Tatsuhiko Yagihashi

Functional hemispheric specialization in processing phonemic and prosodic auditory changes in neonates

This study focuses on the early cerebral base of speech perception by examining functional lateralization in neonates for processing segmental and suprasegmental features of speech. For this purpose, auditory evoked responses of full-term neonates to phonemic and prosodic contrasts were measured in their temporal area and part of the frontal and parietal areas using near-infrared spectroscopy (NIRS). Stimuli used here were phonemic contrast /itta/ and /itte/ and prosodic contrast of declarative and interrogative forms /itta/ and /itta?/. The results showed clear hemodynamic responses to both phonemic and prosodic changes in the temporal areas and part of the parietal and frontal regions. In particular, significantly higher hemoglobin (Hb) changes were observed for the prosodic change in the right temporal area than for that in the left one, whereas Hb responses to the vowel change were similarly elicited in bilateral temporal areas. However, Hb responses to the vowel contrast were asymmetrical in the parietal area (around supra marginal gyrus), with stronger activation in the left. These results suggest a specialized function of the right hemisphere in prosody processing, which is already present in neonates. The parietal activities during phonemic processing were discussed in relation to verbal-auditory short-term memory. On the basis of this study and previous studies on older infants, the developmental process of functional lateralization from birth to 2 years of age for vowel and prosody was summarized.

Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation

Yanagimachi M, Naruto T, Tanoshima R, Kato H, Yokosuka T, Kajiwara R, Fujii H, Tanaka F, Goto H, Yagihashi T, Kosaki K, Yokota S. Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor‐related neurotoxicity after hematopoietic stem cell transplantation. 
Clin Transplant 2010: 24: 855–861.

Is switching antidepressants following early nonresponse more beneficial in acute-phase treatment of depression?: a randomized open-label trial.

RATIONALE Treatment guidelines for major depressive disorder (MDD) recommend a continuous use of antidepressants for several weeks, while recent meta-analyses indicate that antidepressant efficacy starts to appear within 2 weeks and early treatment nonresponse is a predictor of subsequent nonresponse. OBJECTIVES We prospectively compared 8-week outcomes between switching antidepressants and maintaining the same antidepressant in early nonresponders, to generate a hypothesis on possible benefits of early switching strategy. METHOD Patients with MDD without any treatment history for the current episode were included. When subjects failed to show an early response (i.e., ≥20% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS)) to the initial treatment with sertraline 50mg at week 2, they were randomly divided into two groups; in the Continuing group, sertraline was titrated at 50-100mg, whereas sertraline was switched to paroxetine 20-40 mg in the Switching group. A primary outcome measure was a response rate (i.e., ≥50% improvement in the MADRS) at week 8. RESULTS Among 132 subjects, 41 subjects showed early nonresponse. The Switching group (n=20) showed a higher rate of responders than the Continuing group (n=21) (75% vs. 19%: p=0.002). Further, the Switching group was also superior in the rate of remitters (total score of ≤10 in the MADRS) (60% vs. 14%: p=0.004) and continuous changes in the MADRS (19.0 vs. 7.5: p<0.001). CONCLUSIONS Our preliminary findings suggest that patients with MDD who fail to show early response to an initial antidepressant may derive benefits from the early switching antidepressants in the acute-phase treatment of depression.

Effects of the CYP2D6*10 alleles and co‐medication with CYP2D6‐dependent drugs on risperidone metabolism in patients with schizophrenia

Risperidone is converted to 9‐hydroxyrisperidone by CYP2D6. Two parameters were used to examine the influences of CYP2D6 polymorphism and of co‐medication on risperidone metabolism: the risperidone:9‐hydroxyrisperidone concentration ratio (R:9‐OHR ratio) and the sum of the risperidone and 9‐hydroxyrisperidone concentrations divided by the dose (C:D ratio). We evaluated the effect of the CYP2D6*10 allele, which is a prevalent mutant allele among East Asians.

Mechanisms underlying early development of pulmonary vascular obstructive disease in Down syndrome: An imbalance in biosynthesis of thromboxane A2 and prostacyclin.

Patients with Down syndrome (DS) and a left‐to‐right shunt often develop early severe pulmonary hypertension (PH) and pulmonary vascular obstructive disease (PVOD); the pathophysiological mechanisms underlying the development of these complications are yet to be determined. To investigate the mechanisms, we evaluated the biosynthesis of thromboxane (TX) A2 and prostacyclin (PGI2) in four groups of infants, cross‐classified as shown below, by measuring the urinary excretion levels of 11‐dehydro‐TXB2 and 2,3‐dinor‐6‐keto‐PGF1α: DS infants with a left‐to‐right shunt and PH (D‐PH, n = 18), DS infants without congenital heart defect (D‐C, n = 8), non‐DS infants with a left‐to‐right shunt and PH (ND‐PH, n = 12), and non‐DS infants without congenital heart defect (ND‐C, n = 22). The urinary excretion ratios of 11‐dehydro‐TXB2 to 2,3‐dinor‐6‐keto‐PGF1α in the D‐PH, D‐C, ND‐PH, and ND‐C groups were 7.69, 4.71, 2.10, and 2.27, respectively. The ratio of 11‐dehydro‐TXB2 to 2,3‐dinor‐6‐keto‐PGF1α was higher in the presence of DS (P < 0.001), independently of the presence of PH (P = 0.297). The predominant biosynthesis of TXA2 over PGI2, leading to vasoconstriction, was observed in DS infants, irrespective of the presence/absence of PH. This imbalance in the biosynthesis of vasoactive eicosanoids may account for the rapid progression of PVOD in DS infants with a left‐to‐right shunt.

Case report: Adult phenotype of Mulvihill–Smith syndrome†

Mulvihill–Smith syndrome (MSS) is characterized by premature aging, multiple pigmented nevi, decreased facial subcutaneous fat, microcephaly, short stature, mental retardation and recurrent infections, however the adult phenotype of MSS has yet to be delineated. We report a 28‐year‐old woman with Mulvihill–Smith syndrome, who had a solid pseudopapillary cystic tumor of her pancreas at age 17 years. Her distinctive sleep pattern includes severe insomnia with disappearance of sleep spindles and K‐complexes, persisting muscle tone, and loss of slow wave sleep. The clinical and neurophysiological studies are compatible with agrypnia excitata, a sleep disorder attributable to a dysfunction of the thalamo‐limbic system. Brain magnetic resonance imaging and single photon emission computed tomography revealed structural and functional deficits in the dorsomedial region of the thalamus and indicated that an alteration in the thalamo‐limbic system may underlie the sleep disturbances in MSS. Furthermore, the rapid and severe decline in acquired cognitive function showed the distinct cognitive impairments resembling dementia, including intellectual deficits, memory disorder and executive dysfunction. We posit that an early onset tumor, sleep disorder and cognitive decline are adult manifestations of Mulvihill–Smith syndrome. Am. J. Med. Genet.

Recent trends in pediatric bacterial meningitis in Japan – A country where Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines have just been introduced

To investigate the trends in incidence and the characteristics of bacterial meningitis in Japan where Haemophilus influenzae type b (Hib) vaccine and 7-valent pneumococcal conjugated vaccine (PCV7) were introduced in 2008 and 2010, respectively, which was 5-20 years after their introduction in western countries. The nationwide Japanese survey of pediatric and neonatal bacterial meningitis was performed in 2011 and 2012. We analyzed the epidemiological and clinical data, and compared the information obtained in the previous nationwide survey database. We also investigated the risk factors for disease outcome. In the 2011-2012 surveys, 357 patients were evaluated. H. influenzae, Streptococcus pneumoniae, Streptococcus agalactiae and Escherichia coli were the main organisms. The number of patients hospitalized with bacterial meningitis per 1000 admissions decreased from 1.31 in 2009 to 0.43 in 2012 (p < 0.001). The incidence of H. influenzae and S. pneumoniae meningitis also decreased from 0.66 to 0.08 (p < 0.001), and 0.30 to 0.06 (p < 0.001), respectively. Only 0-2 cases with Neisseria meningitidis were reported each year throughout 2001-2012. The median patient age was 10-12 months in 2001-2011, and became lower in 2012 (2 month old) (p < 0.001). The fatality rate for S. agalactiae is the highest (5.9% (11/187)) throughout 2001-2012 among the four organisms. Risk factors for death and sequelae were convulsions at onset, low CSF glucose, S. agalactiae etiology, and persistent positive CSF culture. Hib vaccine and PCV7 decreased the rate of bacterial meningitis. Earlier introduction of these vaccines may have prevented bacterial meningitis among Japanese children.

Age-dependent change in behavioral feature in Rubinstein-Taybi syndrome

Rubinstein‐Taybi syndrome (RTS) is characterized by developmental delay, postnatal growth retardation, typical facial appearance, and broad thumbs and big toes. The behavioral phenotype of children with RTS has been described as friendly and having good social contacts; however, a short attention span and hyperactivity are sometimes present. Little attention has been paid to the behavioral aspects of adults with RTS. We conducted an observational study focusing on behavioral problems in adolescents and adults with RTS compared with children with RTS. A total of 63 patients with RTS and their caretakers answered self‐administered questionnaires regarding behavioral features including the Child Behavior Checklist (CBCL). High total CBCL scores were observed, and the mean score was beyond the clinical cut‐off point. After stratification into two groups according to age, the older group (≥14 years) displayed statistically significant higher scores for Anxious/Depression (P = 0.002) and Aggressive Behavior (P = 0.036) than the younger group (≤13 years). In analyses of single items, statistically significant differences between the younger group and the older group were found for ‘Nervous, high‐strung, or tense’ (31.3% vs 67.7%, P = 0.004) and ‘Too fearful or anxious’ (37.5% vs 64.5%, P = 0.032). Here, we showed that the specific behavioral phenotypes of RTS change during adolescence, with anxiety, mood instability, and aggressive behavior emerging as patients age. A clear need exists to follow‐up patients with RTS to catch the eventual emergence of psychiatric problems with age. If necessary, pharmacological treatment should be considered.

Ophthalmic features of CHARGE syndrome with CHD7 mutations.

Coloboma and various ocular abnormalities have been described in CHARGE syndrome, although the severity of visual impairment varies from case to case. We conducted a multicenter study to clarify the ophthalmic features of patients with molecularly confirmed CHARGE syndrome. Thirty‐eight eyes in 19 patients with CHARGE syndrome and confirmed CHD7 mutations treated at four centers were retrospectively studied. Colobomata affected the posterior segment of 35 eyes in 18 patients. Both retinochoroidal and optic disk colobomata were bilaterally observed in 15 patients and unilaterally observed in 3 patients. The coloboma involved the macula totally or partially in 21 eyes of 13 patients. We confirmed that bilateral large retinochoroidal colobomata represents a typical ophthalmic feature of CHARGE syndrome in patients with confirmed CHD7 mutations; however, even eyes with large colobomata can form maculas. The anatomical severity of the eye defect was graded according to the presence of colobomata, macula defect, and microphthalmos. A comparison of the severity in one eye with that in the other eye revealed a low‐to‐moderate degree of agreement between the two eyes, reflecting the general facial asymmetry of patients with CHARGE syndrome. The location of protein truncation and the anatomical severity of the eyes were significantly correlated. We suggested that the early diagnosis of retinal morphology and function may be beneficial to patients, since such attention may determine whether treatment for amblyopia, such as optical correction and patching, will be effective in facilitating the visual potential or whether care for poor vision will be needed.

Juvenile Muscular Atrophy of a Unilateral Upper Extremity (Hirayama Disease) in a Patient with CHARGE Syndrome

CHARGE syndrome is an autosomal dominant congenital anomaly syndrome, and the causative gene is CHD7. We report a patient with a CHD7 mutation who presented with juvenile muscular atrophy of a unilateral upper extremity, a presumably heterogeneous condition that is also known as Hirayama disease. This association has not been previously described. Weakness and atrophy of the hands should be carefully examined in patients with CHARGE syndrome, since Hirayama disease might be a possible complication in adolescent patients with this syndrome.