[Effects of menopause on depressive and anxiety symptoms in community women in Beijing].

Objective: To determine the effects of menopausal stage, age and other associated risk factors on symptoms of anxiety and depression among women in a community in Beijing. Methods: This study was a community-based prospective cohort. Participants who had transitioned through natural menopause, completed two or more depressive and anxiety symptoms evaluations, aged 35 to 64 years, and did not use hormone therapy were selected from the Peking Union Medical College Hospital aging longitudinal cohort of women in midlife to this analysis. The primary outcome variables were depressive and anxiety symptoms, assessed by hospital anxiety and depression scale (HADS). The generalized estimation equation was used in the statistical analysis. Results: Followed up from 2006 to 2014, 430 women and 2 533 HADS assessments were retained in the cohort. Depressive symptoms were more common than anxiety symptoms during all menopausal stages. The incidences of depressive and anxiety symptoms were 14.5% (19/191) and 3.1% (4/191) in the premenopausal -3 stage, respectively. The incidence increased in both menopausal transition and postmenopausal stage, with the highest incidence in the +1c stage [20.6% (155/751) and 8.8% (66/751), respectively]. However, these differences were not statistically significant (all P>0.05). Depressive symptoms were highest in the ≥60-<65 age group [20.8% (74/355)], and anxiety symptoms were highest in the ≥50-<55 age group [8.2% (62/754)]; but there were no statistical significances between different age groups and depressive and anxiety symptoms (all P>0.05). Multivariable analysis showed that high body mass index, low education status, and poor health status were independently associated with depressive symptoms (all P<0.05), and that poor health status, trouble falling asleep, and early awakening were independently associated with anxiety symptoms (all P<0.01). Conclusions: Depressive and anxiety symptoms are more common during menopausal transition and postmenopausal stage compared with reproductive stage. Depressive symptoms are more common than anxiety symptoms. To screen and assess depressive and anxiety symptoms in perimenopausal women is essential, especially for women with high risk factors.

[Clinical analysis of the character, family history and prognosis of 6 cases with Crouzon syndrome].

Objective:To investigate the clinical characteristics, family history, treatment and prognosis of patients with Crouzon syndrome. Method:We reviewed and analyzed the clinical data of 6 patients with Crouzon syndrome. All patients suffered from snore during sleep, along with mouth opening, in which 5 cases had apnea and could be awaken. In addition, five of six experienced hearing loss, including one case with right ear discharging repeatedly. During the treatment, all patients were operated under general anesthesia. Among six cases, two were performed by tonsillectomy, adenoidectomy, and myringotomy; one was treated by adenoidectomy and myringotomy; two were performed by adenoidectomy; one was treated by external auditory canal cholesteatoma exenteration. Result:Within half a year to seven years' follow-up, 5 patients snore occasionally at night but without sleep apnea, while 1 patient performed by external auditory canal cholesteatoma exenteration has no improvement in sleep snoring. Additionally, the hearing of 5 patients have been greatly improved after operation and the cranial facial deformity of 2 cases have been alleviated than before, while 4 patients have no alleviation in oxycephaly, exophthalmos, mandibular prognathism and malocclusion.Conclusion:Understanding the clinical characteristics of Crouzon syndrome significantly contributes to early diagnosis of this disease. Individual-based treatment should be carried out according to the clinical symptoms and signs of patients. Early intervention benefit to the improvement of prognosis and the life quality of patients.

A mesoscopic reaction rate model for shock initiation of multi-component PBX explosives.

The primary goal of this research is to develop a three-term mesoscopic reaction rate model that consists of a hot-spot ignition, a low-pressure slow burning and a high-pressure fast reaction terms for shock initiation of multi-component Plastic Bonded Explosives (PBX). Thereinto, based on the DZK hot-spot model for a single-component PBX explosive, the hot-spot ignition term as well as its reaction rate is obtained through a "mixing rule" of the explosive components; new expressions for both the low-pressure slow burning term and the high-pressure fast reaction term are also obtained by establishing the relationships between the reaction rate of the multi-component PBX explosive and that of its explosive components, based on the low-pressure slow burning term and the high-pressure fast reaction term of a mesoscopic reaction rate model. Furthermore, for verification, the new reaction rate model is incorporated into the DYNA2D code to simulate numerically the shock initiation process of the PBXC03 and the PBXC10 multi-component PBX explosives, and the numerical results of the pressure histories at different Lagrange locations in explosive are found to be in good agreements with previous experimental data.

Screening of potential biomarkers for cholangiocarcinoma by integrated analysis of microarray data sets.

Cholangiocarcinoma (CCA) continues to harbor a difficult prognosis and it is difficult to diagnose in its early stages. The molecular mechanisms of CCA oncogenesis and progression are poorly understood. This study aimed to identify candidate biomarkers for CCA. Integrated analysis of microarray data sets was performed to identify differentially expressed genes (DEGs) between CCA and normal tissues. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed to identify the functions of DEGs. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed. The expressions of DEGs were validated in human CCA tissues by qRT-PCR. A set of 712 DEGs were identified in CCA compared with normal tissues, including 306 upregulated and 406 downregulated DEGs. It can be shown from the KEGG pathway analysis that some pathways may have important roles in pathology of CCA, including peroxisome proliferator-activated receptor signaling pathway, bile secretion, cell cycle, fat digestion and absorption. PPI network indicated that the significant hub proteins were PKM, SPP1 and TPM1. The abnormally overexpression PKM, SPP1 and TPM1 were closely related to oncogenesis and progression of CCA. PKM, SPP1, TPM1, COL1A1 and COL1A2 may serve as candidate biomarkers for diagnosis and prognosis of CCA.

MTBDRplus results correlate with treatment outcome in previously treated tuberculosis patients.

BACKGROUND: Although MTBDRplus is validated for the detection of multidrug-resistant tuberculosis (MDR-TB), its role in the assessment of treatment outcome is less clear. We evaluated the association of MTBDRplus results with treatment outcome in new and previously treated patients in an endemic setting in China and determined factors associated with poor treatment outcomes. METHODS: We prospectively enrolled 298 smear-positive pulmonary TB patients who received the World Health Organization recommended initial treatment regimen or retreatment regimen. MTBDRplus was compared with conventional drug susceptibility testing and DNA sequencing for the detection of MDR-TB. Treatment responses were monitored using sputum smear, culture and chest radiography. RESULTS: MTBDRplus successfully identified all MDR-TB and had good concordance with sequencing. MDR-TB rates were low among new patients (4/187, 2.1%), but high in previously treated patients (12/28, 42.9%); 65.2% (15/23) of previously treated cases and 17.1% (27/158) of new cases were unsuccessfully treated (P < 0.001). Seven of eight (87.5%) previously treated MDR-TB patients failed the retreatment regimen. In addition to drug resistance, sputum smear positivity at week 8 and cavitation are associated with treatment failure. CONCLUSION: Not only did MTBDRplus correctly identify all MDR-TB cases, MTBDRplus results are also associated with treatment outcomes in previously treated patients. The retreatment regimen should no longer be used; treatment should be guided by molecular testing.

Methylphenidate improves the behavioral and cognitive deficits of neurogranin knockout mice.

Neurogranin (Ng), a brain-specific calmodulin-binding protein, is expressed highly in hippocampus, and is important for cognitive function. Deletion of the Ng gene from mice caused attenuation of signal reaction cascade in hippocampus, impairments in learning and memory and high frequency stimulation-induced long-term potentiation (LTP). Environmental enrichment alone failed to improve cognitive function. In this study, behavioral testing revealed that Ng knockout (NgKO) mice were both hyperactive and socially withdrawn. Methylphenidate (MPH) was given to mice while they were also kept under an enrichment condition. MPH treatment reduced the hyperactivity of NgKO mice tested in both the open field and forced swim chamber. MPH improved their social abilities such that mice recognized and interacted better with novel subjects. The cognitive memories of MPH-treated mutants were improved in both water maze and contextual fear conditioning tests. High frequency stimulation-induced LTP of NgKO mice was also improved by MPH. The present treatment regimen, however, did not fully reverse the deficits of the mutant mice. In contrast, MPH exerted only a minimal effect on the wild type mice. At the cellular level, MPH increased the number of glial fibrillary acidic protein-positive cells in hippocampus, particularly within the dentate gyrus of NgKO mice. Therefore it will be of interest to determine the nature of MPH-mediated astrocyte activation and how it may modulate behavior in future studies. Taken together these NgKO mice may be useful for the development of better drug treatment to improve cognitive and behavioral impairments.

Stimulation-mediated translocation of calmodulin and neurogranin from soma to dendrites of mouse hippocampal CA1 pyramidal neurons.

Calmodulin (CaM) and neurogranin (Ng) are two abundant neuronal proteins in the forebrain whose interactions are implicated in the enhancement of synaptic plasticity. To gain further insight into the actions of these two proteins we investigated whether they co-localize in principle neurons and whether they respond to high frequency stimulation in a coordinated fashion. Immunohistochemical staining of CaM and Ng in mouse hippocampal slices revealed that CaM was highly concentrated in the nucleus of CA1 pyramidal neurons, whereas Ng was more broadly localized throughout the soma and dendrites. The asymmetrical localization of CaM in the nucleus of pyramidal neurons was in sharp contrast to the distribution observed in pyramidal cells of the neighboring subiculum, where CaM was uniformly localized throughout the soma and dendrites. The somatic concentrations of CaM and Ng in CA1 pyramidal neurons were approximately 10- and two-fold greater than observed in the dendrites, respectively. High frequency stimulation (HFS) of hippocampal slices promoted mobilization of CaM and Ng from soma to dendrites. These responses were spatially restricted to the area close to the site of stimulation and were inhibited by the N-methyl-D-asparate receptor antagonist 2-amino-5-phosphonopentanoic acid. Furthermore, HFS failed to promote translocation of CaM from soma to dendrites of slices from Ng knockout mice, which also exhibited deficits in HFS-induced long-term potentiation. Translocated CaM and Ng exhibited distinct puncta decorating the apical dendrites of pyramidal neurons and appeared to be concentrated in dendritic spines. These findings suggest that mobilization of CaM and Ng to stimulated dendritic spines may enhance synaptic efficacy by increasing and prolonging the Ca2+ transients and activation of Ca2+/CaM-dependent enzymes.

Frictional properties of single crystals HMX, RDX and PETN explosives.

The frictional properties of single crystals of cyclotetramethylene tetranitramine (HMX), cyclotrimethylene trinitramine (RDX) and pentaerythritol tetranitrate (PETN) secondary explosives are examined using a sensitive friction machine. The explosive crystals used for the measurements are at least 3.5 mm wide. The friction coefficients between crystals of the same explosive (i.e., HMX on HMX, etc.), crystals of different explosives (i.e., HMX on RDX, etc.), and each explosive and a well-polished gauge steel surface are determined. The frictional surfaces are also studied under an environmental scanning electron microscope (ESEM) to analyze surface microstructural changes under increasing loading forces. The friction coefficients vary considerably with increasing normal loading forces and are particularly sensitive to slider shapes, crystal roughness and the mechanical properties of both the slider and the sample. With increasing loading forces, most friction experiments show surface damage, consisting of grooves, debris, and nano-particles, on both the slider and sample. In some cases, a strong evidence of a localized molten state is found in the central region of the friction track. Possible mechanisms that affect the friction coefficient are discussed based on microscopic observations.

Long-term results of Taiwan Pediatric Oncology Group studies 1997 and 2002 for childhood acute lymphoblastic leukemia.

The long-term outcome of 1390 children with acute lymphoblastic leukemia (ALL), treated in two successive clinical trials (Taiwan Pediatric Oncology Group (TPOG)-ALL-97 and TPOG-ALL-2002) between 1997 and 2007, is reported. The event-free survival improved significantly (P=0.0004) over this period, 69.3+/-1.9% in 1997-2001 to 77.4+/-1.7% in 2002-2007. A randomized trial in TPOG-97 testing L-asparaginase versus epidoxorubicin in combination with vincristine and prednisolone for remission induction in standard-risk (SR; low-risk) patients yielded similar outcomes. Another randomized trial, in TPOG-2002, showed that for SR patients, two reinduction courses did not improve long-term outcome over one course. Decreasing use of prophylactic cranial irradiation in the period 1997-2008 was not associated with increased rates of CNS relapse, prompting complete omission of prophylactic cranial irradiation from TPOG protocols, beginning in 2009. Decreased use of etoposide and cranial irradiation likely contributed to the low incidence of second cancers. High-risk B-lineage ALL, T-cell, CD10 negativity, t(9;22), infant, and higher leukocyte count were consistently adverse factors, whereas hyperdiploidy >50 was a consistently favorable factor. Higher leukocyte count and t(9;22) retained prognostic significance in both TPOG-97 and TPOG-2002 by multivariate analysis. Although long-term outcome in TPOG clinical trials is comparable with results being reported worldwide, the persistent strength of certain prognostic variables and the lower frequencies of favorable outcome predictors, such as ETV6-RUNX1 and hyperdiploidy >50, in Taiwanese children warrant renewed effort to cure a higher proportion of patients while preserving their quality of life.

Cobrotoxin-containing analgesic compound to treat chronic moderate to severe cancer pain: results from a randomized, double-blind, cross-over study and from an open-label study.

Cobrotoxin produces intense analgesia but it has an onset of response of 1-3 h which hampers its clinical use in cancer pain. Recently, a compound analgesic formulation combining cobrotoxin, tramadol hydrochloride and ibuprofen (Compound Keluoqu, CKLQ) has become available in China. The aim of this study was to evaluate the clinical efficacy of CKLQ for moderate to severe cancer pain. A consecutive series of patients with chronic moderate to severe cancer pain was enrolled into two multicenter trials. Of the 230 eligible patients, 119 were assigned to a randomized, double-blind, cross-over study, while 111 entered an open-label study. They were all of Han-China nationality and had a mean age of 52.0 and 55.4 years and a mean body weight of 55.6 and 52.9 kg, respectively. A total of 11 patients discontinued the study, 6 (54.5%) because of insufficient pain relief and 5 due to the occurrence of adverse events. In the cross-over study, 59 patients were randomized to receive a CKLQ package with 2 CKLQ tablets (each containing 0.16 mg cobrotoxin, 25 mg tramadol hydrochloride and 50 mg ibuprofen) and 2 placebo capsules, a placebo package with 2 placebo tablets and 2 placebo capsules, and an active control package with 2 tramadol hydrochloride capsules (each containing 50 mg tramadol hydrochloride) and 2 placebo tablets (arm A), and 60 to receive a tramadol hydrochloride package, a placebo package and a CKLQ package (arm B), sequentially and only once. Patients in the open-label study only received CKLQ and were given the option to continue for up to 7 days as long as they had satisfactory pain relief. Pain response was classified as CR, PR and NC. CR was defined as 100% pain relief, with a pain score of 0 on a 0-10 VAS. PR was defined as decreased to mild pain, with a pain score of no more than 4 on a 0-10 VAS. NC was defined as pain that either remained unchanged or that was reduced from severe to moderate at baseline, with a VAS pain score of more than 4 after treatment. One hundred and eight patients completed the cross-over study with all the three drug units. The overall rate of pain relief was 93/111 (83.7%) for CKLQ, 75/110 (68.2%) for tramadol hydrochloride (P=0.011) and 39/111 (35.1%) for placebo (P<0.001). The mean duration of pain relief with CKLQ was significantly longer than that of the other two agents (P<0.001). Of the 35 patients who did not respond to tramadol hydrochloride, 27 (77.1%) responded to CKLQ, while of the 18 who did not respond to CKLQ, 8 (55.6%) achieved satisfactory pain control with tramadol hydrochloride. In the open-label study, the overall relief rate of a single-dose of CKLQ was 99/111 (89.2%). A reduction in the percentage of complete relief, an increase in that of PR and a significant decrease in duration of relief were observed after continuous treatment with at least 10 doses of CKLQ. The frequency of adverse events for CKLQ was similar to that of tramadol hydrochloride. The results of the randomized, double-blind, cross-over study and the open-label study of CKLQ in cancer patients with chronic moderate to severe cancer pain suggest that the CKLQ may be valuable for the treatment of chronic moderate to severe cancer pain. However, the tolerance of CKLQ remains to be further defined.

Cardiac complications of enterovirus rhombencephalitis.

BACKGROUND: Epidemics of enterovirus 71 infection have caused the death of many children throughout the world. Rhombencephalitis, brain stem encephalitis, and heart failure were present in all of the fatal cases. However, no evidence of myocarditis was noted in the heart specimens, and the mechanism of heart failure remains unknown. AIMS: To characterise the presentation of cardiac complications in children with enterovirus rhombencephalitis and discuss its pathogenesis. METHODS: Ninety one consecutive patients with enterovirus rhombencephalitis underwent echocardiography. Of these, 17 patients (nine male, eight female; median age 14 months, range 4-57 months) with left ventricular dysfunction were studied. RESULTS: Tachycardia was noted in all patients and systemic hypertension in 12. Muscle-brain fraction of creatine kinase was >5% in 14 patients. Plasma norepinephrine and epinephrine levels were significantly raised in the three patients in whom these were analysed. Electrocardiographic abnormalities were noted in eight patients. Pulmonary oedema was complicated in 15 patients. The initial ejection fraction of the left ventricle was 22-58% (mean 37%, SD 11%). All patients deteriorated to hypotensive shock within 12 hours and 13 died. Heart specimens from seven patients showed no evidence of myocarditis, but significant coagulative myocytolysis, myofibrillar degeneration, and cardiomyocyte apoptosis were observed. CONCLUSIONS: Acute heart failure was noted in 19% of patients with enterovirus rhombencephalitis, which had a fatality rate of 77%. It was not caused by myocarditis but possibly by neurogenic cardiac damage.

Age-related deficits in long-term potentiation are insensitive to hydrogen peroxide: coincidence with enhanced autophosphorylation of Ca2+/calmodulin-dependent protein kinase II.

Reactive oxygen species (ROS) can have deleterious effects for both normal aging and Alzheimer's disease (AD). We examined the hypothesis that synapses undergoing long-term potentiation (LTP) are preferentially at risk for ROS-mediated oxidative stress during aging. We observed age-dependent deficits in LTP induced by a high-frequency stimulation (HFS) protocol in the CA1 region of hippocampus from C57BL/6 mice. There was a significant difference between LTP measured over 60 min in young (1-2 months) and old (23-26 months) mice. In oxidative stress studies, exogenous H(2)O(2) (580 micro M) significantly inhibited LTP in young mice; a similar dose of H(2)O(2) failed to inhibit LTP in slices from adult (2-4 months) or from old mice. The results show that there are significant deficits in LTP in aging mice, but such deficits are insensitive to H(2)O(2). Western immunoblotting studies in young mice show that the relative levels of autophosphorylated alpha-Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) are unchanged in hippocampal CA1 treated with H(2)O(2) relative to untreated controls. However with aging, there is a significant enhancement in the levels of autophosphorylated CaMKII in H(2)O(2)-treated CA1 of older mice. Phosphorylation of RC3/neurogranin (Ng) by protein kinase C (PKC) is decreased in CA1 in response to H(2)O(2) treatment, irrespective of age. We propose that, during aging, enhanced local release of H(2)O(2) from mitochondria may induce a compensatory "ceiling" effect at synapses, so that the levels of autophosphorylated alpha CaMKII are aberrantly saturated, leading to alterations in synaptic plasticity.

Neurogranin null mutant mice display performance deficits on spatial learning tasks with anxiety related components.

Neurogranin/RC3 is a protein that binds calmodulin and serves as a substrate for protein kinase C. Neuronally distributed in the hippocampus and forebrain, neurogranin is highly expressed in dendritic spines of hippocampal pyramidal cells, implicating this protein in long-term potentiation and in learning and memory processes. Null mutation of the neurogranin gene Ng generated viable knockout mice for analysis of the behavioral phenotype resulting from the absence of neurogranin protein. Ng -/- mice were normal on measures of general health, neurological reflexes, sensory abilities, and motor functions, as compared to wild type littermate controls. On the Morris water task, Ng -/- mice failed to reach acquisition criterion on the hidden platform test and did not show selective search on the probe trial. In the Barnes circular maze, another test for spatial navigation learning, Ng -/- mice showed impairments on some components of transfer, but normal performance on time spent around the target hole. Abnormal and idiosyncratic behaviors were detected, that appeared to represent an anxiogenic phenotype in Ng -/- mice, as measured in the light<-->dark exploration test and the open field center time parameter. These findings of apparent deficits in spatial learning and anxiety-like tendencies in Ng -/- support a role for neurogranin in the hippocampally-mediated interaction between stress and performance.

Localization of A-type K+ channel subunit Kv4.2 in rat brain.

Kv4.2, a voltage-gated K+ (Kv) channel subunit, has been suggested to be the key component of the subthreshold A-type K+ currents (I(SA)s) recorded from the specific subcellular compartments of certain CNS neurons. To correlate Kv4.2 localization with the I(SA)s detected, immunohistochemistry will be useful. Although the Kv4.2 immunostaining pattern in the hippocampus and cerebellum has been reported, the Kv4.2 antibody used was not specific. Furthermore, Kv4.2 localization in other brain regions remains unclear. In this report, we first demonstrated the specificity of a new Kv4.2 antibody, and then used it to examine Kv4.2 localization throughout adult rat brain by immunohistochemistry. At the cellular level, Kv4.2 was found in neurons but not glias. At the subcellular level, Kv4.2 was localized in the somatodendritic compartment of most neurons examined. Nevertheless, our preliminary data indicated that Kv4.2 might be also present in the axon/terminal compartment. At the functional level, our data indicates that Kv4.2 localization and I(SA) correlate quite well in some CNS neurons, supporting that Kv4.2 is the key component of some I(SA)s recorded in vivo.

Glutathiolation of proteins by glutathione disulfide S-oxide derived from S-nitrosoglutathione. Modifications of rat brain neurogranin/RC3 and neuromodulin/GAP-43.

S-Nitrosoglutathione (GSNO) undergoes spontaneous degradation that generates several nitrogen-containing compounds and oxidized glutathione derivatives. We identified glutathione sulfonic acid, glutathione disulfide S-oxide (GS(O)SG), glutathione disulfide S-dioxide, and GSSG as the major decomposition products of GSNO. Each of these compounds and GSNO were tested for their efficacies to modify rat brain neurogranin/RC3 (Ng) and neuromodulin/GAP-43 (Nm). Among them, GS(O)SG was found to be the most potent in causing glutathiolation of both proteins; four glutathiones were incorporated into the four Cys residues of Ng, and two were incorporated into the two Cys residues of Nm. Ng and Nm are two in vivo substrates of protein kinase C; their phosphorylations by protein kinase C attenuate the binding affinities of both proteins for calmodulin. When compared with their respective unmodified forms, the glutathiolated Ng was a poorer substrate and glutathiolated Nm a better substrate for protein kinase C. Glutathiolation of these two proteins caused no change in their binding affinities for calmodulin. Treatment of [(35)S]cysteine-labeled rat brain slices with xanthine/xanthine oxidase or a combination of xanthine/xanthine oxidase with sodium nitroprusside resulted in an increase in cellular level of GS(O)SG. These treatments, as well as those by other oxidants, all resulted in an increase in thiolation of proteins; among them, thiolation of Ng was positively identified by immunoprecipitation. These results show that GS(O)SG is one of the most potent glutathiolating agents generated upon oxidative stress.

Genomic organization and the promoter region of the round-spotted pufferfish (Tetraodon fluviatilis) CDC37 gene.

The CDC37 gene was isolated from a round-spotted pufferfish genomic library and characterized. This gene is composed of nine exons spanning 3.5 kb. Exon 1 contains the 5'-untranslated region and exon 2 contains the putative translation initiation site. By 5'-RACE (rapid amplication of cDNA ends) and sequence analysis, we deduced the promoter region for the CDC37 gene and found that it does not contain typical TATA or CCAAT box. The 1.8 kb DNA fragment upstream of the putative transcription initiation site contains numerous potential binding sites for transcription factors including CREB, E2A, Ets-1, GATA, NF-IL6 and PEA3. When this DNA fragment was placed upstream of the chloramphenicol acetyltransferase (CAT) reporter gene and transfected into a carp CF cell line, it could drive the synthesis of CAT enzyme four times more efficiently than the promoterless pCAT-Basic did. In addition, the CDC37 gene is linked to the TYK2 gene in a tail-to-head manner with a small intergenic region of 292 bp.

Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: a study with knockout mice.

Neurogranin/RC3 is a neural-specific Ca(2+)-sensitive calmodulin (CaM)-binding protein whose CaM-binding affinity is modulated by phosphorylation and oxidation. Here we show that deletion of the Ng gene in mice did not result in obvious developmental or neuroanatomical abnormalities but caused an impairment of spatial learning and changes in hippocampal short- and long-term plasticity (paired-pulse depression, synaptic fatigue, long-term potentiation induction). These deficits were accompanied by a decreased basal level of the activated Ca(2+)/CaM-dependent kinase II (CaMKII) ( approximately 60% of wild type). Furthermore, hippocampal slices of the mutant mice displayed a reduced ability to generate activated CaMKII after stimulation of protein phosphorylation and oxidation by treatments with okadaic acid and sodium nitroprusside, respectively. These results indicate a central role of Ng in the regulation of CaMKII activity with decisive influences on synaptic plasticity and spatial learning.