Search

Mutation in the fukutin-related protein (FKRP) gene causes alpha-dystroglycanopathies, a group of autosomal recessive disorders associated with defective glycosylated alpha-dystroglycan (α-DG). The disease phenotype shows a broad spectrum, from the most severe congenital form involving brain and eye anomalies to milder limb-girdle form. FKRP-related alpha-dystroglycanopathies are common in European countries. However, a limited number of patients have been reported in Asian countries. Here, we presented the clinical, pathological, and genetic findings of nine patients with FKRP mutations identified at a single muscle repository center in Japan. Three and six patients were diagnosed with congenital muscular dystrophy type 1C and limb-girdle muscular dystrophy 2I, respectively. None of our Asian patients showed the most severe form of alpha-dystroglycanopathy. While all patients showed a reduction in glycosylated α-DG levels, to variable degrees, these levels did not correlate to clinical severity. Fifteen distinct pathogenic mutations were identified in our cohort, including five novel mutations. Unlike in the populations belonging to European countries, no common mutation was found in our cohort., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Individuals with Sturge-Weber syndrome (SWS) often expereince intractable epilepsy and cognitive decline. We hypothesized that the extent of the leptomeningeal capillary malformation (LCM) may correlate with the severity of neurological impairment due to SWS. We tested the hypothesis in a cross-sectional study of seizure severity and electroencephalographic (EEG) findings and a retrospective cohort study for surgical indications related to the extent of the LCM., Methods: We enrolled 112 patients and classified them according to LCM distribution: (1) bilateral, (2) hemispheric, (3) multilobar, and (4) single lobe. Age at seizure onset, seizure semiology and frequency, and EEG findings were compared. Surgical indications were evaluated for each group by Fisher exact test, and predictors for surgery were evaluated by univariate and multivariate analyses. Therapeutic efficacy was evaluated by the SWS-Neurological Score (SWS-NS)., Results: The bilateral and hemispheric groups had early seizure onset (4.0 months old and 3.0 months old), frequent seizures (88.9% and 80.6% had more than one per month), focal-to-bilateral tonic-clonic seizures (88.9% and 74.2%), and status epilepticus (100% and 87.1%). The groups' EEG findings did not differ substantially. Surgical indications were present in 77.8% of the bilateral, 88.1% of the hemispheric, and 46.8% of the multilobar groups. Seizure more than once per month was a predictor of surgical treatment. Seizure subscore improved postoperatively in the hemispheric and multilobar groups. Even after surgical treatment, the bilateral and hemispheric groups exhibited higher SWS-NSs than members of the other groups., Conclusion: Our study demonstrated a strong association between extensive LCM and epilepsy severity. Surgical intervention improved seizure outcome in patients with SWS with large LCMs., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Predicting clinical outcomes can be difficult, particularly for life-threatening events with a low incidence that require numerous clinical cases. Our aim was to develop and validate novel algorithms to identify major adverse cardiovascular events (MACEs) from claims databases. We developed algorithms based on the data available in the claims database International Classification of Diseases, Tenth Revision (ICD-10), drug prescriptions, and medical procedures. We also employed data from the claims database of Jichi Medical University Hospital, Japan, for the period between October 2012 and September 2014. In total, we randomly extracted 100 potential acute myocardial infarction cases and 200 potential stroke cases (ischemic and hemorrhagic stroke were analyzed separately) based on ICD-10 diagnosis. An independent committee reviewed the corresponding clinical data to provide definitive diagnoses for the extracted cases. We then assessed the algorithms' accuracy using positive predictive values (PPVs) and apparent sensitivities. The PPVs of acute myocardial infarction, ischemic stroke, and hemorrhagic stroke were low only by diagnosis (81.6% [95% CI 72.5-88.7]; 31.0% [95% CI 22.8-40.3]; and 45.5% [95% CI 34.1-57.2], respectively); however, the PPVs were elevated after adding the prescription and procedure data (87.0% [95% CI 78.3-93.1]; 44.4% [95% CI 32.7-56.6]; and 46.1% [95% CI 34.5-57.9], respectively). When we added event-specific prescription and procedure data to the algorithms, the PPVs for each event increased to 70%-98%, with apparent sensitivities exceeding 50%. Algorithms that rely on ICD-10 diagnosis in combination with data on specific drugs and medical procedures appear to be valid for identifying MACEs in Japanese claims databases., (© 2020 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

The time to positivity (TTP) of blood culture has significant value for clinicians. However, almost all subjects of previous studies regarding TTP were adults and early infants. Therefore, careful attention is required when referring to previously published data, which might differ according to the age of subjects, as the tendency of infectious focus and pathogens identified from culture vary with age. In this study, we compared the TTP between two pediatric age groups (≤12 months and 13 months to 15 years [>12 months]) at a teaching hospital during a 5-year period. Of the 95 subjects, 41 and 54 were aged ≤12 and > 12 months, among whom true pathogenic bacteria were identified in 12 (29.3%) and 19 (35.2%), respectively. The median TTP for the younger group with pathogenic bacteria was 11.2 (interquartile range, 10.0-11.9) hours, which was significantly shorter than that for the older group (12.6 [interquartile range, 11.9-16.9] hours) (P = 0.01). At 12 h after the initiation of culture, the younger group with pathogenic bacteria had a significantly higher positivity rate (83.3%) than the older group (26.3%) (P < 0.01). The times required for the positivity to exceed 90% were 13.4 and 20.1 h for the younger and older pathogenic groups and 30.4 and 67.8 h for the younger and older contaminant groups, respectively. The range of TTP could be assessed more accurately by considering the effect of age on the infectious background., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

In recent years, there has been great interest in chipless radio-frequency identification (RFID) devices that work in the terahertz (THz) frequency range. Despite advances in RFID technology, its practical use in the THz range has yet to be realized, due to cost and detection accuracy issues associated with shielding materials. In this study, we propose two types of low-cost THz-tags; one is based on the thickness variation of coated polyethylene and the other on the fingerprint spectra of reagents. In the proposed approach, machine learning, specifically a deep-learning method, is used for high-precision tag identification even with weak signals, or when the spectrum is disturbed by passing through shielding materials. We achieved almost 100% identification accuracy despite using an inexpensive tag placed under thick shielding materials with an attenuation rate of about -50 dB. Furthermore, real-time tag identification was demonstrated by combining a multiwavelength injection-seeded THz parametric generator and a convolutional neural network.

Aim: We examined the associations between late preterm (LPT) birth children aged ≥5 years and the frequency of bedwetting. Moreover, those who were born full-term/low birthweight (BW), LPT/low BW, LPT/normal BW and LPT/low BW were compared., Methods: In total, we evaluated 614 patients who underwent assessments for frequent bedwetting at the three hospitals from January 2014 to December 2016. Data at the initial visit were collected from the electronic medical records. We assessed the patients' bladder diaries and questionnaires containing detailed information on demographics and frequency of bedwetting per month. Neonatal data were collected from the Maternal and Child Health Handbook., Results: Frequency of bedwetting in the LPT/low BW group was higher than in the term/low BW group (28 vs. 22.5, p < 0.05). However, the frequency between the LPT/normal BW group and the LPT/low BW group was not significantly different (28 vs. 28, p = 1.00). Multiple regression analyses were conducted to eliminate potential confounding factors, attention-deficit/hyperactivity disorder and intellectual disability, but results were not changed., Conclusion: This study revealed that LPT/low BW was associated with increased frequency of bedwetting in children. The results suggest that gestational age should be considered when examining patients with severe bedwetting., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Although prasugrel exerts stronger antiplatelet effects compared with clopidogrel, the factors affecting platelet reactivity under prasugrel have not been fully determined. This study aimed to find the novel mechanistic differences between two thienopyridines and identify the factor that influence platelet reactivity to each drug., Methods: Forty patients with stable angina who underwent elective percutaneous coronary intervention were randomly assigned to receive either prasugrel (20 mg) or clopidogrel (300 mg) as a loading dose. Platelet function (light transmission, laser light scattering, and vasodilator-stimulated phosphoprotein phosphorylation) and plasma active metabolite levels were measured after the loading dose., Results: Prasugrel consistently inhibited adenosine diphosphate receptor P2Y 12 signalling to abolish amplification of platelet aggregation. Prasugrel abolished even small platelet aggregates composed of less than 100 platelets. On the other hand, clopidogrel inhibited large aggregates but increased small and medium platelet aggregates. Diabetes was the only independent variable for determining antiplatelet effects and active metabolite concentration of prasugrel, but not clopidogrel. Sleep-disordered breathing was significantly correlated with platelet reactivity in patients who had clopidogrel., Conclusions: Prasugrel efficiently abolishes residual P2Y 12 signalling that causes small platelet aggregates, but these small aggregates are not inhibited by clopidogrel. Considering the differential effect of diabetes on antiplatelet effects between these two drugs, the pharmacokinetics of prasugrel, other than cytochrome P450 metabolism, might be affected by diabetes., Trial Registration: UMIN-CTR UMIN000017624, retrospectively registered 21 May 2015., Competing Interests: The study was conducted in agreement with the Declaration of Helsinki. The protocol was approved by the Institutional Review Board (IRB) of Jichi Medical University, and all patients gave their written informed consent before undergoing any study procedure.Not applicable.T.O. has received research funding from Bayer AG. K.K. has received honoraria from Takeda Pharmaceutical Company Limited., Daiichi Sankyo Co., Ltd., and Omron Healthcare Co., Ltd., as well as research grants from Teijin Pharma Limited, Omron Healthcare Co., Ltd., Fukuda Denshi, Bayer Yakuhin Ltd., A&D Co., Ltd., Daiichi Sankyo Co., Ltd., Mochida Pharmaceutical Co., Ltd., EA Pharma, Otsuka Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan Inc., Mitsubishi Tanabe Pharma Corporation, and Medtronic Japan Co., Ltd. The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Purpose: Desmopressin is a synthetic V2 specific analogue of antidiuretic hormone (arginine vasopressin) that is widely used as first line treatment for monosymptomatic nocturnal enuresis. However, no biomarkers to predict desmopressin effectiveness have yet been established. Because arginine vasopressin is unstable, we prospectively measured the major urine concentration factor aquaporin 2 and serum copeptin (as a surrogate marker for vasopressin) in patients with monosymptomatic nocturnal enuresis, and evaluated whether they are useful for predicting desmopressin treatment outcome., Materials and Methods: The study included 32 children 6 to 11 years old with monosymptomatic nocturnal enuresis and nocturnal polyuria. Exclusion criteria were daytime urinary symptoms and underlying diseases causing nocturnal enuresis. Subjects were treated with 120 μg or 240 μg desmopressin oral disintegrating tablet and were divided into responders (at 120 or 240 μg) and nonresponders (at 240 μg). Day/night ratios of plasma copeptin and urinary aquaporin 2 were measured during desmopressin treatment., Results: There was no significant difference in baseline day/night ratio of urinary aquaporin 2 between desmopressin responders and nonresponders. After 8 weeks of treatment there was a significant correlation between day/night ratio of aquaporin 2 and percentage of wet nights. In responders (but not nonresponders) there was a significant difference in the change in aquaporin 2 day/night ratio from before treatment to complete remission (p = 0.0004). For plasma copeptin the baseline day/night ratio for responders at 120 μg was significantly lower than in the 240 μg nonresponder group (p = 0.02)., Conclusions: Urinary aquaporin 2 appears to be a biomarker of desmopressin treatment effectiveness during therapy, while plasma copeptin levels before treatment are predictive of desmopressin response., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

In 2015, the Japanese Society of Child Neurology released new guidelines for the management of febrile seizures, the first update of such guidelines since 1996. In 1988, the Conference on Febrile Convulsions in Japan published "Guidelines for the Treatment of Febrile Seizures." The Task Committee of the Conference proposed a revised version of the guidelines in 1996; that version released in 1996 was used for the next 19years in Japan for the clinical management of children with febrile seizures. Although the guidelines were very helpful for many clinicians, new guidelines were needed to reflect changes in public health and the dissemination of new medical evidence. The Japanese Society of Child Neurology formed a working group in 2012, and published the new guidelines in March 2015. The guidelines include emergency care, application of electroencephalography, neuroimaging, prophylactic diazepam, antipyretics, drugs needing special attention, and vaccines. While the new guidelines contain updated clinical recommendations, many unsolved questions remain. These questions should be clarified by future clinical research., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Long and short sleep durations were reported as independently associated with hypertension, aortic stiffness, and cardiovascular disease. High-sensitivity C-reactive protein (hs-CRP) was shown to be associated with increased aortic stiffness. Here, we investigated the relationship between self-reported sleep duration and pulse wave velocity (PWV) in the elderly at high risk of cardiovascular disease. We also investigated whether hs-CRP moderates this relationship. Among 4310 patients with ≥1 cardiovascular risks recruited for the Japan Morning Surge-Home Blood Pressure Study, a questionnaire including items on daily sleep duration was completed. We measured the brachial-ankle PWV (baPWV) and hs-CRP levels in 2304 of these patients (mean age 64.7 years, 49.6% males). In accord with the patients' sleep duration (<6 hours, ≥6 to <8 hours, and ≥8 hours per night), significant associations between sleep duration and the PWV were observed (1594 vs. 1644 vs. 1763 cm/s, P < .0001). In the multiple regression analysis adjusted for age, body mass index, total cholesterol, HbA1c and clinic systolic blood pressure, long sleep duration (≥8 hours per night) (P < .05), and log hs-CRP (P < .05) were significantly positively associated with PWV when the patients with 6- to 8-hour sleep duration were defined as a reference group. Significant interactions of long sleep duration by age and that by antihypertensive medication for baPWV were observed. The effect of long sleep on PWV was greatest in the oldest age group. Long sleep duration and hs-CRP were significant indicators of increased baPWV in this elderly high-risk Japanese population. Age and antihypertensive medication use were significant modulators of the relationship between long sleep duration and arterial stiffness., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Craniofrontonasal syndrome (CFNS; MIM#304110) is characterized by asymmetric facial features with hypertelorism and a broad bifid nose due to synostosis of the coronal suture. CFNS shows a unique X-linked inheritance pattern (most affected patients are female and obligate male carriers exhibit a mild manifestation or no typical features at all) associated with the ephrin-B1 gene (EFNB1) located in the Xq13.1 region. In this study, we performed targeted, massively parallel sequencing using a next-generation sequencer, and identified a novel EFNB1 mutation, c.270&#95;271delCA, in a Japanese female patient with craniosynostosis. Because subsequent Sanger sequencing identified no mutation in either parent, this mutation was determined to be de novo in origin. After obtaining molecular diagnosis, a retrospective clinical evaluation confirmed the clinical diagnosis of CFNS in this patient. Comprehensive molecular diagnosis using a next-generation sequencer would be beneficial for early diagnosis of the patients with undiagnosed craniosynostosis., (© 2015 Japanese Teratology Society.)

Objective: To clarify the efficacy and safety of fosphenytoin for seizures in children with benign convulsions and mild gastroenteritis., Methods: Using the mailing list of the Annual Zao Conference on Pediatric Neurology, we recruited patients who met the following criteria: (1) clinical diagnosis of benign convulsions with mild gastroenteritis and (2) treatment with intravenous fosphenytoin. Benign convulsions with mild gastroenteritis were defined as a condition of (a) seizures associated with gastroenteritis without electrolyte imbalance, hypoglycemia, or dehydration in patients (b) between 6 months and 3 years of age with (c) no preexisting neurological disorders, (d) no impaired consciousness, and (e) a body temperature less than 38.0 °C before and after the seizures. The efficacy of fosphenytoin was categorized as effective when cessation of seizures was achieved., Results: Data from 16 child patients were obtained (median age, 20 months). Seizures were completely controlled after the initial dose of fosphenytoin in 14 of 16 patients. The median loading dose of fosphenytoin was 22.5 mg/kg. In 10 patients, fosphenytoin was administered after other antiepileptic drugs such as diazepam and midazolam were used. Adverse effects of fosphenytoin, excessive sedation, or intravenous fluid incompatibility were not observed in any patients., Conclusion: Fosphenytoin is effective and well tolerated among children with benign convulsions with mild gastroenteritis., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Although desmopressin therapy is effective in treating polyuric monosymptomatic nocturnal enuresis (MNE), the relatively high rates of recurrence are problematic. To date, the treatment protocol on the discontinuation of oral desmopressin melt (ODM) tablet, MinirinMelt, has not been established. We tested two protocols of tapering ODM when the patients achieved full response on ODM, and compared the treatment outcomes., Methods: One hundred and fifty-seven polyuric MNE children were newly treated with ODM at the authors' outpatient clinics (Juntendo Nerima Hospital and Musashi-Murayama Hospital). When the patients did not respond to the 8 week ODM therapy, we added another options such as alarm, anti-cholinergics, and imipramine (92 patients; 58.6%). Sixty-five patients (41.4%) achieved full response on ODM alone, and 49 of them accepted gradual tapering of ODM: group B (n = 25), 240 μg ODM per day → 120 μg ODM per day → 120 μg ODM per alternate day → cessation; and group C (n = 24), 240 μg ODM per day → 120 μg ODM per day → 60 μg ODM per day → 60 μg ODM per alternate day → cessation., Results: Fourteen patients in group B (56%) and four in group C (17%) had relapses of enuresis after the discontinuation of ODM (P = 0.026)., Conclusions: Gradual tapering of ODM therapy in MNE patients leads to better outcome., (© 2015 Japan Pediatric Society.)

Purpose: To evaluate the efficacy and safety of fosphenytoin (fPHT) for the treatment of seizures in children with acute encephalopathy., Methods: Using responses from physicians on the Annual Zao Conference on Pediatric Neurology mailing list we chose patients who met the following criteria: clinical diagnosis of acute encephalopathy and use of intravenous fPHT for the treatment of seizures. We divided the patients into two groups: acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and other encephalopathies. The efficacy of fPHT was considered effective when a cessation of seizures was achieved., Results: Data of 38 children were obtained (median age, 27 months). Eighteen children were categorized into the AESD group and 20 into the other encephalopathies group. fPHT was administered in 48 clinical events. The median loading dose of fPHT was 22.5 mg/kg and was effective in 34 of 48 (71%) events. The rate of events in which fPHT was effective did not differ according to the presence or absence of prior antiepileptic treatment, subtype of acute encephalopathy, or the type of seizures. One patient experienced apnea and oral dyskinesia as adverse effects of fPHT, whereas arrhythmia, hypotension, obvious reduction of consciousness, local irritation, phlebitis and purple grove syndrome were not observed in any patient., Conclusion: fPHT is effective and well tolerated among children with acute encephalopathy., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: Some patients with Sturge-Weber syndrome (SWS) need epilepsy surgery for adequate seizure control and prevention of psychomotor deterioration. The majority of patients with SWS have leptomeningeal angioma located over the temporal, parietal, and occipital lobes. We applied posterior quadrant disconnection surgery for this type of SWS with intractable seizure. We evaluated the efficacy of this procedure in seizure control and psychomotor development., Methods: Ten patients who were surgically treated using the posterior quadrantectomy (PQT) were enrolled in this study. Surgical outcome was analyzed as seizure-free or not at 2 years after surgery. Psychomotor development was evaluated by the scores of mental developmental index (MDI) and psychomotor developmental index (PDI) in the Bayley Scales of Infant Development II preoperatively, and at 6 and 12 months after the PQT., Results: Eight of 10 patients were seizure-free. Patients without complete elimination of the angiomatous areas had residual seizures. Average MDI and PDI scores before the surgery were 64.8 and 71.6, respectively. Scores of MDI at 6 and 12 months after the PQT in seizure-free patients were 80.5 and 84.5, respectively (p < 0.01). PDI scores at these postoperative intervals were 87.3 and 86.4, respectively (p < 0.05). Patients with residual seizures did not improve in either MDI or PDI., Significance: The PQT achieved good seizure control and improved psychomotor development in patients with SWS. The complete deafferentation of angiomatous areas is required for seizure-free results and psychomotor developmental improvement., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Background: The major pathogenic factors involved in nocturnal enuresis are nocturnal polyuria, small bladder capacity and/or detrusor overactivity, and a high arousal threshold. Desmopressin is the first-line therapy for the patients with diuresis-dependent nocturnal enuresis. Yokukansan, a traditional Japanese medicine, has been used in Japan to treat patients with nervousness, insomnia, and children with night terrors and temper tantrums. We experienced the positive effect of Yokukansan in some of the patients who did not respond well to desmopressin therapy., Methods: In total, 32 children with monosymptomatic nocturnal enuresis with nocturnal polyuria were treated with oral desmopressin melt tablets, which were approved for clinical use in Japan on 29 May 2012. This treatment was effective for 14 of them. For the rest (n = 18), Yokukansan was introduced in combination with desmopressin., Results: Yokukansan was effective for 12 out of the 18 cases., Conclusions: Yokukansan should be a candidate for the medication of nocturnal enuresis., (© 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.)

Oral-facial-digital syndrome type 1 (OFD1; MIM 311200) is characterized by multiple anomalies of the oral cavity, face and digits. We report a family with OFD1, where two female siblings and their mother shared the same mutation of the responsible gene (OFD1) c.1193&#95;1196delAATC. Phenotypic variability was observed among them; the mother showed minimal features of OFD1, whereas her two daughters showed partial features and the full spectrum of OFD1, respectively. Thus, OFD1 was suspected only after a health check-up during pregnancy of the second patient showing fetal brain anomaly and maternal polycystic kidney. For these reasons, there was a delay in the recognition of OFD1 in this family. Patients with OFD1 show phenotypic variability, which poses challenges for genetic counseling., (© 2012 The Authors. Congenital Anomalies © 2012 Japanese Teratology Society.)

With advancements in high-throughput technologies and open availability of bioassay data, computational methods to generate models, that zoom out from a single protein with a focused ligand set to a larger and more comprehensive description of compound-protein interactions and furthermore demonstrate subsequent translational validity in prospective experiments, are of prime importance. In this article, we discuss some of the new benefits and challenges of the emerging computational chemogenomics paradigm, particularly with respect to compound-protein interaction. Examples of experimentally validated computational predictions and recent trends in molecular feature extraction are presented. In addition, analyses of cross-family interactions are considered. We also discuss the expected role of computational chemogenomics in contributing to increasingly expansive network-level modeling and screening projects., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a patient with lidocaine-responsive neonatal epilepsy treated successfully with oral mexiletine. The patient was a male neonate who had seizures since 2days of age. While his seizures were refractory to phenobarbital, lamotrigine, vitamin B6, and midazolam, they were controlled by continuous lidocaine infusion. Oral mexiletine at serum levels of 0.2-0.4μg/ml was used successfully for long-term treatment of his seizures. No delay in psychomotor development was observed at the last follow-up at 20months of age. No mutation was identified in any of four genes: SCN1A, SCN1B, KCNQ2, and KCNQ3. Our patient demonstrates that oral mexiletine can be useful for long-term treatment of patients with lidocaine-responsive epilepsy., (Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Chemical genomics research has revealed that G-protein coupled receptors (GPCRs) interact with a variety of ligands and that a large number of ligands are known to bind GPCRs even with low transmembrane (TM) sequence similarity. It is crucial to extract informative binding region propensities from large quantities of bioactivity data. To address this issue, we propose a machine learning approach that enables identification of both chemical substructures and amino acid properties that are associated with ligand binding, which can be applied to virtual ligand screening on a GPCR-wide scale. We also address the question of how to select plausible negative noninteraction pairs based on a statistical approach in order to develop reliable prediction models for GPCR-ligand interactions. The key interaction sites estimated by our approach can be of great use not only for screening of active compounds but also for modification of active compounds with the aim of improving activity or selectivity.

The development of selective and multitargeted kinase inhibitors has received much attention, because cross-reactivity with unintended targets may cause toxic side effects, while it can also give rise to efficacious multitargeted drugs. Here we describe a deconvolution approach to dissecting kinase profiling data in order to gain knowledge about cross-reactivity of inhibitors from large-scale profiling data. This approach not only enables activity predictions of given compounds on a kinome-wide scale, but also allows to extract residue-fragment pairs that are associated with activity. We demonstrate its effectiveness using a large-scale public chemogenomics data set and also apply our proposed model to a recently published bioactivity data set. We further illustrate that the preference of given compounds for kinases of interest is better understood by residue-fragment pairs, which could provide both biological and chemical insights into cross-reactivity.

Industrial yeasts, including a sake yeast strain Kyokai no. 7 (K7), are generally unable to sporulate. Previously, we have reported that in K7 (Saccharomyces cerevisiae) cells, deletion of the G1 cyclin gene CLN3, a key activator of the cell cycle, allows the cells to induce IME1 transcription and sporulate under sporulation conditions. Here we show that treatment with the immunosuppressive drug rapamycin also restores sporulation competence in K7 cells. Moreover, sporulation was observed after rapamycin treatment in other industrial yeasts, namely bottom fermenting yeast strains and a wine yeast strain, which are not able to sporulate under normal sporulation conditions. These findings suggest that activation of TORC1 under sporulation conditions leads to sporulation incompetence in these yeasts. Thus, rapamycin treatment will be useful to restore sporulation competence in industrial yeasts., (Copyright © 2011 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Context:   Mutations in the GH1 gene have been identified in patients with isolated growth hormone deficiency (IGHD). Mutations causing aberrant splicing of exon 3 of GH1 that have been identified in IGHD are inherited in an autosomal dominant manner, whereas other mutations in GH1 that have been identified in IGHD are inherited in an autosomal recessive manner., Objective:   Two siblings born from nonconsanguineous healthy parents exhibited IGHD. To elucidate the cause, GH1 in all family members was analysed., Results:   Two novel mutations in GH1, a point mutation in intron 3 and a 16-bp deletion in exon 3, were identified by sequence analyses. The intronic mutation was present in both siblings and was predicted to cause aberrant splicing. The deletion was present in one of the siblings as well as the mother with normal stature and was predicted to cause rapid degradation of mRNA through nonsense-mediated mRNA decay. The point mutation was not identified in the parents' peripheral blood DNA; however, it was detected in the DNA extracted from the father's sperms. As a trace of the mutant allele was detected in the peripheral blood of the father using PCR-RFLP, the mutation is likely to have occurred de novo at an early developmental stage before differentiation of somatic cells and germline cells., Conclusions:   This is the first report of mosaicism for a mutation in GH1 in a family with IGHD. It is clear that the intronic mutation plays a dominant role in the pathogenesis of IGHD in this family, as one of the siblings who had only the point mutation was affected. On the other hand, the other sibling was a compound heterozygote for the point mutation and the 16-bp deletion and it may be arguable whether IGHD in this patient should be regarded as autosomal dominant or recessive., (© 2012 Blackwell Publishing Ltd.)

Background: Undue parental fear of fever in children was termed "fever phobia" by Schmitt following a survey in the USA in 1980. In 2000, Crocetti et al. conducted the same survey and concluded that fever phobia existed even 20 years later. In this study, we explore differences in fever phobia between these two US populations and a Japanese sample, and determine whether parents of a single child or those whose child was previously hospitalized or had a febrile seizure report greater anxiety about fever., Methods: A questionnaire was distributed to parents of children who visited a pediatric outpatient clinic in Juntendo University Nerima Hospital between 19 and 30 November 2007., Results: Data was obtained from 211 parents who agreed to participate in the study. Compared with much smaller proportions reported in the two previous studies, 62% of caregivers considered a temperature below 37.8°C to be a fever, although less than half of parents reported that they were "very worried" about fever. Over 90% identified doctors and nurses as their primary information source. In contrast to 7% of parents in the US studies, almost no parents reported that temperatures could rise to or above 43.3°C if fever was left untreated; however, 63% of parents stated that they would visit a hospital., Conclusions: Fever phobia exists on both sides of the border, and while caregivers in Japan appear to have a more accurate understanding of fever, they are more likely to rely on health-care professionals to manage the condition., (© 2011 The Authors. Pediatrics International © 2011 Japan Pediatric Society.)

Dissected specimens of colorectal cancer (CRC) have been intensively studied using molecular sketches (gene signatures) to obtain a set of discriminator gene signatures for accurate prognosis prediction in individual patients. The discriminators obtained so far are not universally applicable, as the gene sets reflect the method and site of the study. In this study, we show that dissected stage II and III CRC samples are significantly heterogeneous in molecular sketches, and are not appropriate sources for discriminator extraction unless handled individually. To search for an accurate discriminator gene set for prediction of metastases, we need to start with less heterogeneous stage II CRC. We examined 198 (92 stage II and 106 stage III) CRC dissected samples for the predictability of discriminator gene signatures by analyzing stage II CRC alone, stage III alone, or in combination. The best predictive power of discriminator genes was obtained only when these genes were extracted and validated with stage II CRC samples. An accurate discriminator gene set for the prediction of CRC metastases can be obtained by focusing on stage II CRC samples.

Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.

The discovery of novel bioactive molecules advances our systems-level understanding of biological processes and is crucial for innovation in drug development. For this purpose, the emerging field of chemical genomics is currently focused on accumulating large assay data sets describing compound-protein interactions (CPIs). Although new target proteins for known drugs have recently been identified through mining of CPI databases, using these resources to identify novel ligands remains unexplored. Herein, we demonstrate that machine learning of multiple CPIs can not only assess drug polypharmacology but can also efficiently identify novel bioactive scaffold-hopping compounds. Through a machine-learning technique that uses multiple CPIs, we have successfully identified novel lead compounds for two pharmaceutically important protein families, G-protein-coupled receptors and protein kinases. These novel compounds were not identified by existing computational ligand-screening methods in comparative studies. The results of this study indicate that data derived from chemical genomics can be highly useful for exploring chemical space, and this systems biology perspective could accelerate drug discovery processes.

There is growing interest in computational chemogenomics, which aims to identify all possible ligands of all target families using in silico prediction models. In particular, kernel methods provide a means of integrating compounds and proteins in a principled manner and enable the exploration of ligand-target binding on a genomic scale. To better understand the link between ligands and targets, it is of fundamental interest to identify molecular interaction features that contribute to prediction of ligand-target binding. To this end, we describe a feature selection approach based on kernel dimensionality reduction (KDR) that works in a ligand-target space defined by kernels. We further propose an efficient algorithm to overcome a computational bottleneck and thereby provide a useful general approach to feature selection for chemogenomics. Our experiment on cytochrome P450 (CYP) enzymes has shown that the algorithm is capable of identifying predictive features, as well as prioritizing features that are indicative of ligand preference for a given target family. We further illustrate its applicability on the mutation data of HIV protease by identifying influential mutated positions within protease variants. These results suggest that our approach has the potential to uncover the molecular basis for ligand selectivity and off-target effects.

Objective: Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to confirm the platinum agent-associated mild, severe, and lethal hypersensitivity reactions., Methods: Authorized pharmacovigilance tools were used for quantitative signal detection, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Excess2, given by the multi-item gamma Poisson Shrinker algorithm, was used to evaluate the effects of dexamethasone and diphenhydramine on oxaliplatin-induced hypersensitivity reactions., Results: Based on 1,644,220 AERs from 2004 to 2009, carboplatin and oxaliplatin proved to cause mild, severe, and lethal hypersensitivity reactions, whereas cisplatin did not. Dexamethasone affected oxaliplatin-induced mild hypersensitivity reactions, but had lesser effects on severe and lethal reactions. The effects of diphenhydramine were not confirmed., Conclusion: The FDA's adverse event reporting system, AERS, with optimized data mining tools is useful to authorize potential associations between platinum agents and hypersensitivity reactions.