were compared. RESULTS: IMDu (62.3%) and JIAu (51.9%) predominated in young females; and IDIu (22.7%) and PP (13.6%) in older children, without sex imbalance. Ocular complications occurred in 45.3% of cases (posterior synechiae [28%], cataracts [16%], band keratopathy [14%], ocular hypertension [11%] and cystoid macular edema [10%]) and were associated with synthetic (86%) and biologic (65%) disease-modifying antirheumatic drug (DMARD) use. Subgroups were significantly associated (p < 0.05) with different characteristics. JIAu was typically anterior (98%), insidious (75%), in ANA-positive (69%), young females (82%) with fewer complications (31%), better visual outcomes, and later use of uveitis-effective biologics. In contrast, IDIu was characteristically anterior (87%) or panuveitic (12.1%), with acute onset (60%) and more complications at onset (59%: synechiae [31%] and cataracts [9.6%]) and less DMARD use, while PP is intermediate, and was mostly bilateral (72.5%), persistent (86.5%) and chronic (86.8%), with more complications (70%; mainly posterior segment and cataracts at last visit), impaired visual acuity at onset, and greater systemic (81.2%), subtenon (29.1%) and intravitreal (10.1%) steroid use. CONCLUSION: Prognosis of childhood uveitis has improved in the "biologic era," particularly in JIAu. Early referral and DMARD therapy may reduce steroid use and improve outcomes, especially in PP and IDIu.

Oral health in children with acute lymphoblastic leukaemia: before and after chemotherapy treatment.

AIM: To evaluate changes in the oral health status of children under the age of 14 years with acute lymphoblastic leukaemia (ALL) attending a cancer centre before and after chemotherapy treatment. MATERIALS AND METHODS: A total of 32 children with ALL without distinction of gender were selected for study. The oral cavity of the patients was evaluated before the induction stage and 17 days later. Clinical evaluation of the submandibular, submental, and cervical lymph nodes was performed. Saliva samples were collected during the early morning hours. Bacterial plaque was assessed by using the Silness and Löe plaque index (SLPI) and gingiva status was evaluated with the gingival Löe and Silness index (GLSI). The WHO toxicity oral scale was used to record the degree of oral mucositis. The resulting data were analysed with McNemar's test, t test (for related samples), and Wilcoxon test. RESULTS: There were statistically significant differences for palpable lymph nodes, paleness of oral mucosa, and ecchymoseis, respectively, P ≤ 0.000, P = 0.03, and P = 0.01, with these manifestations decreasing significantly after treatment. Incipient gingivitis had frequencies of 71.9% and 75% before and after treatment, respectively. The mean SLPI score declined significantly from 1.16 ± 0.52 (before treatment) to 0.56 ± 0.36 (after treatment) (P < 0.000); salivary flow increased significantly from 0.54 ± 0.34 to 1.22 ± 1.07 after chemotherapy treatment (P < 0.00). Oral mucositis was present in 24 children (75%) with a 1-2 severity level. CONCLUSIONS: After chemotherapy treatment, there were changes in the oral conditions of children with ALL. Some manifestations decreased after treatment, whereas in others increased.

Persistent alteration in behavioural reactivity to a mild social stressor in rhesus monkeys repeatedly exposed to sevoflurane in infancy.

BACKGROUND: Socio-emotional development is the expression and management of emotions, which in non-human primates can be examined using responses toward increasing levels of threat. Damage to the limbic system alters socio-emotional development in primates. Thus, neuronal and glial cell loss caused by exposure to general anaesthesia early in infancy might also impact socio-emotional development. We recently reported that repeated sevoflurane exposure in the first month of life alters emotional behaviours at 6 months of age and impairs visual recognition memory after the first year of life in rhesus monkeys. The present study evaluated socio-emotional behaviour at 1 and 2 yr of age in those same monkeys to determine the persistence of altered emotional behaviour. METHODS: Rhesus monkeys of both sexes were exposed to sevoflurane anaesthesia three times for 4 h each time in the first 6 weeks of life. At 1 and 2 yr of age, they were tested on the human intruder task, a well-established mild acute social stressor. RESULTS: Monkeys exposed to sevoflurane as infants exhibited normal fear and hostile responses, but exaggerated self-directed (displacement) behaviours, a general indicator of stress and anxiety in non-human primates. CONCLUSIONS: Early repeated sevoflurane exposure in infant non-human primates results in an anxious phenotype that was first detected at 6 months, and persists for at least 2 yr of age. This is the first demonstration of such a prolonged impact of early anaesthesia exposure on emotional reactivity.

Visual recognition memory is impaired in rhesus monkeys repeatedly exposed to sevoflurane in infancy.

BACKGROUND: Experimental studies in animals have shown that exposure to general anaesthesia in infancy can cause loss of cells in the central nervous system and long-term impairments in neurocognitive function. Some human epidemiological studies have shown increased risk of learning disability after repeated anaesthesia exposure in early childhood. Thus, we investigated in a highly translational rhesus monkey model, whether repeated exposure in infancy to the inhalation anaesthetic sevoflurane is associated with impaired visual recognition memory during the first two yr of life. METHODS: Rhesus monkeys of both sexes were exposed to sevoflurane inhalation anaesthesia on approximately postnatal day 7 and then again 14 and 28 days later, for four h each time. Visual recognition memory was tested using the visual paired comparison task, which measures memory by assessing preference for looking at a new image over a previously-viewed image. Monkeys were tested at 6-10 months of age, again at 12-18 months of age, and again at 24-30 months of age. RESULTS: No memory impairment was detected at 6-10 months old, but significant impairment (reduced time looking at the novel image) was observed at 12-18 and 24-30 months old. CONCLUSIONS: Repeated exposure of infant rhesus monkeys to sevoflurane results in visual recognition memory impairment that emerges after the first yr of life. This is consistent with epidemiological studies that show increased risk of learning disability after repeated exposure to anaesthesia in infancy/early childhood. Moreover, these deficits may emerge at later developmental stages, even when memory performance is unaffected earlier in development.

Memory and socioemotional behavior in monkeys after hippocampal damage incurred in infancy or in adulthood.

The present study reviews the long-term effects of neonatal hippocampal damage in monkeys on the development of memory functions and socioemotional behavior. The results showed that neonatal damage to the hippocampal formation impairs specific memory processes, such as those subserving automatic (as opposed to effortful) recognition memory and relational learning, while sparing the abilities to acquire skills, such as object discriminations. Furthermore, the neonatal hippocampectomy led to a progressive loss of social affiliation and a protracted emergence of locomotor stereotypies. While the memory losses following neonatal hippocampal lesions resemble those found after similar lesions acquired in adulthood, only the neonatal lesions resulted in a protracted emergence of abnormal behaviors. These later findings suggested that, presumably, the neonatal lesions impacted on neural systems remote from the site of damage. This was confirmed by our more recent neurobiological studies, demonstrating that neonatal, but not late, lesions of the medial temporal lobe region, disrupt the normal behavioral and cognitive processes subserved by the prefrontal cortex and the caudate nucleus. All together the data support the neurodevelopmental hypothesis viewing early insult to the medial temporal region as the origin of developmental psychosis in humans, such as schizophrenia.

Long-term effects of neonatal damage to the hippocampal formation and amygdaloid complex on object discrimination and object recognition in rhesus monkeys (Macaca mulatta).

Rhesus monkeys with neonatal aspiration lesions of the hippocampal formation or the amygdaloid complex were tested on concurrent discrimination learning (24-hr intertrial interval [ITI]) at 3 months, on object recognition memory (delayed nonmatching-to-sample [DNMS]) at 10 months, and retested on both tasks at 6-7 years of age. Neonatal amygdaloid damage mildly impaired acquisition at the 24-hr ITI and the performance test of DNMS at both ages. In contrast, early hippocampal lesions impaired performance only on the longest lists of 10 items in DNMS in adult monkeys. Thus, early amygdala lesions appeared to have resulted in a greater object memory loss than early hippocampal lesions. However, in light of recent findings from lesion studies in adult monkeys, the object memory impairment after early amygdaloid lesions is better accounted for by damage to the entorhinal and perirhinal cortex than by damage to the amygdaloid nuclei.

A comparison of kainic acid plus colchicine and ibotenic acid-induced hippocampal formation damage on four configural tasks in rats.

J.W. Rudy and R.J. Sutherland (1989) suggested that the hippocampal formation (HF) is necessary for performance of configural tasks and that rats with kainic acid + colchicine (K-C) damage to the HF were impaired on the negative patterning problem (A+, B+, AB-). However, M. Gallagher and P.C. Holland (1992) found spared performance on a similar task (AC+, B+, AB-, C-) when ibotenic acid (IBO) was used. This study compared the effects of K-C- and IBO-induced HF damage on 4 configural tasks: (a) negative patterning, (b) the Gallagher-Holland task, (c) transverse patterning, and (d) place learning. Rats with IBO lesions performed like controls on the Gallagher-Holland task (replicating M. Gallagher & P.C. Holland) but were impaired on negative patterning, transverse patterning, and place learning. In contrast, rats with K-C lesions were impaired on all 4 tasks. The implications of these results for theories of HF function are discussed.

Rats with damage to the hippocampal-formation are impaired on the transverse-patterning problem but not on elemental discriminations.

We assessed the effects of hippocampal-formation (HF) damage on the rat's ability to learn two sets of concurrent visual discriminations. Each set included three problems. One set, called the transverse-patterning problem, was constructed so that each choice stimulus was ambiguous; sometimes it was the correct (+) and sometimes it was the incorrect (-) choice as follows: A+ vs. B-, B+ vs. C-, and C+ vs. A-. It could not be solved unless rats used configural associations. The stimuli were not ambiguous in the second, elemental problem set, A+ vs. B-, C+ vs. D-, and E+ vs. F-. Rats could solve this set without the use of configural associations. Rats with HF damage solved the set of elemental problems, but their performance on the transverse-patterning problem was impaired. These results support Sutherland and Rudy's (1989) theory that the hippocampal formation is critical for the acquisition of configural associations.

[Hepatobiliary complications detected by ultrasonography in patients undergoing total parenteral nutrition]. / Complicaciones hepato-biliares detectadas por ultrasonografía en pacientes con nutrición parenteral total.

We studied 8 adult patients who received total parenteral nutrition (TPN). An abdominal ultrasound and liver functions test were done weekly looking for biliary sludge, thickening of the gallbladder wall, changes en bile ducts and liver parenchyma. Seven patients developed biliary sludge at week four. We didn't detect changes in bile ducts neither in the gallbladder wall. Two patients had elevations of bilirubin, Alkaline phosphatase and aminotransferase during TPN. 3 patients developed mild liver steatosis detected by ultrasound during the third and sixth week of NPT. Our findings agree with other studies that describe the development of biliary sludge, gallbladder stones, liver steatosis and colestasis in patients receiving TPN. Once TPN is stopped and oral feeding is restarted this changes usually disappear.

Some properties of configural learning: an investigation of the transverse-patterning problem.

Little is known about the conditions that encourage animals to learn to use configural associations to guide their behavior or the consequences of such learning for transfer. This study provided some information about these issues by examining how rats solve the transverse-patterning problem, which requires a configural solution (Spence, 1952). Animals had to concurrently solve 3 simultaneous visual discriminations, represented abstractly as A+ versus B-, B+ versus C-, and C+ versus A-. Experiment 1 indicated that rats use a configural solution even when the problems have an elemental solution, provided that the significance of 1 element (e.g., B) shared by 2 problems is ambiguous (e.g., A+/B-; and B+/C-). Experiments 2 and 3 suggested that, when stimulated to use a configural solution by solving the A+/B- and B+/C- problems, rats transfer the configural solution to problems that have no ambiguous elements.

Reversible inactivation of the medial septum differentially affects two forms of learning in rats.

The contribution of the medial septum to different aspects of spatial information processing was assessed by examining the effects of reversible septal inactivation on radial maze performance of rats. In addition, the selectivity with which the medial septum affects learning was studied by testing the effects of septal inactivation on the acquisition of non-spatial information. Rats were first trained according to a spatial working memory procedure that included a 30-min delay between the first 4 (forced) choices and subsequent test (free) choices. The forced choices comprised the sample phase of the experiment while the free choices comprised the test phase. Saline or tetracaine (a local anesthetic) was injected into the medial septal area either before the sample phase, after the sample phase (i.e. at the beginning of the delay period), or just before the test phase. In contrast to the saline injections, tetracaine injected just before the sample or test phases produced a significant increase in errors at test. Tetracaine injection at the beginning of the delay period did not affect test choice accuracy. EEG records showed that septal inactivation drastically, yet temporarily, reduced the hippocampal theta rhythm. Thus, when septal inactivation occurred either before the sample phase or at the beginning of the delay period, hippocampal theta recovered by the time of the test phase. Septal inactivation also produced a significant retardation of learning on a non-spatial reference memory task, although clear improvement over trials did occur. Moreover, the results of subsequent saline injections suggest that at least some of the performance deficit was due to variables other than learning per se.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of opioid peptides on learning and memory processes in the chick.

Several experiments were conducted to examine the effects of intracranial injection of opioid peptides and antagonists on learning and memory in the chick. Pretraining injection of [leu5]enkephalin and the selective delta receptor agonist [D-Pen2,L-Pen5]enkephalin (DPLPE) into the intermediate medial hyperstriatum ventrale (IMHV) produced impairment. ICI 174,864, a delta-selective antagonist, reversed the impairment produced by either [leu5]enkephalin or DPLE, results indicating that delta receptors may play a role in learning in the chick and suggesting that the impairment produced by [leu5]enkephalin is mediated through delta opioid receptors. beta-endorphin produced a naloxone-reversible impairment in performance, which suggests that this impairment is mediated by opioid receptors. Bilateral injection of beta-endorphin into the IMHV produced impairment, as did unilateral injection into the right, but not left, IMHV. Only bilateral injections into IMHV of [leu5]enkephalin were effective. These results suggest that the effects of beta-endorphin are centrally mediated whereas the effects of [leu5]enkephalin may be localized to other brain regions or are peripherally mediated. These initial results suggest that opioids are associated with learning and memory in the chick.

Time courses of amnesia development in two areas of the chick forebrain.

The roles of different forebrain structures in stages of memory formation were investigated by injecting agents into either the left medial hyperstriatum ventrale (MHV) or right lateral neostriatum (LNS) close to the time of one-trial taste-avoidance training. With L-glutamate injected into either the left MHV or right LNS 5 minutes pretraining, retention was good 1 minute posttraining but significantly impaired at 5 minutes and each subsequent time point. With emetine injected into either area, retention was still good 60 minutes posttraining but significantly impaired at 90 minutes. With ouabain, retention declined more slowly following injection into the right LNS (at 45 minutes) compared to injection in the left MHV (at 30 minutes). A second experiment confirmed the regional difference in amnesia development produced by ouabain. These results indicate that the duration of short-term memory is longer following inhibition of intermediate-term memory (ITM) in the right LNS, compared to inhibition of ITM in the left MHV.

Memory stages and brain asymmetry in chick learning.

Stages of formation of memory and the roles of different forebrain structures in memory formation were investigated by injecting various agents into the brains of chicks close to the time of peck-avoidance training. With L-glutamate injected bilaterally into the hyperstriatum 5 min pretraining, retention was good 1 min posttraining but significantly impaired at 5 min and each subsequent time point from 10 min to 24 hr. With ouabain, retention declined more slowly, showing significant impairment at 15 min and thereafter. With any of three protein synthesis inhibitors (anisomycin, cycloheximide, or emetine), retention was still good 60 min posttraining but significantly impaired at 90 min. The three time courses of decline of retention are consistent with hypotheses of three sequentially dependent stages of memory formation. Glutamate, ouabain, and emetine were found to affect only a restricted volume of tissue. Any of these three agents induced amnesia when injected into the left (but not the right) medial hyperstriatum ventrale or into the right (but not the left) lateral neostriatum; so it appears that both structures are required for formation of memory. Agents that are specific for a presumed stage of memory formation and whose action is restricted spatially should help reveal the roles of different brain structures in different stages of memory formation.

An economically constructed and durable intracerebral cannula system for small rodents.

An easily constructed cannula system is described for applying experimental substances to the brain of freely moving mice. Stainless steel tubing surrounded by a nylon insulator cap glued to the skull provides an economical and durable system which requires little preparation.