Cataract as a phenotypic marker for a mutation in WFS1, the Wolfram syndrome gene.

PURPOSE: Wolfram syndrome (WS) or diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD) (OMIM 222300) is an inherited neurodegenerative disease characterized by diabetes mellitus and optic atrophy as the 2 major criteria, followed later in life by deafness, diabetes insipidus, and various signs of neurologic impairment. The presence of a cataract has been variably mentioned in WS. METHOD: Two members of a family had thorough ophthalmic examination and their DNA was screened for mutations in mitochondrial DNA, WFS1, OPA1, and OPA3 genes. RESULTS: We report a patient who first had surgery for bilateral cataract at age 5 and who subsequently presented typical signs of WS, i.e., diabetes mellitus, optic atrophy with reduced visual acuity at 20/400 on both eyes at age 22, and mild deafness. The patient was found to be a compound heterozygote for 2 truncating mutations in WFS1, the major WS gene. She carried the previously reported c.1231_1233 delCT and a novel c.2431_2465dup35 mutation. She also was heterozygote for a novel OPA1 sequence variant, c.929A>G in exon 9, whose pathogenicity remains uncertain. The patient's mother was a heterozygous carrier of the c.2431_2465dup35 mutation. She did not have diabetes mellitus or optic atrophy but had bilateral polar cataract. She did not carry the OPA1 sequence variant. CONCLUSIONS: Cataract could be a marker for the WFS1 heterozygosity in this family, namely the c.2431_2465dup35 mutation.

Can event-related potential predict the progression of mild cognitive impairment?

This study was designed to evaluate the predictive value of event-related potential (ERP; N2 and P3b) in patients with mild cognitive impairment (MCI). Seventy-one patients with MCI were selected and compared with 31 healthy control subjects. They benefited from an initial assessment that included a neuropsychological evaluation and ERP. We followed them up for 1 year, and during their last visit, they benefited again from ERP and neuropsychological tests. At the end of the study, 2 subgroups of patients with MCI were differentiated according to their clinical evolution from baseline to follow-up: 41 MCI progressors (MCI-P) and 30 MCI nonprogressors (MCI-non P). The MCI-P patients had a significant decline in their executive functions compared with the MCI-non-P group at baseline and follow-up especially on trail making test B (TMT B) and verbal fluency (P < 0.0001). At baseline, MCI-P had increased P3b latencies and low P3b amplitudes compared with MCI-non P. The MCI-P showed an inversion of the P3b rostrocaudal gradient with a significant decrease in the amplitude of P3b in the parietal area compared with the MCI-non P. At follow-up, 17 MCI-P patients had converted to Alzheimer's disease (AD). There was a significant rate of decline of the amplitude of N2 and P3b in the frontal area among the groups. Furthermore, the MCI-P had a higher decrease in the rostrocaudal gradient of P3b and prolonged N2 and P3b latencies than the MCI-non P did. The sensitivity and specificity were approximately 80% and 70%, using P3b amplitude to discriminate the MCI-P from the MCI-non P. Our study underlines the interest of using N2 and P3b as neurophysiological markers for measuring MCI decline progression.

Diagnostic value of event-related evoked potentials N200 and P300 subcomponents in early diagnosis of Alzheimer's disease and mild cognitive impairment.

Event-related potentials (ERPs) have a large application in the evaluation of cognitive processes, particularly in Alzheimer's disease (AD). The aim of the present study was to evaluate the clinical relevance of event-related evoked potentials (N2 and P3 subcomponents) in early diagnosis of AD and mild cognitive impairment (MCI). We prospectively studied 60 subjects. They all underwent the following investigations: neurologic and neuropsychological examination; functional evaluation, i.e., ERPs; cerebral imagery (morphologic and functional). Subjects were classified into 3 groups: group 1: 30 dementia of Alzheimer type (NINCDS-ADRDA, DSM-IV criteria); group 2: 20 MCI; and group 3: 10 control subjects. ERPs were significantly different between the groups (AD, MCI, control subjects), with a marked increase of P3 latencies, particularly when compared with N2 latencies (P < 0.0001). Furthermore, sensitivity was 87% to 95% for the differentiation of AD patients from MCI and control subjects, using prolonged P3 latencies (specificity, 90% to 95%), whereas using N2 prolonged latencies, sensitivity was 70% to 75% (specificity, 70% to 90%). Moreover, in the MCI group, N2 latencies strongly discriminated MCI from control subjects, with 90% sensitivity and 70% specificity and correctly categorized 80% of MCI subjects against 73% for P3. The abnormalities of N2 and P3 components may be linked, in AD and MCI, to an alteration of automatic and controlled attention processing.

Can electroencephalographic analysis be used to determine sedation levels in critically ill patients?

UNLABELLED: Prolonged use of sedative drugs frequently leads to oversedation of intensive care patients. Clinical assessment scales are not reliable in deeply sedated patients. Parameters obtained from spectral and bispectral analysis of electroencephalogram (EEG) records have been combined to create an index (BIS) to monitor anesthesia depth. The role of such parameters in monitoring the depth of the sedation in intensive care unit (ICU) patients has yet to be determined. We designed the present prospective study to redefine and calculate available spectral and bispectral parameters from raw EEG records and estimate their clinical relevance for the diagnosis of under- or oversedation levels in ICU patients. Forty adult patients receiving continuous midazolam and morphine sedation were included. We obtained 167 clinical evaluations of sedation level using Ramsay and COMFORT scales along with an EEG record of 300 s. Six spectral parameters-relative power of 4 frequency bands (beta, alpha, Theta, and delta), 95th percentile of the power spectrum (SEF95), and 50th percentile of the power spectrum (SEF50) and four bispectral parameters, real triple product, bispectrum (Bispectrum), bicoherence, and ratio 10-were calculated. The relevance of each of these parameters and combinations in predicting too light (Ramsay 1 and 2) or deep (Ramsay 5 and 6) sedation levels was assessed. These calculations were performed before and after exclusion of the agitated patients, whose COMFORT 4 score was above 2. The most relevant parameters for predicting levels of deep sedation (Ramsay 5 and 6) were ratio 10 (area under the curve = 0.763; 95% confidence interval, 0.679-0.833) and SEF95 (area under the curve = 0.687; 95% confidence interval, 0.597-0.767). The most relevant parameters for predicting light levels of sedation (Ramsay 1 and 2) were also ratio 10 (area under the curve = 0.829; 95% confidence interval, 0.695-0.917) and SEF95 (area under the curve = 0.798; 95% confidence interval, 0.650-0.898). There is a modest improvement in relevance of their linear combination in predicting sedation level. Results were similar after exclusion of agitated patients. We conclude that various calculated EEG descriptive parameters exhibited large interindividual variability. There was a strong correlation between EEG spectral and bispectral parameters. Bispectral analysis slightly improves the predictive power of simple spectral analysis in distinguishing too light or deep sedation levels in ICU patients. IMPLICATIONS: Spectral edge frequency 95 and Ratio 10 are the most relevant electroencephalogram (EEG) indexes for monitoring the level of sedation in intensive care unit patients but calculated EEG values exhibited large interindividual variability. Bispectral analysis of EEG provides a slight improvement over simple spectral analysis.

Caffeic acid phenethyl ester (CAPE) prevents inflammatory stress in organotypic hippocampal slice cultures.

Caffeic acid phenethyl ester (CAPE) is an antioxidant component of propolis, a natural product secreted by honeybee. Recent literature shows that CAPE inhibits nuclear factor kappa B (NFkappaB) activation in cell lines. Since NFkappaB was shown to be a crucial factor in neuroinflammation and to be associated with some neuropathologies, CAPE might reduce these disorders in brain too and have therapeutic applications. To test this hypothesis we used a model of endotoxic insult (interferon-gamma, followed by lipopolysaccharide) on rat organotypic hippocampal cultures. Cerebral inflammatory responses were strongly inhibited by CAPE (100 microM): reductions of NFkappaB nuclear activity, tumor necrosis factor alpha and nitric oxide productions were observed. At the dose of maximal effects (100 microM), an increase of cAMP-responsive element binding protein (CREB) activity, which anti-inflammatory role is well known, was seen. We compared CAPE effects with those of other drugs: anti-inflammatory as acetyl-salicylate and dexamethasone (glucocorticoid), antioxidant as pyrrolidine dithiocarbamate, or selective permeant inhibitor of NFkappaB as SN 50 peptide. These studies lead us to conclude that CAPE presents an interesting and original neuropharmacological profile compared to these drugs and might be helpful in the prevention of neurotoxic events due to excessive inflammatory reaction in brain. CAPE interferes with several effectors of neuroinflammation that might have complementary and synergic effects and allows a rather durable control since an acute treatment at the time of endotoxin exposure allows to control inflammatory factors for over 48 h.

Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis.

Many experimental studies suggest that NFkappaB, a transcription factor involved in acute inflammation, and cytokines participate in neuronal excitability and/or glial scar formation in epilepsy. In this report, we looked for the expression of NFkappaB in hippocampi surgically removed in patients with medial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS) who had an history of febrile convulsions. We analyzed 18 hippocampi from epileptic patients with MTLE and HS, and we used as control specimens three hippocampi from non-epileptic patients and four hippocampi from patients with cryptogenic MTLE without HS. We used antibodies raised against the NFkappaB-p65 subunit and we identified glial cells with specific antibodies. Hippocampi from patients with MTLE and HS displayed severe neuronal loss surrounded by gliosis in CA1 area and more or less in CA3/CA4 areas. Double immunolabeling showed that reactive astrocytes of lesioned areas over-expressed NFkappaB-p65 (significantly when compared to control specimens). Moreover, some surviving pyramidal neurons in these areas and numerous dentate granule cells were strongly positive for NFkappaB-p65 in cytoplasm and nucleus, whereas control hippocampi showed a faint basal cytoplasmic staining in neurons. These results suggest that in epileptic hippocampi with typical sclerosis, inflammatory processes are chronically active or transiently re-induced by recurrent seizures. Whether NFkappaB over-expression reflects protective or deleterious mechanisms in the epileptic focus remains to be elucidated.

Implication of p53 and caspase-3 in kainic acid but not in N-methyl-D-aspartic acid-induced apoptosis in organotypic hippocampal mouse cultures.

Apoptotic death is known to be an active process requiring the activation of several apoptotic proteins. Depending on the tissue studied and the stimulus used, these processes are distinct. In this work, we studied if there is a putative implication of the p53 and the caspase-3 proteins in kainic acid (KA) and N-methyl-D-aspartic acid (NMDA)-induced apoptosis in organotypic cultures and if there is any relationship between their respective expressions. We found that KA and NMDA both induce apoptosis but only KA-induced apoptosis is p53- and caspase-3-dependent. This demonstrates that KA and NMDA induce apoptosis following different intracellular pathways.