Benefits of a Wearable Cyborg HAL (Hybrid Assistive Limb) in Patients with Childhood-Onset Motor Disabilities: A 1-Year Follow-Up Study.

Rehabilitation robots have shown promise in improving the gait of children with childhood-onset motor disabilities. This study aimed to investigate the long-term benefits of training using a wearable Hybrid Assistive Limb (HAL) in these patients. Training using a HAL was performed for 20 min a day, two to four times a week, over four weeks (12 sessions in total). The Gross Motor Function Measure (GMFM) was the primary outcome measure, and the secondary outcome measures were gait speed, step length, cadence, 6-min walking distance (6MD), Pediatric Evaluation of Disability Inventory, and Canadian Occupational Performance Measure (COPM). Patients underwent assessments before the intervention, immediately after the intervention, and at 1-, 2-, 3-month and 1-year follow-ups. Nine participants (five males, four females; mean age: 18.9 years) with cerebral palsy (n = 7), critical illness polyneuropathy (n = 1), and encephalitis (n = 1) were enrolled. After training using HAL, GMFM, gait speed, cadence, 6MD, and COPM significantly improved (all p < 0.05). Improvements in GMFM were maintained one year after the intervention (p < 0.001) and in self-selected gait speed and 6MD three months after the intervention (p < 0.05). Training using HAL may be safe and feasible for childhood-onset motor disabilities and may maintain long-term improvements in motor function and walking ability.

Longitudinal, prospective study of head impacts in male high school football players.

INTRODUCTION: Repetitive, subconcussive events may adversely affect the brain and cognition during sensitive periods of development. Prevention of neurocognitive consequences of concussion in high school football is therefore an important public health priority. We aimed to identify the player positions and demographic, behavioral, cognitive, and impact characteristics that predict the frequency and acceleration of head impacts in high school football players. METHODS: In this prospective study, three cohorts of adolescent male athletes (N = 53, 28.3% Hispanic) were recruited over three successive seasons in a high school American football program. Demographic and cognitive functioning were assessed at baseline prior to participating in football. Helmet sensors recorded impact frequency and acceleration. Each head impact was captured on film from five different angles. Research staff verified and characterized on-field impacts. Player-level Poisson regressions and year-level and impact-level linear mixed-effect models were used to determine demographic, behavioral, cognitive, and impact characteristics as predictors of impact frequency and acceleration. RESULTS: 4,678 valid impacts were recorded. Impact frequency positively associated with baseline symptoms of hyperactivity-impulsivity [ß(SE) = 1.05 impacts per year per unit of symptom severity (1.00), p = 0.01] and inattentiveness [ß(SE) = 1.003 impacts per year per T-score unit (1.001), p = 0.01]. Compared to quarterbacks, the highest acceleration impacts were sustained by kickers/punters [ß(SE) = 21.5 g's higher (7.1), p = 0.002], kick/punt returners [ß(SE) = 9.3 g's higher (4.4), p = 0.03], and defensive backs [ß(SE) = 4.9 g's higher (2.5), p = 0.05]. Impacts were more frequent in the second [ß(SE) = 33.4 impacts (14.2), p = 0.02)] and third [ß(SE) = 50.9 impacts (20.1), p = 0.01] year of play. Acceleration was highest in top-of-the-head impacts [ß(SE) = 4.4 g's higher (0.8), p<0.001]. CONCLUSION: Including screening questions for Attention-Deficit/Hyperactivity Disorder in pre-participation evaluations can help identify a subset of prospective football players who may be at risk for increased head impacts. Position-specific strategies to modify kickoffs and correct tackling and blocking may also reduce impact burden.

Voluntary-assisted Upper Limb Training for Severe Cerebral Palsy Using Robotics Devices and Neuromuscular Electrical Stimulation: Three Case Reports.

Background: Constraint-induced movement therapy (CIMT) improves the motor function of paralyzed upper limbs of adults after stroke. However, in patients with severe spastic cerebral palsy (CP), the use of CIMT is not warranted. Our aim was to investigate the feasibility and effectiveness of repetitive voluntary-assisted upper limb training (VAUT) for three patients with severe CP using a combination of robotics [Hybrid Assistive Limb (HAL)] and functional electrical stimulation [Integrated Volitional Control Electrical Stimulation (IVES)]. Case: Three patients with CP were enrolled. Patients 1, 2, and 3 were 8-, 19-, and 18-year-old males, respectively. Patient 1 had spastic hemiplegia, while patients 2 and 3 had spastic quadriplegia. VAUT using single-joint HAL was performed for 1 or 2 sessions/month for 50 min/session over an 8-month period for 9-13 sessions in total. One patient's voluntary hand movement was insufficient, affecting his upper limb exercise performance; therefore, IVES was required in addition to HAL. Outcome measures included motor function of the upper limbs and use of paralyzed hands, which were measured before and after intervention. No adverse events were observed during VAUT. After intervention, the Action Research Arm Test scores showed improvements in all three patients. The Children's Hand-use Experience Questionnaire showed improvements in two patients. Discussion: The use of VAUT, together with new systems such as HAL and IVES, for severe CP is safe and may be effective. Our study suggested that upper limb function can be improved for patients with severe CP.

A Japanese case of ichthyosis follicularis with atrichia and photophobia syndrome with an MBTPS2 mutation.

Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome is a rare genetic disorder characterized by the triad of ichthyosis follicularis, alopecia and photophobia. Previous studies have identified five missense mutations in the membrane-bound transcription factor protease, site 2 (MBTPS2) gene in European patients with this syndrome. In this study, we detected the 1286G > A (Arg429His) mutation in MBTPS2 in a Japanese patient with IFAP syndrome. This mutation has previously been detected in a German family with this syndrome. Functional analysis revealed that this mutation was the most severe mutation identified to date for this syndrome. None of the male German patients had been tested for the mutation because they had several visceral and bone anomalies, and had died as neonates or infants. The clinical features of our 5-year-old patient are less severe than those of the German patients. Although he has neurological abnormalities, such as retarded psychomotor development and seizures, he does not have bone or visceral anomalies, except cryptorchidism. This case indicates the existence of other factor(s) that influence the clinical features of this syndrome. Further clinical and genetic studies are required to clarify the relationship between phenotypes and genotypes and to identify such modifying factors.

Ichthyosis follicularis, alopecia, and photophobia syndrome: a case report and a pathological insight into pilosebaceous anomaly.

Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome (OMIM 308205) is an extremely rare X-linked oculocutaneous genetic disorder characterized by follicular keratotic papules, total to subtotal alopecia, and photophobia. Previous reports depicted the histopathological features of affected skin lesions, represented by marked follicular plugging and hypoplastic pilosebaceous structures. However, past studies provided limited pathological information of pilosebaceous unit anomaly. Here, we report a 3-year-old boy's case with this uncommon condition. In this case, scalp biopsy samples were processed by both vertical and transverse sectioning techniques, which enabled a more detailed and quantitative pathological analysis of pilosebaceous structures. In vertical slices, miniaturized anagen hair follicles with characteristic follicular plugs were observed. A transverse section identified abortive sebaceous glands in hair follicles, a finding rarely observed in vertical sections. In addition, a transverse slice demonstrated that the number of total hair follicles was not significantly decreased compared with the average hair follicle density in Asians, suggesting that the pilosebaceous hypoplasia might arise from impaired maturation, not from initiation defect, during hair follicle morphogenesis. This study provides a more comprehensive pathological insight into pilosebaceous anomaly in IFAP syndrome and substantiats the usefulness of the combination of vertical and transverse sectioning approaches in the pathological examination of congenital hypotrichosis, including IFAP syndrome.

Anesthetic management of super-elderly patients with remimazolam: a report of two cases.

BACKGROUND: Remimazolam is a newly developed benzodiazepine with more rapid onset and offset of sedation effects than midazolam. We report elderly patients in whom a small dose of remimazolam was successfully used for general anesthesia. CASE PRESENTATION: Two elderly women (patients 1 and 2, aged 95 and 103 years, respectively) underwent hip fracture surgery under general anesthesia guided by bispectral index (BIS). Anesthesia was induced with 1.2 and 1.0 mg/kg/h and maintained with 0.2 and 0.1 mg/kg/h remimazolam, combined with fentanyl and remifentanil in patients 1 and 2, respectively. Their hemodynamics were stable with a small dose of vasopressor, and they awoke soon after the discontinuation of remimazolam without flumazenil reversal. Their postoperative courses were uneventful without any complications. Conversely, the remimazolam dose required to achieve adequate sedation were much lower than expected. CONCLUSION: Remimazolam could be useful in general anesthesia, particularly for super-elderly patients. However, the appropriate dose for induction and maintenance of anesthesia should be carefully considered based on BIS or vital signs.

A Patient with Rett Syndrome Maintained Motor Function by Periodic Rehabilitation Therapy and Proactive Daily Activities.

BACKGROUND: The motor functions of Rett syndrome patients degrade during the course of the disease. Some patients, however, are able to maintain their motor functions by undertaking exercise programs. CASE: A 2-year-old girl was diagnosed with Rett syndrome after the identification of a mutation in the gene encoding the methyl-CpG-binding protein. The patient started weekly rehabilitation therapy; however, over time, this reduced to monthly sessions, and subsequently, because of worsening epileptic seizures, even fewer sessions were possible. When the patient was 12 years old, intensive rehabilitation therapy was undertaken for 1 month; therapy involved 80 min of in-hospital therapy on weekdays and walking exercises at home at the weekend. An accelerometer (Actiwatch 2, standard type, Philips Respironics) indicated that more than 60 min of daily training at an intensity of 3 metabolic equivalents (METs) or more was achieved at weekends. The patient took the 10-m walk test, and the average time reduced from 18.6 to 13.5 s and the number of steps reduced from 32 to 23 between the start and finish of the first 1-month intensive training regime. After being discharged from the hospital, the patient maintained walking exercises at school during weekdays and performed more than 50 min/day of activity at at least 3 METs at home on weekends, in addition to a weekly home-visit rehabilitation therapy and the annual in-hospital 1-month rehabilitation therapy. Four years later, the patent's average time and number of steps required to walk 10 m remained lower (12.7 s, 24 steps) than those recorded at the first evaluation. DISCUSSION: Periodic rehabilitation therapy and proactive walking exercises at more than 3 METs for a duration of up to 50 min/day were instrumental in maintaining the motor functions of a Rett syndrome patient.

Intraoperative Coronary Artery Spasm Likely Triggered by Surgical Gallbladder Manipulation: A Case Report.

Although the association between cholecystitis and acute coronary syndrome-like symptoms, including chest pain with electrocardiogram (ECG) changes, has been reported previously, it is unclear whether these symptoms can be provoked by direct stimulation to the gallbladder. We present the case of a 44-year-old man who developed coronary artery spasm (CAS) with ST-segment-elevation followed by nonsustained polymorphic ventricular tachycardia during laparoscopic cholecystectomy. The change in ECG occurred only when the gallbladder was manipulated, suggesting that direct stimulation to the gallbladder can cause CAS. Clinicians should be aware that careful ECG monitoring is necessary, especially while the gallbladder is manipulated.

Robot-assisted training using Hybrid Assistive Limb® for cerebral palsy.

PURPOSE: The Hybrid Assistive Limb® (HAL®, CYBERDYNE) is a wearable robot that provides assistance to a patient while they are walking, standing, and performing leg movements based on the wearer's intended movement. The effect of robot-assisted training using HAL® for cerebral palsy (CP) is unknown. Therefore, we assessed the effect of robot-assisted training using HAL® on patients with CP, and compared walking and gross motor abilities between pre-intervention and post-intervention. METHODS: Six subjects with CP were included (mean age: 16.8 years; range: 13-24 years; Gross Motor Function Classification System levels II-IV: n = 1, 4, 1). Robot-assisted training using HAL® were performed 2-4 sessions per week, 20 min per session, within a 4 weeks period, 12 times in total. Outcome measures included gait speed, step length, cadence, single-leg support per gait cycle, hip and knee joint angle in stance, and swing phase per gait cycle, 6-minute walking distance (6 MD), physiological cost index (PCI), knee-extension strength, and Gross Motor Function Measure (GMFM). RESULTS: There were significant increases in self-selected walking speed (SWS), cadence during SWS and maximum walking speed (MWS), single-leg support per gait cycle, hip joint angle in the swing phase, 6 MD, and GMFM. In contrast, gait speed during MWS, step length during SWS and MWS, hip and knee joint angle in the stance phase, knee joint angle in the swing phase, PCI, and knee-extension strength generally improved, but not significantly. CONCLUSION: Robot-assisted training using HAL® may improve walking and gross motor abilities of patients with CP.

Interstitial 1q43-q43 deletion with left ventricular noncompaction myocardium.

We describe a newborn infant with del(1)(q) syndrome, presenting with rare congenital cardiomyopathy and left ventricular noncompaction myocardium (LVNC), as well as typical clinical features such as facial dysmorphism and psychomotor retardation. Although conventional chromosome banding at 850 bands per haploid set indicated a karyotype of 46,XX,add(1)(q42.3), FISH analysis confirmed that the deleted portion was limited to within q43, and q44 was preserved. Therefore, the chromosome constitution is 46,XX,del(1)(q43q43), which has not previously been reported in the literature. Screening for the mutations in the candidate genes for LVNC, i.e. G4.5, CSX, Dystrobrevin, FKBP12, and Desmin, produced negative results. Interestingly, the deleted portion includes the locus for the cardiac ryanodine receptor type 2 gene (RyR2), that selectively binds to the FKBP12 homolog, FKBP12.6. The relationship between this rare myocardial abnormality and deletion of q43 is currently unknown and awaits further accumulation of cases with the same chromosomal aberration.

Molecular genetics of febrile seizures.

Febrile seizures (FSs) represent the most common form of childhood seizures, occurring in 2-5% of infants in Europe and North America and in 6-9% in Japan. It has been recognized that there is a significant genetic component for susceptibility to this type of seizure. Six susceptibility FS loci have been identified on chromosomes 8q13-q21 (FEB1), 19p (FEB2), 2q23-q24 (FEB3), 5q14-q15 (FEB4), 6q22-q24 (FEB5), and 18p11 (FEB6). Furthermore, mutations in the voltage-gated sodium channel alpha-1, alpha-2 and beta-1 subunit genes (SCN1A, SCN2A and SCN1B) and the GABA(A) receptor gamma-2 subunit gene (GABRG2) have been identified in families with a clinical subset of seizures termed "generalized epilepsy with febrile seizure plus (GEFS+)". However, the causative genes have not been identified in most patients with FSs or GEFS+. Common forms of FSs are genetically complex disorders believed to be influenced by variations in several susceptibility genes. Recently, several association studies in FSs have been reported, but the results vary among different groups and no consistent or convincing FS susceptibility genes have emerged. To find a true association, larger sample size and newer methodologic refinements are recommended.

Task-specific enhancement of hippocampus-dependent learning in mice deficient in monoacylglycerol lipase, the major hydrolyzing enzyme of the endocannabinoid 2-arachidonoylglycerol.

Growing evidence indicates that the endocannabinoid system is important for the acquisition and/or extinction of learning and memory. However, it is unclear which endocannabinoid(s) play(s) a crucial role in these cognitive functions, especially memory extinction. To elucidate the physiological role of 2-arachidonoylglycerol (2-AG), a major endocannabinoid, in behavioral and cognitive functions, we conducted a comprehensive behavioral test battery in knockout (KO) mice deficient in monoacylglycerol lipase (MGL), the major hydrolyzing enzyme of 2-AG. We found age-dependent increases in spontaneous physical activity (SPA) in MGL KO mice. Next, we tested the MGL KO mice using 5 hippocampus-dependent learning paradigms (i.e., Morris water maze (MWM), contextual fear conditioning, novel object recognition test, trace eyeblink conditioning, and water-finding test). In the MWM, MGL KO mice showed normal acquisition of reference memory, but exhibited significantly faster extinction of the learned behavior. Moreover, they showed faster memory acquisition on the reversal-learning task of the MWM. In contrast, in the contextual fear conditioning, MGL KO mice tended to show slower memory extinction. In the novel object recognition and water-finding tests, MGL KO mice exhibited enhanced memory acquisition. Trace eyeblink conditioning was not altered in MGL KO mice throughout the acquisition and extinction phases. These results indicate that 2-AG signaling is important for hippocampus-dependent learning and memory, but its contribution is highly task-dependent.

Identification of 33 polymorphisms in the adipocyte-derived leucine aminopeptidase (ALAP) gene and possible association with hypertension.

Adipocyte-derived leucine aminopeptidase (ALAP) inactivates angiotensin II and/or generates bradykinin in the kidney, suggesting a possible role for ALAP in the regulation of blood pressure. We considered the hypothesis that genomic variants of the ALAP gene are associated with hypertension or individual variations in blood pressure. We screened for mutations in the ALAP gene in 48 unrelated Japanese individuals and identified 33 polymorphisms including 15 novel polymorphisms. We then performed a two-stage analysis. In the first stage, the eight missense polymorphisms were evaluated for associations with blood pressure in 96 apparently healthy individuals. In the second stage, only the most promising polymorphisms were evaluated for association with essential hypertension in 143 hypertensive and 348 normotensive subjects. Among the eight missense polymorphisms, the Ile276Met and Lys528Arg polymorphisms showed significant association with blood pressure. Subsequent analysis confirmed association between the Lys528Arg polymorphism and essential hypertension. The estimated odds ratio for essential hypertension was 2.3 for presence of the Arg allele at codon 528, in comparison with presence of the Lys/Lys genotype (P = 0.004). These findings support involvement of ALAP in the regulation of blood pressure.

Possible association between a haplotype of the GABA-A receptor alpha 1 subunit gene (GABRA1) and mood disorders.

BACKGROUND: The gamma-aminobutyric acid (GABA) neurotransmitter system has been implicated in the pathogenesis of mood disorders. The GABRA1 gene encodes one of the subunits of GABA-A receptor and is located on human chromosome 5q34-q35, which is a region reportedly linked to mood disorders. We examined the GABRA1 gene as a candidate for mood disorders. METHODS: We performed mutation screening of GABRA1 in 24 Japanese bipolar patients and evaluated associations in Japanese case-control subjects consisting of 125 patients with bipolar disorder, 147 patients with depressive disorders, and 191 healthy control subjects. Associations were confirmed in the National Institute of Mental Health (NIMH) Initiative Bipolar Pedigrees, which consists of 88 multiplex pedigrees with 480 informative persons. RESULTS: We identified 13 polymorphisms in the GABRA1 gene. Nonsynonymous mutations were not found. Association of a specific haplotype with affective disorders was suggested in the Japanese case-control population (corrected p=.0008). This haplotype association was confirmed in the NIMH pedigrees (p=.007). CONCLUSIONS: These results indicate that the GABRA1 gene may play a role in the etiology of bipolar disorders.

Family-based association study of the NOTCH4 gene in schizophrenia using Japanese and Chinese samples.

BACKGROUND: A family based association study in a British sample found the NOTCH4 gene to be associated with schizophrenia; however, all six replication studies failed to confirm the finding. METHODS: We performed a family based association study of NOTCH4 and schizophrenia in 123 trios (16 Japanese and 107 Chinese). In addition to the original study's polymorphisms, we examined four new single nucleotide polymorphisms (SNPs)--SNPs_A, B, C and D--around SNP1 of the original study. We genotyped all samples for SNPs_A-D and for SNP1 and (CTG)n of the original study. RESULTS: We found no significant associations between NOTCH4 and schizophrenia or its subtypes for all polymorphisms, regardless of gender. The finding remained negative when the Chinese sample was analyzed separately. Exploratory analyses suggested that SNP_A may be associated with early-onset schizophrenia and that SNP1 may be associated with schizophrenia characterized by numerous negative symptoms. CONCLUSIONS: NOTCH4 is not a significant susceptibility gene for schizophrenia when clinical heterogeneity is ignored; however, NOTCH4 may be associated with early-onset schizophrenia or schizophrenia with many negative symptoms, but these findings should be interpreted cautiously.

Mutation analysis of the calpastatin gene (CAST) in patients with Alzheimer's disease.

The calpains, a family of calcium-dependent cysteine proteinases, and calpastatin, their endogenous inhibitor protein, are involved in the proteolysis of amyloid precursor protein, which is thought to be abnormal in patients with Alzheimer's disease (AD). Specific inhibitors of calpains attenuate amyloid beta peptide-induced neuronal death. We hypothesized that some AD patients have functionally deficient mutation(s) of the CAST gene encoding calpastatin, and we screened 40 Japanese patients with AD for mutations in the coding region of CAST. Nine polymorphisms, -82A/G, IVS7-96A/G, 669A/G, 1223C/G (Ser408Cys), IVS20-10C/T, IVS21-65G/A, IVS22+31T/C, IVS24+38Ins/DelA, and IVS25-32A/G, were identified. The 669A allele causes skipping of exon 11, leading to the loss of 13 residues. Comparisons between 101 patients and 90 controls revealed no significant association between CAST polymorphisms and risk for AD, indicating that genomic variations of CAST are not likely to be substantially involved in the etiology of AD.

Failure to find causal mutations in the GABA(A)-receptor gamma2 subunit (GABRG2) gene in Japanese febrile seizure patients.

Recently, mutations in the GABA(A)-receptor gamma2 subunit (GABRG2) gene were identified in two families with generalized epilepsy with febrile seizures plus (GEFS+) and two families with childhood absence epilepsy (CAE) and febrile seizures (FS). We tested the hypothesis that genetic variations in the GABRG2 gene confer susceptibility to FS in the Japanese population. We performed a systematic search for mutations in 94 unrelated Japanese patients with FS and detected six variants (-158C>T, 315C>T, 588T>C, IVS5-55C>T, IVS7+20G>A, and IVS7-141T>A). No non-synonymous mutation was detected. We genotyped three exonic polymorphisms and performed a case control study and a transmission disequilibrium test using 55 independent complete trios with FS and 106 control subjects. None of these polymorphic alleles were significantly associated with FS. Our results indicate that genomic variations of GABRG2 are not likely to be substantially involved in the etiology of FS in the Japanese population.

Failure to find evidence for association between voltage-gated sodium channel gene SCN2A variants and febrile seizures in humans.

The voltage-gated sodium channel type II alpha polypeptide gene (SCN2A) R188W mutation with channel dysfunction was recently identified in a patient with febrile and afebrile seizures. A possible association between SCN2A R19K polymorphism and febrile seizures (FS) associated with afebrile seizures including generalized epilepsy with febrile seizures plus (GEFS+) was also noted. We attempted to identify the R188W mutation and confirm association of the R19K polymorphism in 93 Japanese patients with FS, 35 Japanese patients with FS associated with afebrile seizures including GEFS+, and 100 control subjects. The R188W mutation was not found. There were no significant differences in genotype or allele frequencies of the R19K polymorphism between groups. Our study failed to provide evidence supporting a causal relation between the SCN2A mutation/polymorphism and FS or FS associated with afebrile seizures including GEFS+ in the Japanese population.