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Teaching clinical problem solving in preclinical occlusion courses.

The teaching of the basic principles and concepts of occlusion can be enhanced. Preclinical occlusion courses are made relevant to the clinical experience by introducing clinically related problem-solving exercises. These exercises develop a student's clinical problem-solving skill and create an excitement for active learning in the preclinical laboratory. Examples of these exercises are presented.

Clinical Competence

[Role of the adrenal medulla in reaction of the body to stress (clinical and laboratory studies and experimental research)].

The authors have carried out a clinical study of acute medico-surgical complications occuring in patients hospitalized following psychical stress, myocardial infarction, operatory shock and after the earthquake. In patients with duodenal ulcers and hyperacidity due to vagal neurogenic origins it was noted the presence of a sympatico-adrenergic constitutional background in 38% of the cases. By applying chemical sclerosis of the adrenals medullary the role of the medullary was demonstrated in the production of acute digestive lesions due to stress, as a result of standard electrical stimulus and of their influence on the bioelectrical reactivity of the brain, on the active learning behaviour by conditioned reaction and on the number of the circulating eosinophils following injections of A.C.T.H.

Adrenal Medulla

Ontogeny of active avoidance in the rat: learning and memory.

Ontogenetic development of active avoidance learning, extinction and retention was studied in rats. The learning of a 1-way active avoidance was most rapid between Weeks 4 and 6, although some slight gender-related differences were evident. No such unambiguous development was detected in forced extinction. The 24-hr retention of avoidance peaked at the age of 4 weeks whereas 1-month retention was best in animals trained at the age of 8 weeks. The retrieval of memory trace also had best values at these ages. Retention of forced extinction was found to peak in 6-week animals. The existence of developmental "critical periods" must be considered cautiously as various functions have different time courses depending upon the chosen parameters in assessment.

Animals

Purkinje cell activity during motor learning.

Monkeys were trained to grasp a handle and move it in a horizontal arc to a central position by flexing or extending the wrist. A torque motor applied forces to the handle that switched at random intervals to alternately load flexor and extensor muscles. At each load switch, the handle was displaced transiently from the central position, and then moved back by the monkeys and held there steadily again. Recordings were made from cerebellar Purkinje cells (P-cells) whose simple spike (SS) activity was related to the task. The magnitude of one of the oppositely directed loads was then altered and the monkeys took about 12-100 trials with the novel load before performing as regularly as previously. During this period with one known and one novel load, some P-cells underwent increases in complex spike (CS) frequency at specific times after the load switch. This increased CS frequency would last for a similar number of trials as that taken by the monkey to adapt to the novel load before decreasing to near its previous level. Associated with the increased CS frequency ther were decreases in SS frequency that persisted after the CS frequency had decreased to near its previous level. These results are consistent with theoretical proposals that motor learning takes place in the cerebellum through changes in the strength of transmission of parallel fiber synapses on P-cells caused by the climbing fiber input. These results further suggest that climbing fiber firing causes a decrease in the strength of parallel fiber synapses.

Action Potentials

Identification of pyramidal cells as the critical elements in hippocampal neuronal plasticity during learning.

The activity of single neurons recorded from rabbit hippocampus during classical conditioning of the nictitating membrane reflex was studied. All cells were first categorized according to their responses after fornix stimulation--i.i., antidromic activation, orthodromic activation, or no activation. The majority of cells that were antidromically activated--pyramidal cells--showed a highly positive correlation between the pattern of unit discharge and the topography of the nicititating membrane response within trial periods. Units that were orthodromically driven by fornix stimulation tended to inhibit during the presentation of trial stimuli, whereas most non-activated cells maintained low spontaneous levels of activity at all times. Thus, the major output neurons of the hippocampus appear to be the neuroanatomical substrate for the large and rapidly developing neuronal plasticity induced by this classical conditioning paradigm.

Action Potentials

Teratopsychogenetic effects apparently produced by nonphysiological neurotransmitter concentrations during brain differentiation.

In male rats treated with pargyline, reserpine or pyridostigmine during neonatal life significant permanent changes of sexual behaviour and conditioned learning behaviour were observed in juvenile and/or adult life. Male sexual activity and learning capacity were permanently decreased in neonatally pargyline- or reserpine-treated animals, but permanently increased in neonatally pyridostigmine-treated rats. These findings suggest that nonphysiological concentrations and/or turnover rates of neurotransmitters, if produced during a critical period of brain differentiation, are able to induce lifelond effective behavioural changes, i.e. teratopsychogenetic effects.

Animals

[Effectiveness of different types of reinforcement in a controlled experiment].

The paper shows the possibility for animals to learn to change the form of their own evoked electrical brain activity in the course of a controlled experiment. The stimulation of the brain and cutaneous pain stimuli served for rats as the reinforcing factor. The presence of two factos, functioning throughout such reinforcement, is shown: specific one, providing for the adaptive change in the evoked response, and non-specific one, always lowering the EP amplitude due to general activation. The learning is successful only in case when both factors act in one direction.

Animals

Model phenylketonuria (PKU) in the albino rat: behaviroal, biochemical, and neuroanatomical effects.

Model phenylketonuria was induced in albino rats by injecting (at 1-20 days of age) and feeding (at 21-80 days) L-phenylalanine and D-L-para-chloro-phenylalanine. Behavioral testing on an eight-item battery occurred twice: first, whil the animals were either receiving the excess phenylalanines or not (original); and second, following a 90-day drug-free recovery period (retention). Results indicated drug-dependent deficits in learning and activity on both original and retention tests. Serum phenylalanine, serum tryptophan, and liver phenylalanine hydroxylase activity levels were positively correlated with the behavioral deficit. Clumped dense material in some myelin sheaths and associated degeneration of axons were found in experimental subjects.

Animals

APNet, an explainable sparse deep learning model to discover differentially active drivers of severe COVID-19.

MOTIVATION: Computational analyses of bulk and single-cell omics provide translational insights into complex diseases, such as COVID-19, by revealing molecules, cellular phenotypes, and signalling patterns that contribute to unfavourable clinical outcomes. Current in silico approaches dovetail differential abundance, biostatistics, and machine learning, but often overlook nonlinear proteomic dynamics, like post-translational modifications, and provide limited biological interpretability beyond feature ranking. RESULTS: We introduce APNet, a novel computational pipeline that combines differential activity analysis based on SJARACNe co-expression networks with PASNet, a biologically informed sparse deep learning model, to perform explainable predictions for COVID-19 severity. The APNet driver-pathway network ingests SJARACNe co-regulation and classification weights to aid result interpretation and hypothesis generation. APNet outperforms alternative models in patient classification across three COVID-19 proteomic datasets, identifying predictive drivers and pathways, including some confirmed in single-cell omics and highlighting under-explored biomarker circuitries in COVID-19. AVAILABILITY AND IMPLEMENTATION: APNet's R, Python scripts, and Cytoscape methodologies are available at https://github.com/BiodataAnalysisGroup/APNet.

COVID-19

Activity of dentate granule cells during learning: differentiation of perforant path input.

Experiments were conducted which extended previous findings regarding the activity of the perforant path and its synaptic relationship to the granule cells of the dentate gyrus during conditioning. A differential conditioning paradigm was utilized in which rats were trained to respond to one of two different tone frequencies. Results demonstrated that (1) tone elicited averaged evoked potentials recorded from the perforant path terminal zone in the outer molecular layer of the dentate gyrus were similar for both the positive and negative tones regardless of frequency or reversal of the reinforcement condition; (2) extracellular unit discharge patterns of dentate granule cells were differentially associated with the positive and negative tones as demonstrated by post stimulus histograms (PSHs); (3) this differential pattern of unit discharges could be reversed following establishment of criterion differential behavioral responding after reversal of the reinforcement contingency between the two tone stimuli and (4) the differential unit discharge pattern was not present when behavioral responding was not differentiated to the two tone stimuli, e.g., immediately following reversal of the reinforcement contingency. The results are discussed within the context of other anatomically defined functional circuits within the hippocampus which could serve as the basis for alteration of the non differentiated excitatory perforant path input into a differential dentate granule cell discharge pattern for behaviorally relevant sensory stimuli.

Acoustic Stimulation

Facilitation of retention performance in mice by posttraining diethyldithiocarbamate.

These experiments examined the effects in mice of posttraining injections of diethyldithiocarbamate (DDC) upon retention (7 days after training) of active avoidance learning and upon whole brain catecholamine levels. When administered immediately following training, DDC enhanced retention performance. The degree of enhancement varied directly with dose. DDC did not significantly affect retention performance if the injections were delayed 1 or 4 hours after training. Also, DDC administered 30 min prior to training did not affect retention performance. DDC (900 mg/kg) produced a large but transient increase in whole brain dopamine (DA) levels while norepinephrine (NE) levels were lowered.

Animals

Seizure severity and acquisition and performance of operant tasks in a monkey model.

Several studies utilizing an alumina-gel monkey model demonstrated a relationship between degree of epileptic activity and learning difficulty. Three operant tasks were employed: single-unit, gross-motor positive reinforcement, and avoidance conditioning. The data indicated that the number of hours needed to learn any one of the tasks increased with seizure frequency and/or number of EEG interictal bursts. The learning impairment appeared to be a function of the relevance of the required response to the site of the epileptogenic focus.

Animals

Protective effect of tryptophan and 5-hydroxytryptophan on experimental phenylketonuria induced with phenylalanine+ p-cholorophenylalanine in rats.

An experimental phenylketonuria-like syndrome was produced in rats by oral administration of 1-phenylalanine (Phe, 500 mg/kg) and dl-p-chloro-phenylalanine (pCPA, 100-125 mg/kg) daily from the 2nd-3rd day of life to the age of 42 days. The effects of added dl-5-hydroxytryptohan (5HTP, 5 mg/kg) or 1-tryptophan (Trp, 100-125 mg/kg) were also studied. The groups receiving Phe+pCPA gained less weight than normal and less than the Phe controls. When tested during the last week of treatment the Phe+pCPA rats made more errors in the swim maze without changes in swimming times, and they showed significantly poorer learning of conditioned shock avoidance. These effects were partly antagonized by 5HTP or Trp. One to three weeks after the end of the treatments similar differences still remained in conditioned shock avoidance (and Trp and 5HTP prevented the effect of pCPA), but no more in maze learning, motor activity, or exploration on open field. Brain 5HT and 5-hydroxyindoleacetic acid (5HIAA) were lowered in all the pCPA treated rats during the treatment but returned to normal after it. Trp and 5HTP in the doses used only partly corrected the decrease of 5HT and 5HIAA. Brain noradrenaline did not change much.

5-Hydroxytryptophan

Long-term consequences of early iron deficiency in the rat.

A period of severe early iron deficiency (birth to 28 days of age) produced a persistent deficit (22%) in brain non-heme iron in adult rehabilitated animals. Long-term effects on behavior and physiological responsiveness were also observed. Although rehabilitated and control animals did not differ either in basal levels of plasma corticosterone or in the time course of the stress response following ether and cardiac puncture, possible differences in pituitary-adrenal responsiveness appeared to emerge following testing in an exploratory task. In addition, significant differences between rehabilitated and control animals were observed in both active and passive avoidance learning. Rehabilitated males made more intertrial responses than control males during active avoidance learning, and rehabilitated animals of both sexes performed better (i.e. showed longer reentry latencies) in a passive avoidance situation. It was suggested that shock may differentially affect motivation or arousal in rehabilitated and control animals.

Animals