1. Intraaxonal recordings were obtained in vitro from the sural nerve (SN), the muscle branch of the anterior tibial nerve (ATN), or the deafferented ATN (dATN) in 5- to 7-wk-old rats. Whole-nerve sucrose gap recordings were obtained from the SN and the ATN. This allowed study of cutaneous (SN), mixed motor and muscle afferent (ATN), and isolated muscle afferent (dATN) axons. 2. Application of the potassium channel blocking agent 4-aminopyridine (4-AP) to ATN or dATN resulted in a slight prolongation of the action potential. In contrast, a distinct delayed depolarization followed the axonal action potential in cutaneous afferents (SN) exposed to 4-AP. The delayed depolarization could be induced by a single whole-nerve stimulus or by injection of constant-current depolarizing pulses into individual axons. The delayed depolarization often gave rise to bursts of action potentials and was followed by a prominent afterhyperpolarization (AHP). 3. In paired-pulse experiments on single SN axons, the recovery time (half-amplitude of the action potential) was 3.06 +/- 1.82 (SE) ms (n = 12). After exposure to 4-AP the recovery time of the delayed depolarization was considerably longer (half-recovery time: 99.0 +/- 28.3 ms; n = 15) than that of the action potential (18.8 +/- 9.1 ms; n = 16). 4. Application of tetraethylammonium (TEA) to cutaneous or muscle afferents alone had little effect on single action potential waveform. However, TEA reduced the amplitude of the AHP elicited by a single stimulus in cutaneous afferent axons after exposure to 4-AP and resulted in repetitive spike discharge. 5. The delayed depolarization and spike burst activity induced by 4-AP in SN was present in Ca(2+)-free solutions containing 1 mM ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and was not blocked by Cd2+ (1.0 mM). 6. We obtained whole-cell patch-clamp recordings to study Na+ currents from either randomly selected dorsal root ganglion neurons or cutaneous afferent neurons identified by retrograde labeling with Fluoro-Gold. The majority of the randomly selected neurons had a singular kinetically fast Na+ current. In contrast, no identified cutaneous afferent neurons had a singular fast Na+ current. Rather, they had a combination of kinetically separable fast and slow currents or a singular relatively slow Na+ current.(ABSTRACT TRUNCATED AT 400 WORDS)
CMT represents a feasible and resource-conservative pedagogical format to promote critical thinking and to integrate basic science principles during the preclinical curriculum.
D‐2‐Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D‐2‐hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early‐infantile‐onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D‐2‐hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid γ‐aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D‐2‐hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes. Ann Neurol 1999;45:111–119
The myasthenic syndrome due to abnormal acetylcholine resynthesis is characterized by early onset, recessive inheritance, and recurrent episodes of potentially fatal apnea. Mutations in the gene encoding choline acetyltransferase (CHAT) have been found to account for this condition. We have identified five patients from three independent families with features of this disease including, in four patients, a paradoxical worsening of symptoms with cold temperatures. Electrodiagnostic studies demonstrated impaired neuromuscular transmission in all patients. In vitro microelectrode studies performed in the anconeus muscle biopsies of two patients showed moderate reduction of quantal release. Electron microscopy of the neuromuscular junction was normal in both patients. Each patient had two heterozygous CHAT mutations including L210P and P211A (family 1), V194L and V506L (family 2), and R548stop and S694C (family 3). Three of these mutations have previously been reported and suggest that, in this syndrome, some molecular defects may be more prevalent than others.
Residency programs should incorporate systems thinking models into their curricula. Trainees should be taught to understand systems at an abstract level, in order to analyze their own healthcare systems, and participate in quality and patient safety activities. We suggest that a developmental trajectory for systems thinking be developed, similar to the model described by Dreyfus and Dreyfus.
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