Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as "Nasu-Hakola disease," is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype.

ABSTRACTcAMP͞cAMP-dependent protein kinase (PKA) signaling pathway has been recently proposed to participate in both the late phase of long term potentiation in the hippocampus and in the late, protein synthesis-dependent phase of memory formation. Here we report that a late memory consolidation phase of an inhibitory avoidance learning is regulated by an hippocampal cAMP signaling pathway that is activated, at least in part, by D 1 ͞D 5 receptors. Bilateral infusion of SKF 38393 (7.5 g͞side), a D 1 ͞D 5 receptor agonist, into the CA 1 region of the dorsal hippocampus, enhanced retention of a step-down inhibitory avoidance when given 3 or 6 h, but not immediately (0 h) or 9 h, after training. In contrast, full retrograde amnesia was obtained when SCH 23390 (0.5 g͞side), a D 1 ͞D 5 receptor antagonist, was infused into the hippocampus 3 or 6 h after training. Intrahippocampal infusion of 8Br-cAMP (1.25 g͞side), or forskolin (0.5 g͞side), an activator of adenylyl cyclase, enhanced memory when given 3 or 6 h after training. KT5720 (0.5 g͞side), a specific inhibitor of PKA, hindered memory consolidation when given immediately or 3 or 6 h posttraining. Rats submitted to the avoidance task showed learning-specific increases in hippocampal 3 H-SCH 23390 binding and in the endogenous levels of cAMP 3 and 6 h after training. In addition, PKA activity and P-CREB (phosphorylated form of cAMP responsive element binding protein) immunoreactivity increased in the hippocampus immediately and 3 and 6 h after training. Together, these findings suggest that the late phase of memory consolidation of an inhibitory avoidance is modulated cAMP͞PKA signaling pathways in the hippocampus.Memory is a temporally graded process during which new information becomes consolidated and stored (1-3). From mollusks to mammals, memory can be divided into at least two phases: a protein and RNA synthesis-independent phase that lasts minutes to 1-3 h (short term memory) and a protein and RNA synthesisdependent component [long term memory (LTM)] that lasts several hours to days, weeks, or even longer periods (4-7).Recent work in Aplysia (8-10), Drosophila (11, 12), and mouse (13) has clearly demonstrated that cAMP-responsive transcription, mediated by the CREB (cAMP responsive element binding protein) family of proteins, is a crucial step for the establishment of LTM. cAMP-responsive genes participate in the long term facilitation of neurotransmitter release in Aplysia neurons, a model of nonassociative learning (8-10); the overexpression of a CREB repressor isoform blocks the formation of LTM for a Pavlovian odor avoidance task in Drosophila (11) whereas it does not affect a consolidated, protein synthesis-independent form of memory (7), and, more importantly, transgenic flies expressing an activating isoform of CREB showed an enhancement of LTM (12); in CREB knockout mice, LTM of fear conditioning and spatial learning is disrupted whereas acquisition and short term memory, which lasts 30-60 minutes, are normal (13). Taken together, these findings st...

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Summary:Purpose: Posterior cortex epilepsies (PCEs) encompass a group of epilepsies originating from the occipital, parietal, or occipital border of the temporal lobe, or from any combination of these regions. When their seizures are refractory to pharmacologic treatment, these patients are usually referred for surgery. The aim of our study was to analyze clinical characteristics of all PCE patients referred for surgery from 1994 to 2003, and to search for predictors of surgical outcome.Methods: We performed a retrospective analysis of clinical and laboratory data from 81 consecutive refractory PCE patients referred for surgery. Surgical and nonsurgical groups of patients were compared, and detailed analyses of all variables of the surgical cases were performed in the search for predictors of seizure outcome.Results: Risk factors for PCEs included gliosis (34.56%), malformations of cortical development (33.33%), tumors (8.64%), brain trauma (3.70%), Sturge-Weber disease (4.93%), vascular malformations (3.70%), family history of epilepsy (3.70%), history of CNS infections (2.46%), and low IQ (2.46%). Of the 81 patients, 44 were submitted to surgery at the time of the completion of this study. Surgical treatment was highly effective in improving seizures (p < 0.001) when compared with previous pharmacologic treatment alone. Twenty-eight (65.11%) patients became seizure free after surgery versus none in the nonsurgical group. Regarding outcome predictors, patients with shorter duration of epilepsy and those without neurologic abnormalities on clinical examination had higher chances of favorable evolution.Conclusions: Surgical treatment is effective for the treatment of PCEs and superior to pharmacologic therapy alone. In our series, shorter duration of epilepsy and normal neurologic examination were the only independent variables that predicted better surgical outcome.