Changes in prognostic nutritional index during hospitalization and outcomes in patients with acute heart failure.

Although the prognostic nutritional index (PNI) is reported as a prognosticator in patients with heart failure (HF), that is evaluated usually on one occasion, and any changes in PNI during hospitalization are not considered. This study aimed to assess between changes in the PNI during hospitalization and outcomes in patients with acute HF. We enrolled 141 patients (median age, 84 years, 75 male) admitted to our hospital for the treatment of acute HF. The PNI was calculated on admission and at discharge based on the original report. According to the PNI change during hospitalization, patients were classified as either improved (PNI at discharge ≥ PNI on admission) or deteriorated (PNI at discharge < PNI on admission). Primary outcomes were all-cause death or unplanned hospitalization due to HF within the first year. Forty-nine events occurred (19 deaths, 30 HF hospitalizations). The event-free survival rate determined by Kaplan-Meier analysis was significantly higher in patients in the improved group (log-rank test, P < 0.0001), regardless of the PNI value on admission. Multivariate analysis showed that younger age (HR 1.06, 95% CI 1.01-1.11, P = 0.016), higher body mass index (HR 0.90, 95% CI 0.82-0.98, P = 0.021) and the PNI in the improved group (HR 0.30, 95% CI 0.14-0.57, P = 0.0006) were independently associated with favorable outcomes. In conclusion, changes in nutritional status during hospitalization, evaluated using the PNI on admission and at discharge, were independently associated with 1-year outcomes in patients with acute HF.

Plasma exchange and infliximab as a third-line therapy for refractory infantile Kawasaki disease.

BACKGROUND: The treatment for Kawasaki disease (KD) patients refractory to intravenous immunoglobulin (IVIG) therapy is still controversial, and the efficacy of plasma exchange (PE) and infliximab (IFX) therapy for infantile KD is unknown. METHODS: A total of 22 infantile KD patients refractory to initial and additional IVIG, who received either PE or IFX as third-line therapy from October 2008 to February 2020 were examined retrospectively. The patients' sex, age, days of first IVIG, days of PE or IFX therapy, laboratory data preceding PE or IFX therapy, coronary artery lesions (CALs), and adverse effects were investigated. RESULTS: Thirteen patients received PE and nine patients received IFX as the third-line therapy. For the median age at onset, the median days of first IVIG and PE or IFX, and pre-PE or IFX therapy blood test results, there were no significant between-group differences. At admission, and before and after the third-line therapy, there were also no significant differences in occurrence of CALs. The frequency of serious adverse events was significantly higher in the PE group than in the IFX group. CONCLUSIONS: Although there were no significant differences in patient background, blood test results, or frequency of CALs, the frequency of adverse events was significantly higher in the PE group. With the trend of expansion of IFX therapy for KD patients refractory to IVIG, the role of PE as the additional therapy may become more limited.

Action-at-a-distance mutations at 5'-GpA-3' sites induced by oxidised guanine in WRN-knockdown cells.

G:C sites distant from 8-oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine) are frequently mutated when the lesion-bearing plasmid DNA is replicated in human cells with reduced Werner syndrome (WRN) protein. To detect the untargeted mutations preferentially, the oxidised guanine base was placed downstream of the reporter supF gene and the plasmid DNA was introduced into WRN-knockdown cells. The total mutant frequency seemed higher in the WRN-knockdown cells as compared to the control cells. Mutation analyses revealed that substitution mutations occurred at the G:C pairs of 5'-GpA-3'/5'-TpC-3' sites, the preferred sequence for the apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3 (APOBEC3)-family cytosine deaminases, in the supF gene in both control and knockdown cells. These mutations were observed more frequently at G sites than C sites on the DNA strand where the GO base was originally located. This tendency was promoted by the knockdown of the WRN protein. The present results imply the possible involvement of APOBEC3-family cytosine deaminases in the action-at-a-distance (untargeted) mutations at G:C (or G) sites induced by GO and in cancer initiation by oxidative stress.

Long-term seizure outcomes in patients with hypothalamic hamartoma treated by stereotactic radiofrequency thermocoagulation.

OBJECTIVE: To investigate long-term seizure outcomes in patients with hypothalamic hamartoma (HH) following stereotactic radiofrequency thermocoagulation (SRT). METHODS: A total of 131 patients with HH who underwent SRT and were followed for at least three years after the last SRT were enrolled. Seizure outcomes were evaluated for gelastic seizures (GS) and other types of seizures (nGS) separately using the International League Against Epilepsy classification. Classes 1 and 2 were considered seizure-free. Kaplan-Meier survival analyses were used to estimate the proportion remaining seizure-free after the first and last SRTs. Risk factors relating to outcomes were analyzed by log-rank tests and a multivariate Cox proportional hazards model. RESULTS: Reoperation was performed in 34 patients (26.2%). Median total follow-up was 61 (range, 36-202) months. Seizure freedom was obtained in 116 patients (88.6%) for GS and 85 of 108 patients (78.7%) for nGS at the last follow-up. Mean GS-free survival times improved from after the first (64.1 [95%CI 57.3-70.9] months) to after the last SRT (80.2 [95%CI 75.7-84.8] months). About 90% of GS recurrences after the first SRT were found within 6 months, though a few patients recurred more than 2 years after the first SRT. On the other hand, mean nGS-free survival times after the first and last SRTs were not different between after the first SRT (84.4 [95%CI 73.0-90.7] months) and after the last SRT (83.1 [95%CI 74.1-92.0] months). There was no factor related to GS outcomes, but the significant factor for nGS-free survival after the last SRT was multiple previous treatments (p=0.01, hazard ratio=15.65, 95%CI 1.79-137.16). SIGNIFICANCE: The last SRT was almost equivalent to achieving complete disconnection of HHs from the hypothalamus according to our strategy. Considering the epileptogenic network, GS outcomes depend on complete disconnection, whereas nGS outcomes are not affected by surgical factors but independency of secondary epileptogenesis.

Association Between Albumin-Bilirubin Score at Admission and In-Hospital Mortality in Patients with Acute Heart Failure.

Liver dysfunction is one of the most recognized complications in patients with acute heart failure (HF) and therefore a liver function score may be useful for risk-stratification in those patients. Recently, the albumin-bilirubin (ALBI) score was developed as a new model to assess liver function in liver disease. We explored the association between the ALBI score at admission and in-hospital mortality in patients with acute HF.We enrolled 262 patients (median age, 86 years, 137 males) who were admitted to our hospital for treatment of acute HF. The following data were recorded: vital signs, laboratory data including B-type natriuretic peptide (BNP) level, echocardiographic data at admission, demographic and clinical characteristics, and treatment and prognostic information. The Get With the Guidelines-Heart Failure (GWTG-HF) risk score was calculated as an established risk model for each patient. The primary outcome was all-cause in-hospital mortality.During hospitalization, 37 patients (14.1%) died. The in-hospital mortality rate was significantly higher in patients with ALBI scores > -2.25 compared with patients with ALBI scores ≤ -2.25 (21.1% versus 4.5%, respectively; P = 0.0001). Multivariate analysis revealed that the GWTG-HF score (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.08-1.25, P < 0.0001), BNP level (OR 1.0007, 95% CI 1.0003-1.001, P = 0.0003) and ALBI score (OR 6.0, 95% CI 1.8-19.6, P = 0.0017) were independently associated with in-hospital mortality.Our results indicated that the ALBI score was independently associated with in-hospital mortality in patients hospitalized for acute HF.

[Adult Prepubertal-Type Teratoma Diagnosed Using Fish Analysis : A Case Report].

A 34-year-old man visited our hospital complaining of a small painless left scrotal mass. His serum alpha-fetoprotein and human chorionic gonadotropin-beta levels were normal. Ultrasonography revealed a solitary 14 mm mass. Magnetic resonance imaging revealed a mass with high intensity on T2-weighted imaging. Computed tomography revealed a heterogeneous tumor in the left scrotum. Left high orchiectomy was performed. The histopathological diagnosis was a teratoma without germ cell neoplasia in situ (GCNIS). Fluorescence in situ hybridization analysis showed no appearance of i(12p). The patient was clinically diagnosed as having a prepubertal-type testicular teratoma. Adult teratomas contain GCNIS and are aggressively treated as malignant germ cell tumors. However, a prepubertal-type teratoma is benign and does not relapse. It is essential to validate the appearance of i(12p) to differentiate prepubertal and postpubertal-type teratoma.

Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (KAICA): a randomised controlled, open-label, blinded-endpoints, phase 3 trial.

BACKGROUND: Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. METHODS: We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. FINDINGS: We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25-0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). INTERPRETATION: Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. FUNDING: Japan Agency for Medical Research and Development (grant CCT-B-2503).

Significance of the electrophysiological border between hypothalamic hamartomas and the hypothalamus for the target of ablation surgery identified by intraoperative semimicrorecording.

OBJECTIVE: Ablation surgery has become the first line of treatment for hypothalamic hamartomas (HHs). For effective treatment, optimum targeting of ablation is mandatory. The present study aimed to evaluate the correspondence between the electrophysiological features of HHs and morphological targeting by semimicrorecording during stereotactic radiofrequency thermocoagulation (SRT). METHODS: Eighty HH patients who underwent SRT were involved. Semimicrorecording was performed on the first trajectory. The distance from the center of the target at the morphological border (TMB) determined by magnetic resonance imaging, differences in discharge patterns, and area potentials (APs) were measured. RESULTS: The electrophysiological border (EB) between the HH and hypothalamus was detected by semimicrorecording in 73 (91.3%), AP increase (API) in the HH was detected in 31 (38.8%), and spike discharges (SDs) of the HH were detected in 56 patients (70.0%). Semimicrorecording showed significantly different APs among structures passing through the trajectory, except between API and SDs. The median distances from the center of the TMB to the EB, API, SDs, and AP decline were -3.50, -2.49, -1.38, and +2.00 mm, respectively. SIGNIFICANCE: The electrophysiological features of HHs were shown by semimicrorecording during SRT. The EB corresponded to the morphological border. The electrophysiologically active area of HHs was located near the border. Ablation surgery should focus on disconnection at the border between the HH and the hypothalamus to maximize its effectiveness, as well as to reduce complications.

Clinical outcomes of microdissection testicular sperm extraction and intracytoplasmic sperm injection in Japanese men with Y chromosome microdeletions.

PURPOSE: We investigated the clinical results of Japanese men with Y chromosome microdeletions. METHODS: This study retrospectively examined 2163 azoospermic or severe oligozoospermic patients. We investigated the frequency of azoospermia factor (AZF) deletions and sperm retrieval rate (SRR) by microTESE in patients with these deletions, then analyzed the ICSI outcomes. RESULTS: Azoospermia factor deletions were found in 201 patients. SRR was significantly higher than that of the control group (74.0% vs 20.4%, P < .001). Thirty-three couples underwent ICSI using testicular spermatozoa retrieved by microTESE, and eight couples underwent ICSI using ejaculatory spermatozoa. The fertilization rate and clinical pregnancy rate per embryo transfer cycle were significantly higher in the ejaculatory group than that of the testicular group (66.4% vs 43.7%, P < .001, 53.3% vs 24.7%, P = .03, respectively). When compared with the control group, the fertilization rate was significantly lower in the testicular group with AZFc microdeletions (43.7% vs 53.6%, P < .001). CONCLUSIONS: Our study highlights that although microTESE in azoospermic men with AZFc microdeletions led to a higher SRR, ICSI outcomes of these men were worse than that of men without AZF deletions, even if testicular spermatozoa were retrieved.

Genetic deletion of Cav3.2 T-type calcium channels abolishes H2S-dependent somatic and visceral pain signaling in C57BL/6 mice.

We tested whether genetic deletion of Cav3.2 T-type Ca2+ channels abolishes hydrogen sulfide (H2S)-mediated pain signals in mice. In Cav3.2-expressing HEK293 cells, Na2S, an H2S donor, at 100 µM clearly increased Ba2+ currents, as assessed by whole-cell patch-clamp recordings. In wild-type C57BL/6 mice, intraplantar and intracolonic administration of Na2S evoked mechanical allodynia and visceral nociceptive behavior, respectively, which were abolished by TTA-A2, a T-type Ca2+ channel blocker. In Cav3.2-knockout mice of a C57BL/6 background, Na2S caused neither somatic allodynia nor colonic nociception. Our study thus provides definitive evidence for an essential role of Cav3.2 in H2S-dependent somatic and colonic pain.

Asymmetric gelastic seizure as a lateralizing sign in patients with hypothalamic hamartoma.

Gelastic seizure (GS) is a cardinal symptom of hypothalamic hamartoma (HH), which is intractable but surgically remediable. Although facial asymmetry with GS has not been extensively discussed, asymmetric GS has been frequently recognized in our large series. We hypothesized that asymmetric GS represents a lateralizing sign caused by the epileptic propagation from the attachment of the HH. To examine this hypothesis, the positive predictive value (PPV) and diagnostic odds ratio (DOR) of asymmetric GS were validated to predict the side of HH attachment. In 103 cases registered to the present analysis, asymmetric GS was recognized in 71 patients and symmetric GS in 32. Asymmetric GS with a lopsided grimace was exclusively observed on the side contralateral to unilateral HH in 39 patients and to the dominant attachment of 23 HHs with bilateral attachment (true positive, n = 62). In contrast, asymmetric GS was exhibited independently on both sides in 4 patients with bilaterally attached HH and on the side ipsilateral to the dominant attachment in the other 4. Symmetric HH attachments were identified in 1 patient (false negative, n = 9). Asymmetric GS was a reliable lateralizing sign with high DOR (6.08) and PPV (78%) to predict the side of epileptic propagation. Furthermore, the present study demonstrated the probability of seizure propagation from bilateral attachment, and this evidence provides a new rationale to the surgical strategy of bilateral disconnection for HH with bilateral attachment.

Infliximab for the Treatment of Refractory Kawasaki Disease: A Nationwide Survey in Japan.

OBJECTIVE: To assess the safety and efficacy of infliximab (IFX) for the treatment of patients with Kawasaki disease (KD). STUDY DESIGN: This was a nationwide survey of 274 Japanese institutions exploring how IFX was used to treat patients with KD. The patients' sex, age, treatment course, pre- and post-IFX therapy blood test results, coronary artery lesions (CALs), and adverse events (AEs) were evaluated. RESULTS: We analyzed 434 patients with KD who received IFX between March 2005 and November 2014. The median age at onset was 33 months (range 1-138), and 66 patients (15.2%) were under 1 year old. In all cases, IFX was administered as additional treatment. The median days of illness at the initiation of IFX was 9 days. In 275 patients (63.4%), IFX was administered as third-line treatment, and in 106 patients (24.4%), IFX was administered as fourth-line treatment. Single dose IFX 5 mg/kg was administered to 412 patients (94.9%). After IFX, 363 patients (83.6%) became afebrile within 2 days, and the white blood cell count, percentage of neutrophils, and serum C-reactive protein levels significantly decreased (P < .001), although 119 patients (27.4%) received additional treatment. Before IFX, 132 patients (30.4%) had already developed CALs. In patients without CALs before IFX, 31 patients (10.3%) newly developed CAL after IFX, whereas 32 patients (24.2%) with CAL before IFX showed increased CAL severity. Eighty AEs were observed in 69 patients (15.9%); however, serious AEs were few and reversible. CONCLUSIONS: IFX might be an effective and tolerable treatment for refractory KD.

Rice HRZ ubiquitin ligases are crucial for response to excess iron.

Iron is essential for virtually all organisms but is toxic when present in excess. To acquire the proper amount of iron, plants induce expression of various genes involved in iron uptake and translocation in response to low iron availability. Two iron-binding ubiquitin ligases, OsHRZ1 and OsHRZ2, negatively regulate such iron deficiency responses in rice (Oryza sativa). Transgenic rice plants with repressed expression of OsHRZ1 and OsHRZ2 (HRZ knockdown lines) are tolerant to low iron availability and accumulate iron in shoots and seeds under both iron-sufficient and -deficient conditions without a growth penalty. Although the expression of OsHRZ1 and OsHRZ2 is transcriptionally upregulated under iron-deficient conditions, the physiological relevance of this induction is not known. In the present study, we analyzed the response of HRZ knockdown lines to excess iron. In the presence of severe excess iron, the HRZ knockdown lines grew worse than non-transformants. The HRZ knockdown lines showed stunted shoot and root growth and more severe leaf bronzing compared to non-transformants. Moreover, these lines accumulated more iron in shoots and exhibited severely elevated expression of various genes involved in iron uptake and translocation as well as jasmonate signaling compared to non-transformants. These results indicate that HRZ ubiquitin ligases are crucial for repressing iron deficiency responses and protecting cells from iron toxicity in the presence of excess iron. These results support the possibility that HRZs are intracellular Fe sensors and provide clues for developing plants tolerant of either iron deficiency or excess with higher iron contents in edible parts.

Risk factors of long hospital stay for immunoglobulin A vasculitis: Single-center study.

BACKGROUND: Immunoglobulin A (IgA) vasculitis is a common, systemic childhood disease that occasionally interferes with oral intake of food and necessitates hospitalization. In Japan, there are no reports on the length of hospitalization or factors related to long-term hospitalization in children with IgA vasculitis. In this study, we investigated the factors related to long-term hospitalization. METHODS: We reviewed the medical records of children aged ≤15 years with IgA vasculitis who were admitted to the National Center for Child Health and Development (Tokyo, Japan) between March 2008 and April 2017. We reviewed their gender, age, previous episodes, digestive symptoms, fever, laboratory data, urine analysis, ultrasound, and use of glucocorticoid on admission day. We compared the long-stay (≥10 days) group (L) and the short-stay (≤9 days) group (S) on logistic regression analysis. RESULTS: Of the 68 children included in the analysis, 34 were male, and the average age was 71.9 ± 26.4 months. The median period of hospitalization was 10.5 days (range, 0.5-75 days), and 36 children were allocated to group L. In the logistic regression model including age, gender, gastrointestinal (GI) bleeding, and use of glucocorticoid, male sex (OR: 4.2; 95%CI: 1.3-13.5) and GI bleeding (OR: 7.6; 95%CI: 1.4-41.5) were significantly associated with hospitalization ≥10 days. CONCLUSIONS: In children with IgA vasculitis, male patients and those with GI bleeding were more likely to have a hospital stay ≥10 days.

The iron-chelate transporter OsYSL9 plays a role in iron distribution in developing rice grains.

KEY MESSAGE: Rice OsYSL9 is a novel transporter for Fe(II)-nicotianamine and Fe(III)-deoxymugineic acid that is responsible for internal iron transport, especially from endosperm to embryo in developing seeds. Metal chelators are essential for safe and efficient metal translocation in plants. Graminaceous plants utilize specific ferric iron chelators, mugineic acid family phytosiderophores, to take up sparingly soluble iron from the soil. Yellow Stripe 1-Like (YSL) family transporters are responsible for transport of metal-phytosiderophores and structurally similar metal-nicotianamine complexes. Among the rice YSL family members (OsYSL) whose functions have not yet been clarified, OsYSL9 belongs to an uncharacterized subgroup containing highly conserved homologs in graminaceous species. In the present report, we showed that OsYSL9 localizes mainly to the plasma membrane and transports both iron(II)-nicotianamine and iron(III)-deoxymugineic acid into the cell. Expression of OsYSL9 was induced in the roots but repressed in the nonjuvenile leaves in response to iron deficiency. In iron-deficient roots, OsYSL9 was induced in the vascular cylinder but not in epidermal cells. Although OsYSL9-knockdown plants did not show a growth defect under iron-sufficient conditions, these plants were more sensitive to iron deficiency in the nonjuvenile stage compared with non-transgenic plants. At the grain-filling stage, OsYSL9 expression was strongly and transiently induced in the scutellum of the embryo and in endosperm cells surrounding the embryo. The iron concentration was decreased in embryos of OsYSL9-knockdown plants but was increased in residual parts of brown seeds. These results suggested that OsYSL9 is involved in iron translocation within plant parts and particularly iron translocation from endosperm to embryo in developing seeds.

Predictors of cognitive function in patients with hypothalamic hamartoma following stereotactic radiofrequency thermocoagulation surgery.

OBJECTIVE: To determine the predictors of cognitive function in patients with drug-resistant gelastic seizures (GS) related to hypothalamic hamartoma (HH) before and after stereotactic radiofrequency thermocoagulation surgery (SRT). METHODS: We studied 88 patients with HH who underwent SRT between October 1997 and December 2014. Patients received neuropsychological tests preoperatively and postoperatively. Based on the preoperative measures, patients were categorized as "high-functioning" (full-scale intelligence quotient [FSIQ] ≥70; n = 48) and "low-functioning" group (FSIQ <70; n = 40). Univariate and multivariate linear regression analyses determined the clinical, electroencephalography (EEG), and imaging factors associated with preoperative cognitive function as well as postoperative cognitive change. RESULTS: Eighty-seven patients (98.8%) were followed postoperatively for an average of 3.3 years, and 75 (85.2%) of them achieved GS remission at the last hospital visit. Neuropsychological performance was significantly improved after surgery in both groups. Multivariate linear regression analysis showed that a smaller HH size (p = 0.002) and a smaller number of antiepileptic drugs (p < 0.001) were preoperatively associated with better neuropsychological performance. Multivariate linear regression analysis showed that better postoperative improvement in cognition was associated with a shorter duration of epilepsy (p = 0.03). SIGNIFICANCE: Cognitive impairment related to epileptic encephalopathy may improve following SRT in substantial proportions of HH patients. Reduced improvement in postoperative cognitive function in patients with longer duration of epilepsy warrants further studies to determine if earlier SRT provides a greater chance of postoperative cognitive improvement in patients with HH.

Ca2+ -permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma.

Hypothalamic hamartoma (HH), composed of neurons and glia without apparent cytologic abnormalities, is a rare developmental malformation in humans. Patients with HH often have characteristic medically refractory gelastic seizures, and intrinsic epileptogenesis within the lesions has been speculated. Herein we provide evidence to suggest that in HH neurons, Ca2+ permeability through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is aberrantly elevated. In needle biopsy specimens of HH tissue, field potential recordings demonstrated spontaneous epileptiform activities similar to those observed in other etiologically distinct epileptogenic tissues. In HH, however, these activities were clearly abolished by application of Joro Spider Toxin (JSTX), a specific inhibitor of the Ca2+ -permeable AMPA receptor. Consistent with these physiologic findings, the neuronal nuclei showed disappearance of adenosine deaminase acting on RNA 2 (ADAR2) immunoreactivity. Furthermore, examination of glutamate receptor 2 (GluA2) messenger RNA (mRNA) revealed that editing efficiency at the glutamine/arginine site was significantly low. These results suggest that neurons in HH may bear Ca2+ -permeable AMPA receptors due to dislocation of ADAR2.

Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb.

OBJECTIVE: Focal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb. METHODS: We collected a total of 24 blood-brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole-exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments. RESULTS: We identified four lesion-specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. INTERPRETATION: We found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb.

Alternating zones selective to faces and written words in the human ventral occipitotemporal cortex.

Recognition of faces and written words is associated with category-specific brain activation in the ventral occipitotemporal cortex (vOT). However, topological and functional relationships between face-selective and word-selective vOT regions remain unclear. In this study, we collected data from patients with intractable epilepsy who underwent high-density recording of surface field potentials in the vOT. "Faces" and "letterstrings" induced outstanding category-selective responses among the 24 visual categories tested, particularly in high-γ band powers. Strikingly, within-hemispheric analysis revealed alternation of face-selective and letterstring-selective zones within the vOT. Two distinct face-selective zones located anterior and posterior portions of the mid-fusiform sulcus whereas letterstring-selective zones alternated between and outside of these 2 face-selective zones. Further, a classification analysis indicated that activity patterns of these zones mostly represent dedicated categories. Functional connectivity analysis using Granger causality indicated asymmetrically directed causal influences from face-selective to letterstring-selective regions. These results challenge the prevailing view that different categories are represented in distinct contiguous regions in the vOT.