The weather condition and epidemics as triggers for febrile seizure: A single-center retrospective observational study.

OBJECTIVE: The objective of this study was to investigate the association between the weather and epidemic condition and risk of febrile seizures (FSs) in Japan. STUDY DESIGN: This single-center, retrospective study included 560 children (age, 6-60 months) with FSs who were transported to our center by ambulance from January 2011 through December 2018. The weather (temperature, atmospheric pressure, relative air humidity, amount of rainfall, sunshine duration, and air concentration of nitrogen dioxide [NO2] and sulfur dioxide [SO2]) and epidemic (influenza virus infection, infectious gastroenteritis, and exanthem subitum) conditions in this region were compared between the periods (days or weeks) with the transportation of children with FS to our hospital and those without such transportation. RESULTS: In the univariate analyses, neither daily or weekly weather condition nor weekly epidemic condition was correlated to FS transportation. Furthermore, the multiple logistic regression analysis suggested that epidemic influenza virus infection (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.08-1.73) and infectious gastroenteritis (OR, 1.64; 95% CI, 1.09-2.54) were the independent risk factors for FS occurrence and weather condition was not associated with FS risk. CONCLUSIONS: Febrile seizure incidence may be increased by epidemic febrile infections but not by weather condition.

Short-term neurodevelopmental outcomes of focal febrile seizures.

OBJECTIVE: The effect of complex febrile seizures (FS), specifically focal FS, on long-term neurodevelopmental outcome is not well known. The aim of this study was to assess the association between complex FS and neurodevelopmental outcome. METHODS: A single-center, retrospective, cohort study was performed. The study included 282 children aged 6-60 months who experienced FS. Of these, 61 (22%) experienced recurrent FS, 33 (12%) prolonged FS, and 17 (6%) focal FS. The effect of these complex FS on subsequent need for special neurodevelopmental support was investigated. The neurodevelopmental status after FS was evaluated by a questionnaire. RESULTS: During a median follow-up period of 3 years post FS, 12 children (4.3%) required special neurodevelopmental support. Univariate analysis demonstrated a significant association between focal FS and the need for subsequent special neurodevelopmental support, as well as a correlation between prolonged FS and pre-existing neurodevelopmental abnormality. Multiple logistic regression analysis demonstrated that focal FS (odds ratio [OR]: 12.27; 95% confidence interval [CI]: 2.11-71.22) and pre-existing neurodevelopmental abnormality (OR: 262; 95% CI: 17-3944) were significantly associated with the need for subsequent special support. CONCLUSION: An association was found between focal FS and subsequent neurodevelopmental impairment; therefore, close follow-up with particular attention to neurodevelopmental status is required for children who experience focal FS.

Change in the strategy for prophylactic diazepam use for febrile seizures and the impact on seizure recurrence within 24 h.

PURPOSE: To investigate the association between reduced prophylactic diazepam usage and short-term recurrence of febrile seizures (FSs) after the FS practice guideline was updated in Japan. METHOD: In this single-center, retrospective study, children (6-60 months of age) with FS who were transported to our center by ambulance from January 2011 through December 2018 were included. Rectal administration of diazepam (0.3-0.5 mg/kg) after the first seizure and seizure recurrence within 24 h were compared between 2011-2015 (pre-guideline revision) and 2016-2018 (post-guideline revision). RESULTS: Among the total of 509 children, 297 were transported to our hospital in 2011-2015 and 212 in 2016-2018. Rectal diazepam administration was decreased in 2016-2018 (17 %) compared to 2011-2015 (53 %, P < 0.0001), while seizure recurrence was increased in 2016-2018 (20 %) compared to 2011-2015 (12 %, P = 0.0087). Similarly, hospital revisits (23 %) and hospital admissions (26 %) were increased in 2016-2018 compared to 2011-2015 (15 %, P = 0.031 and 18 %, P = 0.026, respectively). Multiple logistic regression analyses showed that prophylactic diazepam administration was the only factor related to preventing seizure recurrence. FS recurrence after the initial seizure was significantly less frequent with diazepam use (6 %) than without diazepam use (21 %, P < 0.0001; relative risk reduction, 70 %; number needed to treat, 6.8 children). CONCLUSION: The FS practice guideline revision was associated with reduced prophylactic diazepam usage and increased FS recurrence within 24 h in Japan. Prophylactic diazepam use should be determined based on clinical safety, local health infrastructure, and parental anxiety.

The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.

The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.

Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin.

Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of four genes mutated in NPHP subtypes 1-4 (refs. 4-9) has linked the pathogenesis of NPHP to ciliary functions. Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.

Identification of neuron-specific promoters in Ciona intestinalis.

We isolated 5' flanking regions of four genes, Ci-Galphai1, Ci-arr, Ci-vAChTP, and Ci-vGAT, each of which is expressed in distinct sets of neurons in the central nervous system of the ascidian Ciona intestinalis, and we examined their function by introducing green fluorescent protein (GFP)-fusion constructs into Ciona embryos. The reporter gene driven by the 5' flanking region of Ci-Galphai1, Ci-arr, and Ci-vAChTP recapitulated the endogenous gene expression patterns, while that of Ci-vGAT can drive GFP expression in particular subsets of neurons expressing the endogenous gene. Deletion analysis revealed that the Ci-Galphai1 promoter consists of multiple regulatory modules controlling the expression in different types of cells. The GFP fluorescence enabled visualization of cell bodies and axons of different sets of neurons in ascidian larvae. These promoters can be a powerful tool for studying molecular mechanisms of neuronal development as well as neuron networks and functions in ascidians.

Sensitization and habituation of the swimming behavior in ascidian larvae to light.

Ascidian larvae of Ciona intestinalis change their photic behavior during the course of development. Newly hatched larvae show no response to a light stimulus at any intensity. At 4 hr after hatching, larvae were induced to start to swimming upon the cessation of illumination, and to stop swimming upon the onset of illumination. At a weaker light intensity (5.0 x 10(-3) J/m (2).s), the larvae showed similar responses to either a single stimulus or repeated stimuli of onset and cessation of light until 10 hr after hatching. At a stronger light intensity (3.2 x 10(-1) J/m(2).s), when the stimulus was repeated, they showed sensitization and habituation of the swimming response. At 3 hr after hatching the larvae failed to show any response to an initial stimulus at any intensity of light, but after several repeated stimuli (sensitization) they showed a swimming response at light intensities above 4.0 x 10(-2) J/m (2).s. At 5 hr and with intensity above 1.0 x 10 (-2) J/m(2).s, the larvae showed photoresponses to the first stimulus, but after several repetitions the larvae failed to stop swimming upon the onset of light (habituation). A repeated series of stimuli at stronger intensities of light caused greater habituation; this habituation was retained for about 1 min. Since the larval central nervous system in Ciona is comprised of only about 100 neurons, learning behavior in ascidian larvae should provide insights for a minimal mechanism of memory in vertebrates.

Gene expression profiles in tadpole larvae of Ciona intestinalis.

A set of 12,779 expressed sequence tags (ESTs), both the 5'-most and 3'-most ends, derived from Ciona intestinalis tadpole larvae was categorized into 3521 independent clusters, from which 1013 clusters corresponding to 9424 clones were randomly selected to analyze genetic information and gene expression profiles. When compared with sequences in databases, 545 of the clusters showed significant matches (P < E-15) with reported proteins, while 153 showed matches with putative proteins for which there is not enough information to categorize their function, and 315 had no significant sequence similarities to known proteins. Sequence-similarity analyses of the 545 clusters in relation to the biological functions demonstrated that 407 of them have functions that many kinds of cells use, 104 are associated with cell-cell communication, and 34 are transcription factors or other gene-regulatory proteins. Sequence prevalence distribution analysis demonstrated that more than one-half of the mRNAs are rare mRNAs. All of the 1013 clusters were subjected to whole-mount in situ hybridization to analyze the gene expression profile in the tadpole larva. A total of 361 clusters showed expression specific to a certain tissue or organ: 96 showed epidermis-specific expression, 60 were specific to the nervous system, 108 to endoderm, 34 to mesenchyme, 5 to trunk lateral cells, 4 to trunk ventral cells, 23 to notochord, 28 to muscle, and 3 to siphon rudiments. In addition, 190 clusters showed expression in multiple tissues. Moreover, nervous system-specific genes showed intriguing expression patterns dependent on the cluster. The present study highlights a broad spectrum of genes that are used in the formation of one of the most primitive chordate body plans as well as for the function of various types of tissue and organ and also provides molecular markers for individual tissues and organs constituting the Ciona larva.