Foxo3a transcription factor is a negative regulator of Skp2 and Skp2 SCF complex.

Skp2 (S-phase kinase-associated protein-2) SCF complex displays E3 ligase activity and oncogenic activity by regulating protein ubiquitination and degradation, in turn regulating cell cycle entry, senescence and tumorigenesis. The maintenance of the integrity of Skp2 SCF complex is critical for its E3 ligase activity. The Skp2 F-box protein is a rate-limiting step and key factor in this complex, which binds to its protein substrates and triggers ubiquitination and degradation of its substrates. Skp2 is found to be overexpressed in numerous human cancers, which has an important role in tumorigenesis. The molecular mechanism by which the function of Skp2 and Skp2 SCF complex is regulated remains largely unknown. Here we show that Foxo3a transcription factor is a novel and negative regulator of Skp2 SCF complex. Foxo3a is found to be a transcriptional repressor of Skp2 gene expression by directly binding to the Skp2 promoter, thereby inhibiting Skp2 protein expression. Surprisingly, we found for the first time that Foxo3a also displays a transcription-independent activity by directly interacting with Skp2 and disrupting Skp2 SCF complex formation, in turn inhibiting Skp2 SCF E3 ligase activity and promoting p27 stability. Finally, we show that the oncogenic activity of Skp2 is repressed by Foxo3a overexpression. Our results not only reveal novel insights into how Skp2 SCF complex is regulated, but also establish a new role for Foxo3a in tumor suppression through a transcription-dependent and independent manner.

An exploratory study on cultural variations in oral health attitudes, behaviour and values of freshman (first-year) dental students.

OBJECTIVE: To identify similarities and differences in oral health attitudes, behaviour and values among freshman dental students. DESIGN: Cross-cultural survey of dental students. SETTING: 18 cultural areas. PARTICIPANTS AND METHODS: 904 first-year dental students completed the Hiroshima University-Dental Behavioural Inventory (HU-DBI) translated into their own languages. Individual areas were clustered by similarity in responses to the questions. RESULTS: The first group displayed an 'occidental-culture orientation' with the exception of Brazil (Cluster 1 comprised: Australia, United Kingdom, Ireland, Belgium and Brazil, Cluster 2: Germany, Italy, Finland and France). The second group displayed an 'oriental-cultural orientation' with the exception of Greece and Israel (Cluster 3 comprised: China and Indonesia, and Cluster 4: Japan, Korea, Israel, Hong Kong, Malaysia, Thailand and Greece). Australia and United Kingdom were the countries that were most alike. Ireland was the 'neighbour' to these countries. Greece and Malaysia had similar patterns of oral health behaviour although geographic conditions are very different. Although it was considered that in Hong Kong, occidental nations have affected the development of education, it remained in the oriental-culture group. Comparison with the data from the occidentals indicates that a higher percentage of the orientals put off going to the dentist until they have toothache (p < 0.001). Only a small proportion of the occidentals (8%) reported a perception of inevitability in having false teeth, whereas 33% of the orientals held this fatalistic belief (p = 0.001). CONCLUSIONS: Grouping the countries into key cultural orientations and international clusters yielded plausible results, using the HU-DBI.

Magnetoencephalographic yield of interictal spikes in temporal lobe epilepsy. Comparison with scalp EEG recordings.

To compare magnetoencephalography (MEG) with scalp electroencephalography (EEG) in the detection of interictal spikes in temporal lobe epilepsy (TLE), we simultaneously recorded MEG and scalp EEG with a whole-scalp neuromagnetometer in 46 TLE patients. We visually searched interictal spikes on MEG and EEG channels and classified them into three types according to their presentation on MEG alone (M-spikes), EEG alone (E-spikes), or concomitantly on both modalities (M/E-spikes). The M-spikes and M/E-spikes were localized with MEG equivalent current dipole modeling. We analyzed the relative contribution of MEG and EEG in the overall yield of spike detection and also compared M-spikes with M/E-spikes in terms of dipole locations and strengths. During the 30- to 40-min MEG recordings, interictal spikes were obtained in 36 (78.3%) of the 46 patients. Among the 36 patients, most spikes were M/E-spikes (68.3%), some were M-spikes (22.1%), and some were E-spikes (9.7%). In comparison with EEG, MEG gave better spike yield in patients with lateral TLE. Sources of M/E- and M-spikes were situated in the same anatomical regions, whereas the average dipole strength was larger for M/E- than M-spikes. In conclusion, some interictal spikes appeared selectively on either MEG or EEG channels in TLE patients although more spikes were simultaneously identified on both modalities. Thus, simultaneous MEG and EEG recordings help to enhance spike detection. Identification of M-spikes would offer important localization of irritative foci, especially in patients with lateral TLE.

Magnetoencephalographic study of rhythmic mid-temporal discharges in non-epileptic and epileptic patients.

To evaluate the source location and clinical significance of rhythmic mid-temporal theta discharges (RMTD) by MEG in non-epileptic and epileptic patients, we conducted simultaneous MEG and EEG recordings with a whole-scalp 306-channel neuromagnetometer in three patients: one with right temporal lobe epilepsy (TLE), one with right frontal lobe epilepsy (FLE), and one with tension headache. We visually detected the RMTD activity and interictal spikes, and then localised their generators by MEG source modelling. We repeated MEG measurement 3 months after right anterior temporal lobectomy (ATL) in the TLE patient; 3 months after anticonvulsant medication in the FLE patient. In epileptic patients, RMTD activities were found during drowsiness over the left temporal channels of both MEG and EEG recordings, and their generators were localised to the left posterior inferior temporal region. In the patient with tension headache, RMTD was localised in the right inferior temporal area. When the epileptic patients became seizure free with disappearance of epileptic spikes, RMTD was still found over the left temporal channels. Besides, some bursts of RMTD appeared also in the right temporal channels in our TLE patient after ATL. Our results indicate that the source of RMTD activity is located in the fissural cortex of the posterior inferior temporal region. As a physiologic rhythm related to dampened vigilance, RMTD has no direct relation to epileptogenic activity.

The effect of intra-operative video on patient anxiety.

We conducted a randomised controlled study to evaluate whether watching video compact discs intra-operatively using a liquid crystal display (LCD) unit decreased anxiety. Forty-four patients undergoing elective surgery under regional anaesthesia were assigned to either the LCD or control group. Anxiety was measured using the Chinese version of the State-Trait Anxiety Inventory (STAI) and visual analogue score (VAS). The mean (SD) anxiety trait scores were 46.15 (6.28) and 46.40 (7.32) in the control and LCD groups, respectively. The state anxiety of the LCD group [35.50 (7.96)] measured immediately postoperatively was significantly lower than the control group [41.50 (9.02); p = 0.03]. The median (range) reduction in VAS anxiety score was not significantly greater in the LCD group [20 (20 to 80) mm] compared with the control group [12.5 (70 to 60) mm]. Watching video intra-operatively reduces patient anxiety as measured by the STAI.

Radiological and manometric diagnosis of cricopharyngeal dysphagia in a Japanese encephalitis survivor.

Japanese encephalitis (JE) is endemic throughout most of the western Pacific region where Taiwan is located. About half the survivors are left with neurological damages. We report a 55-year-old male who survived from JE and was left with sequela of parkinsonism and severe swallowing disorder. Later, it was proved to be cricopharyngeal dysphagia (CPD) using esophagogram and manometry, which disclosed involuntary hypertonic and hyperreflexic cricopharyngeal muscle contraction. CPD, a life-threatening neurological sequel of JE, has never been reported in the JE survivors before and possibly results from disseminated lesions over pyramidal and extrapyramidal systems.

Lateralizing value of early head turning and ictal dystonia in temporal lobe seizures: a video-EEG study.

To investigate early head turning, we retrospectively studied videotapes of 262 seizures from 82 patients who were seizure free after temporal lobectomy. Early head movements were arbitrarily classified into non-tonic turning, tonic turning, and absence of turning. Among the 222 seizures which showed early head turning, 168 (75.7%) had non-tonic turning and 54 (24.3%) had tonic turning. The direction of the first head turning was ipsilateral to the epileptogenic foci in 132 (78.6%) seizures with non-tonic turning and in 35 (64.8%) seizures showing tonic head turning. The proportion of seizures with turning towards the ipsilateral side in the presence of tonic and non-tonic head turning were significantly different (P= 0.04). Seventy-four seizures (28.2%) evolved to secondary generalization, more frequently found in seizures with early head turning (P= 0.0015) and especially those showing tonic turning (P< 0.0001). The direction of head turning immediately preceding secondary generalization was contralateral to the lesion side in 53 seizures (82.8%). Dystonic upper limb posturing occurred in 86 seizures (32.8%), exclusively contralateral to the seizure focus, whereas 65 (75.6%) were associated with initial head turning ipsilateral to the focus. In summary, temporal lobe seizures with tonic head turning tends to secondarily generalize and the direction of head turning before secondarily generalized was contralateral to the seizure foci. Earlier in the seizures the direction of non-tonic head turning tends to be towards the epileptogenic hemisphere. In addition, dystonic posturing of the extremities is a significant lateralizing sign to the contralateral hemisphere in temporal lobe seizures.

Power spectrum analysis of heart rate variability in children with epilepsy.

OBJECT: Children with epilepsy have been found to be at increased risk of death during childhood. Sudden unexpected death (SUDEP) has accounted for at least 12% of deaths of children with epilepsy. The exact mechanisms of SUDEP are unknown; however, theories suggested have, to date, focused on autonomic instability. The purpose of this study was to investigate autonomic function in children with chronic epilepsy by means of power spectrum analysis of heart rate variability. METHODS: Thirty patients with epilepsy and 30 control subjects, all between the ages of 4 and 10 years, were enrolled in this study. Power spectrum analysis of heart rate variability (HRV) was performed under standardized conditions after the patients had rested for 15 min. Each patient was tested in a supine position first and then again in a head-up tilted position, with 15 min between the two tests. RESULTS: There was no significant difference between the low-frequency component (LF) and the high-frequency component (HF) of heart rate variability, or the LF/HF ratio, between the study and control groups, whether the test subjects were in the supine or the head-up tilt position. In the control group, however, the subjects showed a significantly greater LF component and a smaller HF component of heart rate variability, and a greater LF/HF ratio in the head-up position than in the supine position. This implies a normal sympathovagal balance. This phenomenon was not observed in the study group. This implies that the modulating effects on autonomic function deriving from the hemisphere were probably disturbed, owing to the brain lesions that each of the study group patients had already sustained. CONCLUSIONS: A disturbed balance of activity between the sympathetic and parasympathetic nervous system might result from the loss of hemispheric influence in patients with epilepsy. Nevertheless, further investigation is clearly necessary to ascertain the possible association of this disturbed balance with SUDEP. Further investigation is also needed to establish the exact location of the region in the brain that gives rise to this modulating influence.

Antiepileptic drug withdrawal in patients with temporal lobe epilepsy undergoing presurgical video-EEG monitoring.

PURPOSE: To investigate antiepileptic drug (AED) withdrawal during video-EEG monitoring in adult patients with temporal lobe epilepsy (TLE). METHODS: Between 1995 and 1997, 102 consecutive patients with refractory TLE were admitted to the epilepsy monitoring unit for presurgical evaluation. Patients were monitored with ongoing AEDs being rapidly decreased and discontinued in 4-6 days. The monitoring was continued until sufficient numbers of seizures were recorded. Serum AED levels were checked at admission and after the first complex partial seizure (CPS). RESULTS: In all, 89 patients had 429 CPSs (mean, 4.8 per patient), including 156 (36.4%) secondarily generalized. A mean of 153.8 h (16-451 h) was required for completing the monitoring in each patient. Forty-three (48.3%) patients experienced seizure clusters, and eight (9.0%) had generalized seizures that had never occurred or had been absent for years. However, none evolved to status epilepticus. Carbamazepine was the most commonly used AED in 71.9% of patients, followed by valproate and phenytoin. When the first CPS occurred, mean 77.2 h since the beginning of the monitoring, serum levels of these three AEDs were mostly subtherapeutic rather than minimal. CONCLUSIONS: Acute AED withdrawal effectively provoked seizures in TLE patients undergoing presurgical video-EEG monitoring. However, nearly 50% of patients had seizure clusters or secondarily generalized seizures. Serum AED levels were mostly subtherapeutic when the first CPS occurred.

Seizure outcomes after anterior callosotomy in patients with posterior-dominant and with anterior-dominant epileptiform discharges.

OBJECTS: We wished to find whether there was any difference in the postoperative seizure outcome between patients with bisynchronous anterior-dominant and those with posterior-dominant EDs after anterior callosotomy. METHODS: Seizure outcomes after anterior callosotomy in 7 patients with bisynchronous posterior-dominant epileptiform discharges and in 54 patients with anterior-dominant seizures were compared. All 61 cases had been followed up for more than 2 years after operation. One patient (14.3%) had become seizure free. Two patients (28.6%) had more than 50% reduction in seizure frequency, but 4 patients (57.2%) showed no improvement at all. The percentage of cases with significant improvement (more than 50% reduction of seizure frequency) was 43% (3 in 7), which is lower than in the patients with bisynchronous anterior-dominant EDs (64.8%). CONCLUSIONS: Our preliminary results suggest that anterior partial callosotomy could still be helpful in cases with bisynchronous posterior-dominant epileptiform discharges but the prognosis may be less optimistic than for those with anteriorly located discharges.

Predictors of maternal depression for families having a child with epilepsy.

The purpose of this study was to use a descriptive correlational design to examine the relationship among maternal uncertainty, boundary ambiguity and depression in families having a child with epilepsy. Three hundred and twenty-four mothers from the child epilepsy day-clinics of three teaching hospitals in Taiwan participated in this study. Data collection was performed by well-trained research assistants who helped mothers fill out the well-developed Chinese version of the Parental Perception of Uncertainty Scale, the Boundary Ambiguity scale, and the Beck Depression Inventory. Uncertainty was positively associated with boundary ambiguity and depression. Boundary ambiguity was positively associated with depression. Stepwise regression analysis demonstrated that boundary ambiguity, uncertainty and mother's age are predictors of a mother's depression which account for 21.49% of the total variance of depression. The results provide a scientific knowledge base for nursing interventions that aim to provide clear information about the child's illness and help to establish appropriate patterns of parent-child interaction in terms of maintaining family boundary integrity and mothers' functional adaptability.

Identification and characterization of Podophyllum emodi by API-LC/MS/MS.

An API-LC/MS/MS method was developed for the identification of the medicinal herb Podophyllum emodi based on the profile of its aryltetrahydronapthalene and related lignan marker compounds. This was done by matching the structural information from the tandem mass spectrometric data with those lignan marker compounds already reported for the herb. The method could be employed in the absence of reference standards for the markers and was particularly useful in view of the scarcity of supply of these chemical standards. It has been used successfully to differentiate Podophyllum emodi from two commonly used medicinal herbs of a different genus but having similar appearance, Radix clematidis and Radix gentiana, as well as a closely related herb, Podophyllum peltatum.

Postcallosotomy seizure outcome in hemiconvulsion-hemiatrophy-epilepsy syndrome.

Recently, three patients with hemiconvulsion-hemiplegia-epilepsy syndrome who underwent callosotomy were monitored for more than four years. All patients had atrophy of the right brain hemisphere with left hemiparesis and seizures. Two cases were probably the result of traumatic intracranial hemorrhage and one was due to an unknown cause. Wada tests were done in cases 1 and 2, which showed spared motor function of the atrophic hemisphere, supporting the choice of callosotomy instead of hemispherectomy. Patient 1 had atypical absence seizures and asymmetric generalized tonic seizures before surgery, the latter of which decreased by about 60% after callosotomy. Patient 2 had simple partial seizures of the motor type and complex partial seizures, the latter of which were also induced by touch (somatosensory-induced reflex epilepsy). This patient's complex partial seizures disappeared completely, but the simple partial seizures remained unchanged. Patient 3 had generalized tonic seizures, simple partial seizures of the sensory type and complex partial seizures. After surgery, the frequency of the generalized tonic seizures decreased more than 90%. The simple partial seizures of the sensory type remained unchanged. There were two new types of seizures after surgery, simple partial seizures of the motor type and brief generalized myoclonic jerks. All patients had significant reductions in numbers of seizures of more than 50%.

Postictal psychosis with forced normalization.

A 22-year-old female patient with epilepsy for more than six years who had prominent psychiatric manifestations, including paranoia, delusions and hallucinations, after a series of major seizure attacks caused by sudden withdrawal of anticonvulsant medication was monitored. This reported episode of psychosis occurred eight hours after the last seizure attack and lasted for two weeks. The psychosis gradually disappeared after administration of lorazepam. The electroencephalogram (EEG) performed during the period of psychosis showed intermittent slow activity in the bilateral frontal regions of the brain. There were active bisynchronous epileptiform discharges bisynchronously in both frontotemporal regions after the resolution of the psychotic episode. The clinical picture and course were consistent with the diagnosis of "postictal psychosis", and the transient near normal EEG during psychosis was most likely a phenomenon known as "forced normalization". The patient has not had a similar psychotic attack since the one reported here.

Mah-jong epilepsy: a new reflex epilepsy.

BACKGROUND: Flickering light and color patterns, reading, language, movement, decision making, eating, tapping and touching, hot water immersion and auditory stimulation can induce seizures in some patients. This is known as "reflex epilepsy". The mechanism of reflex epilepsy is not clear. Recently, we cared for 12 patients (11 men and 1 woman, age 41-74 years; mean age = 63.1 years) whose seizures were induced by playing mah-jong, with mean age at seizure onset of 48.7 years. Nine of the 12 patients had seizures exclusively while playing mah-jong. METHODS: We retrospectively reviewed the medical records of 12 epileptic patients who visited our neurologic clinic from 1987 to 1999, with the chief complaint of mah-jong induced seizures. All patients underwent examinations including electroencephalography, brain computed tomography or magnetic resonance imaging, analysis of clinical manifestation of seizures, family history and past medical history. All were given anticonvulsant therapy for preventing seizures. RESULTS: Clinically, 10 patients had generalized tonic-clonic seizures and two patients had partial seizures with secondary generalization. Interictally, normal results on EEG were found in six patients, three had focal temporal spikes, and three had intermittent slow activity in the frontotemporal regions. Neuroimaging studies of the brain were normal in seven patients, two had lacunar infarctions, one had generalized atrophy and one had focal left parietal lesions of an unclear nature. Only one patient had a family history of epilepsy. All 12 patients received anticonvulsant therapy, and of these, nine had good epilepsy control. CONCLUSIONS: "Mah-jong epilepsy," a new reflex epilepsy, is probably related to thinking and decision making while playing mah-jong. The easy control of seizures induced by mah-jong suggests a benign nature. In addition to anticonvulsant therapy, avoiding playing mah-jong may be essential in preventing seizures.

Postoperative seizure outcome after corpus callosotomy in reflex epilepsy.

Flickering light and color patterns, reading, language, movement, decision making, eating, tapping and touching, hot water immersion and auditory stimulation can induce seizures in some epileptic patients. These are known as the "reflex epilepsies". The mechanism of reflex epilepsy is not clear. Recently, we performed anterior two-thirds corpus callosotomies in two reflex epilepsy patients (ages 12 and 14 years), with follow-up for more than three years. Patient 1 had Lennox-Gastaut syndrome with auditory-induced generalized atonic or tonic seizures (startle epilepsy), which decreased by 60% after callosotomy. Patient 2 had Lennox-Gastaut syndrome with somatosensory-induced generalized tonic seizures (tap epilepsy). He was seizure-free for one year immediately after callosotomy, but his seizures recurred with the same degree and frequency as before surgery. The nonsignificant postoperative seizure outcome suggests that the corpus callosum only plays a partial role in seizure generation. Our report also discusses the possible mechanisms of generation of reflex seizures.

Parental smoking practices and caries experience in pre-school children.

Voluntary and involuntary smoking influence general health. Links between voluntary smoking and oral health are confirmed for periodontal diseases and oral cancer/precancer. Since recent reports have suggested an association between parental smoking and caries experience in young children, this study aimed to explore varying patterns of parental smoking, adjusted for social class, with caries prevalence, using data derived from the UK National Diet and Nutrition Survey (1995). Data analysis was confined to 749 children aged 3.0-4.5 years, to avoid confounding effects of unerupted teeth. Bivariate analysis indicated that the prevalence of maternal rather than paternal smoking was significantly related to caries and substantially attenuated social class differences. The reported number of cigarettes smoked was not important. To compensate for the association between social class and maternal smoking, data were dichotomised by social class (manual/non-manual). With caries prevalence as the dependent variable, logistic regression analysis recorded maternal smoking as a significant independent variable in each case, with odds ratios of 1.55/1.96, respectively. The process was repeated for the combined dataset, using the more extensive (six) social class categories. This further analysis yielded an odds ratio for maternal smoking of 1.54 compared with 1.46 for social class. Nutrition status (as growth parameters) and dietary intake (as household spending on confectionery) were not significant independent variables in these equations. The rationale for these findings is discussed. Further research is required to determine mechanisms underlying these observations. It is concluded that maternal smoking is a significant factor to be considered as an additional risk indicator beyond social class when predicting caries risk in young children.

Coexistence of epilepsy, myasthenia gravis and psoriasis vulgaris.

We report the case of a 36-year-old Chinese man with a history of complex partial seizure of temporal lobe origin since the age of 12 years, superimposed by myasthenia gravis since the age of 27 years and psoriasis vulgaris since the age of 29 years. With an eight-year follow-up, the above three diseases remained without complete remission. Anticonvulsant therapy (phenytoin and trimethadione) caused drug-induced myasthenia gravis, which should gradually disappear after discontinuing the drugs. However, the myasthenic symptoms and serum acetylcholine receptor antibody persisted following the discontinuation of phenytoin in our patient. Myasthenia gravis and psoriasis are both autoimmune diseases and correlate with specific human histocompatibility antigens. This suggests a close connection between these two diseases. The coexistence of epilepsy, myasthenia gravis and psoriasis vulgaris has not been previously reported, and to the best of our knowledge, our patient is the first reported case. The relationship among these three diseases requires further investigation.

Seizure outcome after corpus callosotomy: the Taiwan experience.

From September 1989 to August 1996, we performed anterior corpus callosotomy in 83 patients. Unfortunately, 9 patients were lost to follow-up. Among the remaining 74 patients, 59 had Lennox-Gastaut syndrome (evolved from infantile spasms in 22), 9 had complex partial seizures with or without secondary generalized seizures, 1 had multifocal independent epileptogenic foci (MISF) syndrome, 3 had hemiconvulsion-hemiplegia-epilepsy (HHE), and 2 had infantile spasms. All cases were followed up for at least 2 years after surgery. The highest rate of significant improvement (more than 50% reduction in seizure frequency) was noted in the patients with generalized tonic-clonic seizures, 82.1% of whom experienced significant improvement, followed by those with generalized tonic seizures (76. 7%), atonic seizures (72.7%), myoclonic seizures (64.9%), atypical absences (58.6%), and complex partial seizure with or without secondary generalization (61.5%). Complete freedom from seizures was noted in 14 cases (18.9%). One patient had the anterior half of his right palm amputated following radial artery thrombosis complicated by insertion of an arterial line during anesthesia. Otherwise, there were no major postoperative complications except for brief mutism and multifocal jerks in some patients during the 1st postoperative week. Thus, we conclude that corpus callosotomy is a safe alternative treatment for all kinds of medically intractable seizures, especially generalized epilepsy.