Learning-induced activation of protein kinase C

PKC activation has been shown to mimic the biophysical consequences of classical conditioning in both rabbit hippocampus and Hermissenda type B cells. Furthermore, conditioning in rabbits results in the 24 h translocation of PKC from cytosol to membrane, which is probably responsible for mediating the biophysical consequences of conditioning. A model has been presented that suggests that long-term translocation of PKC occurs via the synergistic activation of a DG dependent pathway that activates PKC and a calcium dependent pathway that activates CaM kinase. Translocation of PKC to the plasma membrane, by altering ion channel properties, could subserve memory lasting for days, whereas translocation to the nuclear membrane could induce cellular change, by genomic regulation, lasting beyond days. We are, therefore, suggesting that protein kinase C may play a critical role in the formation of short, intermediate, and long-term associative memory.     

Bryostatin enhancement of memory in Hermissenda

Bryostatin, a potent agonist of protein kinase C (PKC), when administered to Hermissenda was found to affect acquisition of an associative learning paradigm. Low bryostatin concentrations (0.1 to 0.5 ng/ml) enhanced memory acquisition, while concentrations higher than 1.0 ng/ml down-regulated the pathway and no recall of the associative training was exhibited. The extent of enhancement depended upon the conditioning regime used and the memory stage normally fostered by that regime. The effects of two training events (TEs) with paired conditioned and unconditioned stimuli, which standardly evoked only short-term memory (STM) lasting 7 min, were--when bryostatin was added concurrently--enhanced to a long-term memory (LTM) that lasted about 20 h. The effects of both 4- and 6-paired TEs (which by themselves did not generate LTM), were also enhanced by bryostatin to induce a consolidated memory (CM) that lasted at least 5 days. The standard positive 9-TE regime typically produced a CM lasting at least 6 days. Low concentrations of bryostatin (<0.5 ng/ml) elicited no demonstrable enhancement of CM from 9-TEs. However, animals exposed to bryostatin concentrations higher than 1.0 ng/ml exhibited no behavioral learning. Sharp-electrode intracellular recordings of type-B photoreceptors in the eyes from animals conditioned in vivo with bryostatin revealed changes in input resistance and an enhanced long-lasting depolarization (LLD) in response to light. Likewise, quantitative immunocytochemical measurements using an antibody specific for the PKC-activated Ca2+/GTP-binding protein calexcitin showed enhanced antibody labeling with bryostatin. Animals exposed to the PKC inhibitor bisindolylmaleimide-XI (Ro-32-0432) administered by immersion prior to 9-TE conditioning showed no training-induced changes with or without bryostatin exposure. However, if animals received bryostatin before Ro-32, the enhanced acquisition and demonstrated recall still occurred. Therefore, pathways responsible for the enhancement effects induced by bryostatin were putatively mediated by PKC. Overall, the data indicated that PKC activation occurred and calexcitin levels were raised during the acquisition phases of associative conditioning and memory initiation, and subsequently returned to baseline levels within 24 and 48 h, respectively. Therefore, the protracted recall measured by the testing regime used was probably due to bryostatin-induced changes during the acquisition and facilitated storage of memory, and not necessarily to enhanced recall of the stored memory when tested many days after training.     

The Mentally Retarded Infant — Is Placement Feasible?

A 1968 questionnaire about placement resources for mentally retarded infants that was sent to public agencies in all 58 California counties showed:• Resources for counseling, placement, and financial aid for out-of-home placement are not uniformly available to all groups within the population.• Financial help with out-of-home placement of a member of a family that is not medically indigent may be available in less than one-fourth of the counties of the state.• Knowledge of resources is often inadequate. A family could be referred inappropriately from one agency to another.     

Apolipoprotein E3 (ApoE3) but not ApoE4 protects against synaptic loss through increased expression of protein kinase C epsilon

Synaptic loss is the earliest pathological change in Alzheimer disease (AD) and is the pathological change most directly correlated with the degree of dementia. ApoE4 is the major genetic risk factor for the age-dependent form of AD, which accounts for 95% of cases. Here we show that in synaptic networks formed from primary hippocampal neurons in culture, apoE3, but not apoE4, prevents the loss of synaptic networks produced by amyloid β oligomers (amylospheroids). Specific activators of PKCε, such as 8-(2-(2-pentyl-cyclopropylmethyl)-cyclopropyl)-octanoic acid methyl ester and bryostatin 1, protected against synaptic loss by amylospheroids, whereas PKCε inhibitors blocked this synaptic protection and also blocked the protection by apoE3. Blocking LRP1, an apoE receptor on the neuronal membrane, also blocked the protection by apoE. ApoE3, but not apoE4, induced the synthesis of PKCε mRNA and expression of the PKCε protein. Amyloid β specifically blocked the expression of PKCε but had no effect on other isoforms. These results suggest that protection against synaptic loss by apoE is mediated by a novel intracellular PKCε pathway. This apoE pathway may account for much of the protective effect of apoE and reduced risk for the age-dependent form of AD. This finding supports the potential efficacy of newly developed therapeutics for AD.     

Impact of ivermectin on onchocerciasis transmission: assessing the empirical evidence that repeated ivermectin mass treatments may lead to elimination/eradication in West-Africa

BACKGROUND: The Onchocerciasis Control Program (OCP) in West Africa has been closed down at the end of 2002. All subsequent control will be transferred to the participating countries and will almost entirely be based on periodic mass treatment with ivermectin. This makes the question whether elimination of infection or eradication of onchocerciasis can be achieved using this strategy of critical importance. This study was undertaken to explore this issue. METHODS: An empirical approach was adopted in which a comprehensive analysis was undertaken of available data on the impact of more than a decade of ivermectin treatment on onchocerciasis infection and transmission. Relevant entomological and epidemiological data from 14 river basins in the OCP and one basin in Cameroon were reviewed. Areas were distinguished by frequency of treatment (6-monthly or annually), endemicity level and additional control measures such as vector control. Assessment of results were in terms of epidemiological and entomological parameters, and as a measure of inputs, therapeutic and geographical coverage rates were used. RESULTS: In all of the river basins studied, ivermectin treatment sharply reduced prevalence and intensity of infection. Significant transmission, however, is still ongoing in some basins after 10-12 years of ivermectin treatment. In other basins, transmission may have been interrupted, but this needs to be confirmed by in-depth evaluations. In one mesoendemic basin, where 20 rounds of four-monthly treatment reduced prevalence of infection to levels as low as 2-3%, there was significant recrudescence of infection within a few years after interruption of treatment. CONCLUSIONS: Ivermectin treatment has been very successful in eliminating onchocerciasis as a public health problem. However, the results presented in this paper make it almost certain that repeated ivermectin mass treatment will not lead to the elimination of transmission of onchocerciasis from West Africa. Data on 6-monthly treatments are not sufficient to draw definitive conclusions.     

Management of complex groin wounds: preferred use of the rectus femoris muscle flap

This study reviews our experience with the rectus femoris muscle flap for complex groin wound reconstruction. Over the past 5 years, the rectus femoris has become our routine method of groin wound reconstruction. The rectus femoris is harvested through a midanterior incision extending over the distal two-thirds of the thigh. The muscle is elevated on its pedicle and transposed into the groin wound defect either directly or through an intervening skin bridge. Hospital and outpatient records were reviewed for all patients undergoing groin wound reconstruction with this technique from 1999 through 2003. Thirty-seven rectus femoris muscle flaps were performed in 33 patients. The mean patient age was 65.3 years (range, 25 to 88 years). Thirty groin wounds (81.1 percent) occurred after infrainguinal revascularization, 23 (76.7 percent) of which contained prosthetic material. Five (21.7 percent) of these wounds had their prosthetic material removed at the time of reconstruction. The remaining seven groin wounds (18.9 percent) occurred after femoral vessel cannulation for either cardiac or transplant surgery. There were no intraoperative mortalities and no anastomotic hemorrhages. There were no flap losses. Thirty-five of the 37 treated wounds healed (94.6 percent), 26 primarily (70.3 percent) and nine (24.3 percent) after delayed healing and contracture. Reoperation was performed in one patient for flap readvancement and in three patients for prosthetic graft removal after initial flap reconstruction. Two patients (6.1 percent) died during their hospitalization with persistent open groin wounds after flap reconstruction. All muscle flap donor incisions healed, with only two (5.4 percent) experiencing minimal delayed healing. There were no donor-site wound infections and no donor sites required reoperation. Thirty-three groin wounds (89.2 percent) demonstrated culture-positive microbial infection, 15 (45.5 percent) of which were polymicrobial. The 30-day mortality rate was 15.2 percent and the 6-month mortality rate increased to 27.2 percent, with multisystem organ failure as the most common cause. The rectus femoris muscle flap is an effective and reliable means of complex groin wound reconstruction. The muscle flap is dependable and the donor site is not problematic, even in the presence of peripheral vascular disease. On the basis of our clinical results, we believe that the rectus femoris muscle flap is the flap of choice for groin wound reconstruction.     

Prevention of beta-amyloid neurotoxicity by blockade of the ubiquitin-proteasome proteolytic pathway

In many neurodegenerative disorders, such as Alzheimer's disease, inclusions containing ubiquitinated proteins have been found in the brain, suggesting a pathophysiological role for ubiquitin-mediated proteasomal degradation of neuronal proteins. Here we show for the first time that the beta-amyloid fragment 1-40, which in micromolar levels causes the death of cortical neurons, also induces the ubiquitination of several neuronal proteins. Prevention of ubiquitination and inhibition of proteasome activity block the neurotoxic effect of beta-amyloid. These data suggest that beta-amyloid neurotoxicity may cause toxicity through the activation of protein degradation via the ubiquitin-proteasome pathway. These findings suggest possible new pharmacological targets for the prophylaxis and/or treatment of Alzheimer's disease and possibly for other related neurodegenerative disorders.