Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex.

The rat insular cortex (IC) subserves the memory of conditioned taste aversion (CTA), in which a taste is associated with malaise. When the conditioned taste is unfamiliar, formation of long-term CTA memory depends on muscarinic and beta-adrenergic receptors, mitogen-activated protein kinase (MAPK), and protein synthesis. We show that extinction of CTA memory is also dependent on protein synthesis and beta-adrenergic receptors in the IC, but independent of muscarinic receptors and MAPK. This resembles the molecular signature of the formation of long-term memory of CTA to a familiar taste. Thus, memory extinction shares molecular mechanisms with learning, but the mechanisms of learning anew differ from those of learning the new.

The role of identified neurotransmitter systems in the response of insular cortex to unfamiliar taste: activation of ERK1-2 and formation of a memory trace.

In the behaving rat, the consumption of an unfamiliar taste activates the extracellular signal-regulated kinase 1-2 (ERK1-2) in the insular cortex, which contains the taste cortex. In contrast, consumption of a familiar taste has no effect. Furthermore, activation of ERK1-2, culminating in modulation of gene expression, is obligatory for the encoding of long-term, but not short-term, memory of the new taste (Berman et al., 1998). Which neurotransmitter and neuromodulatory systems are involved in the activation of ERK1-2 by the unfamiliar taste and in the long-term encoding of the new taste information? Here we show, by the use of local microinjections of pharmacological agents to the insular cortex in the behaving rat, that multiple neurotransmitters and neuromodulators are required for encoding of taste memory in cortex. However, these systems vary in the specificity of their role in memory acquisition and in their contribution to the activation of ERK1-2. NMDA receptors, metabotropic glutamate receptors, muscarinic, and beta-adrenergic and dopaminergic receptors, all contribute to the acquisition of the new taste memory but not to its retrieval. Among these, only NMDA and muscarinic receptors specifically mediate taste-dependent activation of ERK1-2, whereas the beta-adrenergic function is independent of ERK1-2, and dopaminergic receptors regulate also the basal level of ERK1-2 activation. The data are discussed in the context of postulated novelty detection circuits in the central taste system.

Specific and differential activation of mitogen-activated protein kinase cascades by unfamiliar taste in the insular cortex of the behaving rat.

Rats were given to drink an unfamiliar taste solution under conditions that result in long-term memory of that taste. The insular cortex, which contains the taste cortex, was then removed and assayed for activation of mitogen-activated protein kinase (MAPK) cascades by using antibodies to the activated forms of various MAPKs. Extracellular responsive kinase 1-2 (ERK1-2) in the cortical homogenate was significantly activated within <30 min of drinking the taste solution, without alteration in the total level of the ERK1-2 proteins. The activity subsided to basal levels within <60 min. In contrast, ERK1-2 was not activated when the taste was made familiar. The effect of the unfamiliar taste was specific to the insular cortex. Jun N-terminal kinase 1-2 (JNK1-2) was activated by drinking the taste but with a delayed time course, whereas the activity of Akt kinase and p38MAPK remained unchanged. Elk-1, a member of the ternary complex factor and an ERK/JNK downstream substrate, was activated with a time course similar to that of ERK1-2. Microinjection of a reversible inhibitor of MAPK/ERK kinase into the insular cortex shortly before exposure to the novel taste in a conditioned taste aversion training paradigm attenuated long-term taste aversion memory without significantly affecting short-term memory or the sensory, motor, and motivational faculties required to express long-term taste aversion memory. It was concluded that ERK and JNK are specifically and differentially activated in the insular cortex after exposure to a novel taste, and that this activation is required for consolidation of long-term taste memory.

NMDA receptor and the tyrosine phosphorylation of its 2B subunit in taste learning in the rat insular cortex.

We demonstrate that the NMDA receptor is involved in taste learning in the insular cortex of the behaving rat and describe two facets of this involvement. Blockage of the NMDA receptor in the insular cortex by the reversible antagonist APV during training in a conditioned taste aversion (CTA) paradigm impaired CTA memory, whereas blockage of the NMDA receptor in an adjacent cortex or before a retrieval test had no effect. When rats sampled an unfamiliar taste and hence learned about it, either incidentally or in the context of CTA training, the tyrosine phosphorylation of the NMDA receptor subunit 2B (NR2B) in the insular cortex was specifically increased. The level of tyrosine phosphorylation on NR2B was a function of the novelty of the taste stimulus and the quantity of the taste substance consumed, properties that also determined the efficacy of the taste stimulus as a conditioned stimulus in CTA; however, blockage of the NMDA receptor by APV during training did not prevent tyrosine phosphorylation of NR2B. We suggest that tyrosine phosphorylation of NR2B subserves encoding of saliency in the insular cortex during the first hours after an unfamiliar taste is sampled and that this encoding is independent of another, necessary role of NMDA receptors in triggering experience-dependent modifications in the insular cortex during taste learning. Because a substantial fraction of the NR2B protein in the insular cortex seems to be expressed in interneurons, saliency and the tyrosine phosphorylation of NR2B correlated with it may modulate inhibition in cortex.

Carbachol mimics effects of sensory input on tyrosine phosphorylation in cortex.

We have recently shown that in the gustatory cortex of the rat, taste learning enhances protein tyrosine phosphorylation and taste memory is blocked by muscarinic antagonists. A major protein whose tyrosine phosphorylation is stimulated by taste learning in cortex is a 180 kDa synaptic glycoprotein identified as the NMDA receptor subunit 2B (NR2B). Here we report that microinjection of carbachol into the taste cortex modulates protein tyrosine phosphorylation similarly to the effect of unfamiliar taste, and that a 180 kDa protein whose tyrosine phosphorylation is enhanced in vivo by carbachol is NR2B. These data, combined with our previous findings, are in line with the hypothesis that muscarinic input plays a role in encoding new items in memory, and that tyrosine phosphorylation of NR2B is involved in this process.

Calvarial deformity regeneration following subtotal craniectomy for craniosynostosis: a case report and theoretical implications.

We describe an infant with combined sagittal and unilateral coronal synostosis who underwent "total vault" craniectomy for skull reshaping. The operative procedure was interrupted without replacement of the calvarial bone grafts. Follow-up over the ensuing 2 months revealed regeneration of the entire cranium and supraorbital rims, as well as (in contrast to earlier reports) redevelopment of fusion within the suture at the same site noted in the initial operation, associated with similar skull deformity. These observations are reviewed with special emphasis on the theoretical implications for the etiology of craniosynostosis and skull deformity.

Lidocaine diffusion in five tissue expanders: an in vitro and in vivo study.

Previous work in our laboratory has demonstrated that tissue expanders are permeable to lidocaine. In this two-part study, we assessed the in vitro lidocaine diffusion in the following five common tissue expanders: Dow Corning, McGhan, Cox-Uphoff, Hyer-Schulte (Mentor), and Surgitek. In part 1, we demonstrated that wall thickness appeared to be the major determinant for diffusion. Part 2 reports an in vivo study of lidocaine diffusion from tissue expanders used for breast reconstruction. We initially determined that there is incomplete mixing between the valve and connecting tubing and the contents of the expanders, over the period of 1 week. We subsequently examined the lidocaine diffusion from seven tissue expanders placed in a submuscular position for breast reconstruction. The rate of lidocaine diffusion was highly variable, but on average was about 3% per day.

Steroid and benzyl alcohol diffusion through tissue expanders and double lumen breast implants.

The rate of diffusion of benzyl alcohol (the bacteriostatic agent in the provided diluent) and methylprednisolone 21-hemisuccinate and related rearrangement and hydrolysis products ("steroid") through tissue expanders was examined. The rate of diffusion of steroid through double lumen breast implants was also studied. It was found that benzyl alcohol rapidly diffused through tissue expanders into a saline bath. By 24 hours, one-half of the benzyl alcohol had diffused through the expander. The steroid was much slower to diffuse out of the expander. By 141 days, only 2% of the steroid was found in the bath. This rate was comparable for both the tissue expander and double lumen implants. In addition, a significant amount of the steroid is located in the expander wall, associated with the surface of the expander or precipitated out of solution or both. The clinical significance of these findings is discussed.

Total cranial vault reconstruction for parietal encephalocele.

A 3-year-old boy underwent skull reconstruction in order to reduce a parietal encephalocele. The reduction of the encephalocele was accomplished fully and safely while simultaneously correcting a concomitant turriscaphocephaly skull-shape irregularity. A combination of the modified prone position and cranial reconstruction using barrel stave expansion of the basal vault was employed.

The dartos musculocutaneous island flap in urethral reconstruction.

Reconstruction of the burned penile urethra has received scant attention in the surgical literature. Techniques used in repairing congenital hypospadias may not be applicable in this situation. We describe a dartos musculocutaneous island flap used to reconstruct the distal burned penile urethra in a 13-year-old boy who sustained burns to 85% of his total body surface area. Reconstruction was completed in one surgical procedure, and at two-year follow-up good results were demonstrated.

Lidocaine permeability in silicone tissue expanders: an in vitro analysis.

Tissue expansion has achieved a prominent role in soft-tissue reconstruction. Expansion-induced pain is often a limiting factor in this process and can affect patients for as long as 24 to 48 hours following each expansion session. Although lidocaine is known to be an effective analgesic, only anecdotal reports of its usefulness when placed within a tissue expander currently exist. This two-part study was designed first to determine if in fact silicone is readily permeable to lidocaine, and second to determine if the potential diffusion dynamics can be defined. In part 1 of the study, the silicone polymer was indeed found to be readily permeable to lidocaine as measured with fluorescence immunoassay technique. In part 2, two groups of Surgitek and Dow Corning expanders were filled with saline and lidocaine and placed in saline baths. At several intervals over a 48-hour period, aliquots of the surrounding saline were sampled and the lidocaine levels subsequently determined. A rather predictable and consistent diffusion curve was demonstrated. The significant difference in diffusion characteristics between the two expander types was apparently due to wall thickness differences inherent in the manufacturing. In this in vitro study, filler-valve leakage did not significantly contribute to lidocaine migration from within these tissue expanders. This basic in vitro work will now set the stage for further in vivo and clinical investigations to more precisely define the role of lidocaine in the tissue-expansion process.

Hostility and hallucinations as a consequence of midazolam administration.

A 74-year-old woman experienced an apparent psychotic reaction several hours after administration of iv midazolam as a premedicant for gastroscopy. The reaction included confusion, hallucinations, and hostility and required administration of haloperidol to calm her. The woman subsequently underwent colonoscopy with meperidine as a premedication and experienced no behavioral changes. Although other causes cannot be completely ruled out, the evidence points strongly to midazolam as the precipitating agent for the psychotic reaction.

Principles of emergency wound management.

Every traumatic wound treated in the emergency department is a result of a finite energy source that caused tissue disruption. The dynamics of this exchange of energy will determine the magnitude of injury. Disruption of the body covering leaves the once-sterile underlying integument exposed to contamination. The contaminants are derived from either the victim (endogenous) or the exogenous energy source. The presence of a contaminant such as bacteria makes the care of the wound an exercise in microbiology. Other contaminants, such as dirt, also may reside in the recesses of the wound. Emergency physicians must understand the consequences of tissue trauma. A study of the mechanism of injury will provide a reliable indication of damages. Whether the tissue injury will be limited to the initial wounding depends on the outcome of the interaction between the contaminants and the wound. In the event that the contaminants are very reactive, a relatively insignificant wound may become a catastrophe. This circumstance can be averted by the implementation of a well-devised plan based on the biology of wound healing and infection.

Microvascular silicon replamineform grafts of 2- and 5-cm lengths: experimental studies.

Replamineform silicone microvascular grafts 1 mm in diameter were cut to clinically useful lengths (2 and 5 cm) and used to reconstruct segments of the femoral artery in the rabbit. Despite initial patency and flow rates comparable to flow seen in vein graft repairs and primary repair, no long-term patency was observed. The theoretical biomechanical advantages of this kind of graft material have not solved the problem of long microvascular grafting.

Endobronchial inflammatory polyp associated with a foreign body. Successful treatment with corticosteroids.

We describe a case of endobronchial polyp associated with a foreign body. To our knowledge, this is the first report of such an occurrence. The polyp was successfully treated with steroids. This is only the third report of steroid treatment of endobronchial polyps.