Elevated receptor for activated C kinase 1 expression is involved in intracellular Ca2+ influx and potentially associated with compromised regulatory T cell function in patients with asthma.

BACKGROUND: Regulatory T cells (T(regs)) are activated during anergy in response to T cell receptor (TCR) activation and functional immune suppression. Anergy of paediatric T(regs) is partially dependent on intracellular calcium mobility; following TCR activation, T(regs) do not exhibit increased intracellular Ca(2+) concentration ([Ca(2+) ](i)). OBJECTIVE: We determined whether [Ca(2+) ](i) in adult T(regs) defined their anergy, if intracellular Ca(2+) movement was linked to regulatory functions, whether [Ca(2+)](i) was indicative of asthma pathology, and the potential molecular mechanism responsible for Ca(2+) movement in T(regs). METHODS: T(regs) were purified by the magnetic bead method, and their regulatory functions were assessed by monitoring carboxyfluorescein succinimidyl ester-labelled responder T cell proliferation. The Ca(2+) response of Fura-2-labelled cells was measured using a video image analysis system. To analyse the functions of T(regs) at the molecular level, we generated Jurkat Tet-On(®) clones with doxycycline (Dox)-induced forkhead box P3 (FOXP3) protein expression. RESULTS: CD4(+) CD25(+) CD127(-/low) T(regs) from participants without asthma did not elicit Ca(2+) influx in response to TCR activation, exhibited little proliferation and suppressed proliferation of CD4(+) CD25(-) T cells. In contrast, under similar conditions, T(regs) from patients with asthma exhibited increased [Ca(2+)](i) and robust proliferation with partial loss of regulatory functions. FOXP3 protein levels in Tet-On(®) clones were high after both 2- and 5-day Dox treatment; however, 5-day cells were comparable with T(regs) from patients with asthma, whereas 2-day cells were similar to T(regs) from participants without asthma. Increasing [Ca(2+)](i) induced a high level of receptor for activated C kinase 1 (RACK1) expression in 5-day cells. CONCLUSIONS AND CLINICAL RELEVANCE: We confirmed that T(regs) in patients with asthma are functionally impaired and that the abnormal regulatory functions of these cells can be analysed by [Ca(2+)](i) following TCR engagement. Furthermore, the impaired functioning of T(regs) evident in patients with asthma may be due to a high level of RACK1.

PET in infancy predicts long-term outcome during adolescence in cryptogenic West syndrome.

BACKGROUND AND PURPOSE: Developmental and seizure outcomes in patients with cryptogenic West syndrome are variable. Our aim was to clarify the relationship between FDG-PET findings in infancy and long-term seizure and developmental outcome in cryptogenic West syndrome. MATERIALS AND METHODS: From 1991 to 1999, we prospectively performed FDG-PET from the onset of cryptogenic West syndrome in 27 patients. PET was performed at onset and at 10 months of age. In 2012, we evaluated the educational status, psychomotor development, and seizure outcome in 23 of the 27 patients (13-22 years of age). The correlation between PET findings and outcome was evaluated. RESULTS: At onset, PET showed hypometabolism in 13 patients (57%). The second PET after the initial treatment revealed cortical hypometabolism in 7 patients (30%). While hypometabolism at onset disappeared on the second PET in 9 patients, it was newly revealed in 3 patients on the second PET. In 2012, seven patients had persistent or recurrent seizures. Eight patients had intellectual impairment. The first PET did not correlate with seizure or developmental outcome. Five of 7 patients (71%) with hypometabolism seen on the second PET had persistent or recurrent seizures, while 14 of 16 (88%) patients with normal findings on the second PET were free of seizures. Five of 7 patients (71%) showing hypometabolism on the second PET had intellectual impairment. Thirteen of 16 (81%) patients with normal findings on the second PET showed normal intelligence. A significant correlation was found between the second PET and long-term seizure (P = .01) or developmental outcome (P = .03). CONCLUSIONS: Cortical hypometabolism is not permanent; it changes with clinical symptoms. Hypometabolism after initial treatment predicts long-term seizures and poor developmental outcome.

Congenital infiltrating lipomatosis of the face with ipsilateral hemimegalencephaly, band heterotopia, and hypertrophy of brainstem and cerebellum.

The simultaneous appearance of congenital infiltrating lipomatosis of the face that causes facial hemihypertrophy and ipsilateral hemimegalencephaly is extremely rare. We report a 4-year-old boy with congenital facial asymmetry and infantile-onset epilepsy. Magnetic resonance imaging (MRI) results led to the diagnosis of infiltrating lipomatosis of the face; the diagnosis was confirmed on the basis of the results of pathological examinations. Additionally, brain MRI revealed ipsilateral hemimegalencephaly, associated with band heterotopia and the hemihypertrophy of the ipsilateral brainstem and cerebellum. He had no nevi or other skin abnormalities suggesting neurocutaneous syndrome. His seizures were so intractable that they necessitated functional hemispherectomy. The lipomatous lesion was successfully resected without relapse. Psychomotor delay and left hemiplegia were observed at the last follow-up.

The clinical characterizations of benign partial epilepsy in infancy.

The aim of this study is to clarify the detailed clinical features of benign partial epilepsy in infancy. The subject of the study was 33 patients with benign partial epilepsy in infancy confirmed by a long-term follow-up beyond 8 years of age. The data were obtained from medical records of the patients in combination with the data obtained from telephone interview. The median age at the first and last seizure was 5 and 8 months, respectively. In 26 patients, seizures disappeared within 3 months after the onset. Family history of benign partial epilepsy in infancy was seen in 17 patients. The median number of seizures was 7. A cluster of seizures was observed in 26 patients. The type of seizures was complex partial seizures alone in 6 patients, secondarily generalized seizures alone in 9, and both types in 18. Decreased responsiveness, lateral eye deviation, and cyanosis were commonly observed. Initial interictal electroencephalograms were normal in all patients. However, paroxysmal discharges were recognized in 2 patients in the second EEG during the first year of life. The main features of benign partial epilepsy in infancy were a high incidence of a cluster of seizures, short persistence of seizures, and normal initial interictal EEGs.

Japanese collaborative study for fibrinogen assay: variability of the fibrinogen assay between different laboratories does not improve when a common calibrator is used.

Several national and local external quality assurance schemes have been developed to improve the plasma fibrinogen assay in Japan over the past 30 years. Now most commercial calibrant plasma may be calibrated against an International Standard preparation, in order to achieve agreement of results obtained by different laboratories. However, we have never achieved satisfactory results, according to an external quality control survey regarding the fibrinogen assay. Therefore, we distributed two kinds of fibrinogen standards to be used as common calibrators, along with three plasma samples, among 183 general laboratories in Japan. The results of this collaborative study showed that the assigned value for the commercially available calibrators remained problematic. Furthermore, it was concluded that the between-laboratory variability could not be improved beyond a certain degree of standardization, even if a common calibrator was used for the Clauss-derived assay carried out by an automatic coagulometer.

Guillain-Barré syndrome associated with central nervous system lesions.

We report the clinical course, and neurophysiological and neuroimaging findings of a patient with Guillain-Barré syndrome associated with central nervous system lesions. During a course of intravenous immunoglobulin therapy, she had headache with meningism. Cerebral magnetic resonance imaging showed lesions in both frontal and right occipital lobes. Cerebrospinal fluid showed a raised protein concentration accompanied by mild pleocytosis. Her symptoms resolved within two months. Subsequent magnetic resonance imaging revealed cavity formation in the deep white matter and atrophic changes in the right occipital lobes.

Symptomatology of infantile spasms.

Epileptic spasms in West syndrome consist of a brief phasic contraction followed by a gradually relaxing tonic component, associated with typical ictal electroencephalographic (EEG) patterns. Three different EEG patterns are associated with a clinical spasm: fast wave bursts, high voltage slow waves (HVS), and desynchronization, occurring in this order. HVS are consistently seen and correspond to a clinical spasm, but usually preceded by fast wave bursts, which may be associated with an inhibition of muscle activity. Epileptic spasms can be classified into: symmetric spasms, asymmetric/asynchronous spasms, focal spasms, spasms with partial seizures, subtle spasms, spasms preceded by brief atonia, or subclinical spasms. Although clinical spasms are usually symmetric, ictal fast waves are always localized, and the following slow waves are not bilaterally synchronous and generalized, suggesting a focal cortical origin of spasms.

A pilot study on benign partial epilepsy in children with complex partial seizures.

In a review of 145 children with partial onset epilepsy, the authors were able to determine a focus of children whose complex partial seizures (CPS) ran a benign course, who had no identifiable lesion on scanning and whose EEG focus was not fixed, but tended to shift. The authors suggest that a benign form of CPS in children can be recognised.

Induction of CD4+ regulatory T cells by 12-O-tetradecanoylphorbol 13-acetate in mice. Part 1: The strain difference in this induction.

12-O-Tetradecanoylphorbol 13-acetate (TPA), an activator of signal transduction, induced antigen-nonspecific regulatory T (Tr) cells for delayed-type hypersensitivity (DTH) in the spleen. A marked strain difference in the induction of Tr cells was observed when the study was performed by using the several strains of mice at 6-8 weeks old. TPA painting induced CD4+Tr cells in C3H/He (H-2k), C3H/HeN (H-2k), DBA/2 (H-2d) and AKR/N (H-2k) mice, but not in C57BL/6 (H-2b), C57BL/10 (H-2b), BALB/c (H-2d) and A/J (H-2a). Regulatory cells were also induced by incubating spleen cells from unprimed mice with TPA in vitro and were seemed to act by the production of soluble factor(s). A downregulatory activity of the soluble factor(s) was abrogated by SXC-1 (anti-IL-10 monoclonal antibody), but not by SXC-2 (anti-IL-10 monoclonal antibody) and anti-IL-4. For purification of the factor(s), we established the T cell hybridoma 4C5-1 by the fusion of spleen cells from TPA-treated C3H/He mice with AKR thymoma Bw5147 cells. The 4C5-1 cells secrete the factor(s) which can inhibit DTH response. The inhibitory activity of the factor(s) could be neutralized by SXC-1, but not by SXC-2, anti-IL-4, anti-IL-6 and anti-TGF-beta antibodies. The factor(s) could not affect the proliferation and IFN-gamma production of alpha s1-casein-specific 3D20 Th1 cells. The factor(s) termed DIF (DTH Inhibitory Factor) may be a novel cytokine, since they have reduced the footpad swelling response by local injection, and have no immune crossreactivity with the DTH regulatory cytokines and no inhibitory activity for in vitro Th1 response.

Inflammatory pathological changes in a 2-year-old boy with Charcot-Marie-Tooth disease.

We report histopathological findings in a 2-year-old boy with Charcot-Marie-Tooth (CMT) 1A, which had some similarities to those of chronic inflammatory demyelinating polyneuropathy. These findings are unusual in adult CMT patients but are reported in some patients with corticosteroid-responsive hereditary motor and sensory neuropathy (HMSN) that are characterized by rapid worsening of symptoms. We administered betamethasone based on the inflammatory pathological features but no improvement was seen. Active demyelination is also reported as an early morphological feature in HMSN. It is probable that edema, active demyelination and a few onion bulb formations, which were recognized in this patient, are characteristic early histological changes of HMSN rather than those of corticosteroid-responsive HMSN.

Five-year follow-up of patients with partial epilepsies in infancy.

The aim of this study is to clarify the long-term outcome of patients with partial epilepsies that begin in the first 2 years of age. Thirty-nine infants who experienced partial epilepsies with onset by 2 years of age were followed until they were at least 5 years of age. Seizure and developmental outcome were investigated in relation to the following items: delayed psychomotor development before onset of seizures; interictal electroencephalogram (EEG) abnormalities; abnormal neuroimaging; family history of epilepsy; and history of neonatal seizures. Thirty-three infants achieved freedom from seizures and 27 achieved normal development. Delayed development before the onset and abnormal interictal EEG correlated with both poor seizure and developmental outcome. Abnormal neuroimaging findings correlated with a poor seizure outcome. A history of neonatal seizures and lack of a family history of epilepsy correlated with poor developmental outcome. The combination of the first four factors predicted a normal outcome with a sensitivity of 0.79 and a specificity of 0.87. The seizure and developmental outcomes were better in this study than those in previous studies. The combination of the four factors will be useful for predicting the outcomes in patients with partial epilepsies in infancy.

Synergistic cytotoxic action of vitamin C and vitamin K3.

We investigated the combination effect of sodium ascorbate (vitamin C) and menadione (vitamin K3) on the viability of various cultured cells. Human oral squamous cell carcinoma (HSC-2, HSC-3) and human promyelocytic leukemia (HL-60) cells were more sensitive to these vitamins as compared to normal cells (human gingival fibroblast HGF, human periodontal ligament fibroblast HPLF, human pulp cell HPC). The combination of vitamin C and vitamin K3 produced synergistic cytotoxicity against all these 6 cell lines. Treatment with vitamin C or vitamin K3, or their combination, induced internucleosomal DNA fragmentation only in HL-60 cells, but not in the oral tumor cell lines (HSC-2, HSC-3, HSG). ESR spectroscopy showed that vitamins C and K3 produce radicals under alkaline conditions and that the combination of these two vitamins synergistically enhanced their respective radical intensities.

[Psoas compartment block for surgery of the femoral neck (trochanteric) fracture in a patient with severe heart failure due to rheumatoid myocarditis].

A 72-year-old female with severe heart failure due to rheumatoid myocarditis underwent open reduction of the left femoral neck (trochanteric) fracture. We performed psoas compartment block (PCB) at L3/4 level in the lateral position with the fractured side up, using a 22 G Tuohy needle to inject 10 ml of normal saline and 20 ml of 2% mepivacaine. Anesthesia was maintained with propofol (1-2 mg.kg-1.hr-1) under spontaneous breathing with oxygen (2 l.min-1) through mask. The patient did favorably during and after the operation. We conclude that PCB is useful for surgery of the lower extremity in patients with heart failure.

Transient seizure remission in intractable localization-related epilepsy.

We sought to elucidate the clinical features of transient seizure remission in intractable cryptogenic or symptomatic localization-related epilepsy of childhood onset. Transient seizure remission has been reported to occur in mesial temporal sclerosis or focal cortical dysplasia, but few reports have focused on this phenomenon. We retrospectively scrutinized the temporal profiles of seizure frequency of 99 patients with intractable localization-related epilepsy by reviewing their medical charts. Ten patients (10%) had transient seizure remissions that lasted for 2 years or longer. When an appropriate antiepileptic agent was administered, seizure remission occurred within 1-18 months. Without any triggering factors, the seizures recurred abruptly in seven patients and gradually in three. Epileptiform discharges on electroencephalography disappeared during the transient remission in seven patients and reappeared in five of them after recurrence. After recurrence, no antiepileptic agent was able to control the seizures. In comparison with those without transient seizure remission, these 10 patients tended to have normal intelligence and a positive family history for epilepsy. Transient seizure remission occurs in a variety of pathologic changes and may be a result of an interaction between the progressive nature of some types of epileptogenic foci and an effect of the antiepileptic drugs.

Increase in participation of vasoactive intestinal peptide in relaxation of the distal colon of Wistar rats with age.

Changes in participation of vasoactive intestinal peptide (VIP) in nonadrenergic noncholinergic (NANC) relaxation of longitudinal muscle of the distal colon with age were studied in 2- to 50-week-old Wistar rats in vitro. The extent of the VIP-mediated component of the relaxation induced by electrical field stimulation (EFS) was determined by the effect of VIP(10 - 28), a VIP receptor antagonist. In 2-week-old rats, the extent of the VIP-mediated component of the relaxation was scarce, about 10%, whereas the component gradually increase with age and reached the maximum extent 66% at 50-week-old. Since our previous results suggest that VIP induces NANC relaxation via activation of charybdotoxin (ChTx, a blocker of large conductance Ca(2+)-activated K(+) channel)-sensitive K(+) channels with concomitant slow hyperpolarization in the muscle cells, we next studied whether ChTx-sensitive component and slow hyperpolarization changes with age. Extent of ChTx-sensitive component of the relaxation increased with age, showing a very similar pattern to VIP-mediated one. EFS induced monophasic inhibitory junction potentials (i.j.ps) in longitudinal muscle cells of the distal colon of 2- and 4-week-old. EFS also induced biphasic i.j.ps in many longitudinal muscle cells of 8- and 50-week-old: rapid and subsequent slow hyperpolarization. A VIP receptor antagonist selectively inhibited the slow hyperpolarization. Exogenously added VIP induced no appreciable change in the membrane potential of longitudinal muscle cells of 2-week-old, whereas it induced slight slow hyperpolarization of the cell membrane in 4-week-old and magnitude of the hyperpolarization increased with age. On the other hand, relaxant response of the longitudinal muscle to exogenously added VIP was high in younger rats. The present results suggest that the role of VIP in mediating NANC relaxation of longitudinal muscle of the Wistar rat distal colon is very little at neonatal stage, but it increases with age.

Cerebral oxygenation state in childhood moyamoya disease: a near-infrared spectroscopy study.

Near-infrared spectroscopy was used to measure the relative concentration changes of oxygenated hemoglobin (HbO(2)), deoxygenated hemoglobin (HbR), and total hemoglobin (t-Hb) before, during, and after hyperventilation in eight patients with childhood moyamoya disease who underwent surgery. The patients were divided into the following two groups: those with and those without re-build-up phenomenon on electroencephalography. All patients except one exhibited decreased concentrations of HbO(2) and t-Hb during hyperventilation and decreased concentrations of HbO(2) and increased concentrations of HbR after hyperventilation. The difference between the hemoglobin concentration during and after hyperventilation was significantly greater in the group with the re-build-up phenomenon than the group without it (P <0.03, Mann-Whitney U test). The patients with the re-build-up phenomenon had lower HbO(2) and higher HbR concentrations after hyperventilation. The concentrations of HbO(2) and HbR reflect an alteration in the oxygenated blood supply and/or oxygen use. Thus, it is strongly suggested that regional cerebral hypoxia and metabolic oxygen disturbances play an important role in the occurrence of the re-build-up phenomenon. Near-infrared spectroscopy is a useful noninvasive method to evaluate the efficacy of surgical treatment in childhood moyamoya disease.

Early recognition of benign partial epilepsy in infancy.

PURPOSE: The aim of this study is to determine how precisely we can recognize the outcome in infants with epilepsy beginning in the first year of life. METHODS: We performed a prospective 5-year follow-up study on 63 patients who developed epilepsy in the first year of life. We first judged that patients met the criteria of "possible benign partial epilepsy in infancy (BPEI)" on enrollment in this study. At 2 years of age, we reevaluated the seizure and developmental outcome in the patients who were diagnosed as having "possible BPEI." We finally judged that patients met the criteria of "definite BPEI" at age 5 years. "Possible BPEI" was defined as epilepsy meeting all the following conditions: (a) complex partial seizures and/or secondarily generalized seizures; (b) normal psychomotor development and neurologic findings before onset; (c) normal interictal electroencephalograms; (d) normal cranial computed tomography (CT) and magnetic resonance imaging (MRI) findings; and (e) no seizures during the first 4 weeks of life. "Definite BPEI" was defined as epilepsy meeting all the following criteria in addition to those of "possible BPEI": (a) normal psychomotor development beyond age 5 years, and (b) no seizures beyond age 2 years. RESULTS: Thirty-two of the 63 patients met the inclusion criteria completely and were included in the "possible BPEI" group. Twenty-five of the 32 patients completed the 5-year follow-up. At age 2 years, four patients were excluded from the "possible BPEI" group because of seizure recurrence and/or delayed development. By age 5 years, one had a recurrence of seizures, and another exhibited mildly delayed psychomotor development. We finally diagnosed 19 patients as having "definite BPEI." "Definite BPEI" accounted for 76% of the patients diagnosed as having "possible BPEI" at the first presentation and 90% of those who met the conditions on reevaluation at age 2 years. CONCLUSIONS: Recognition of BPEI is possible, to some extent, at the first presentation, and reevaluation at age 2 years is useful for a more precise diagnosis.

EMG activities of two heads of the human lateral pterygoid muscle in relation to mandibular condyle movement and biting force.

Electromyographic (EMG) activities of the superior (SUP) and inferior heads (INF) of the lateral pterygoid muscle (LPT) were recorded in humans during voluntary stepwise changes in biting force and jaw position that were adopted to exclude the effects of acceleration and velocity of jaw movements on the muscle activity. The SUP behaved like a jaw-closing muscle and showed characteristic activity in relation to the biting force. It showed a considerable amount of background activity (5-32% of the maximum) even in the intercuspal position without teeth clenching and reached a nearly maximum activity at relatively lower biting-force levels than the jaw-closing muscles during increment of the biting force. Stretch reflexes were found in the SUP, the function of which could be to stabilize the condyle against the biting force that pulls the condyle posteriorly. This notion was verified by examining the biomechanics on the temporomandibular joint. The complex movements of the mandibular condyle in a sagittal plane were decomposed into displacement in the anteroposterior direction (Ac) and angle of rotation (RAc) around a kinesiological specific point on the condyle. In relation to Ac, each head of the LPT showed quite a similar behavior to each other in all types of jaw movements across all subjects. Working ranges of the muscle activities were almost constant (Ac <3 mm for the SUP and Ac >3 mm for the INF). The amount of EMG activity of the SUP changed in inverse proportion to Ac showing a hyperbola-like relation, whereas that of the INF changed rather linearly. The EMG amplitude of the SUP showed a quasilinear inverse relation with RAc in the hinge movement during which the condyle rotated with no movement in the anteroposterior direction. This finding suggests that the SUP controls the angular relationship between the articular disk and the condyle. On the other hand, the position of the disk in relation to the maxilla, not to the condyle, is controlled indirectly by the INF because the disk is attached to the condyle by tendinous ligaments.

MRI findings in patients with symptomatic localization-related epilepsies beginning in infancy and early childhood.

We studied MRI findings in patients with symptomatic localization-related epilepsy (S-LRE) beginning in infancy and early childhood and their relation to some clinical features. MRI findings were investigated in 183 patients with S-LRE beginning before 6 years of age. S-LRE was defined as an epileptic syndrome manifesting with only partial seizures at least for a certain period during the clinical course, having specific neuroimaging abnormalities considered to be related to epileptic seizures, moderate or severe mental retardation, or cerebral palsy. The timing of injury was divided into the following four groups; prenatal, perinatal, postnatal and unknown. It was presumed prenatal in 56 patients (31%), perinatal in 25 (14%), postnatal in 32 (18%) and unknown in 70 (38%). The median age at the onset of partial seizures was 24 months in the congenital (prenatal and unknown) group, 39 months in the perinatal group and 25 months in the postnatal group. The onset of partial seizures was later in the perinatal group than in the congenital group. There were no significant differences in the other clinical characteristics among groups except for more frequent association of cerebral palsy in the perinatal group than in the congenital group. Our study suggests that congenital (prenatal and unknown group) disorders may be most common in patients with S-LRE beginning in infancy and early childhood. The onset of partial seizures occurred later in the perinatal group.

Epileptic spasms preceded by partial seizures with a close temporal association.

PURPOSE: To investigate the distinctive features of patients with West syndrome who had partial seizures followed by epileptic spasms (PS-ES). METHODS: We examined 45 patients with West syndrome whose epileptic spasms were recorded with simultaneous video-electroencephalography (EEG) monitoring between 1982 and 1996. We investigated the patients who had PS-ES and compared the PS-ES patients with the 37 patients without PS-ES. RESULTS: Of the 45 patients who had epileptic spasms in clusters (ES) and hypsarrhythmia on the interictal EEG, eight (17%) had ES preceded by partial seizures (PS) with a close temporal association. Seven of these eight were female patients. The underlying disorders were tuberous sclerosis (one patient), Aicardi syndrome (one), nonketotic hyperglycinemia (one), and focal cortical dysplasia (one). The etiology was unknown in the remaining four patients, but was suspected to be of prenatal origin in three. Three types of seizure sequence were identified: PS followed several seconds later by ES (two patients), alternating PS and ES starting with PS (three), and PS gradually replaced by ES with overlapping of the two (three). PS-ES disappeared or was replaced by other types of seizures in 1-34 months. Six patients could not walk, and all patients could not speak any sentences at age 3 years. CONCLUSIONS: Compared with patients without PS-ES, those with PS-ES more often had organic brain lesions of prenatal origin, other types of seizures before the onset of ES, asymmetric hypsarrhythmia on the EEG, and poor psychomotor outcome.