Genotype-Phenotype Correlations in Thirty Japanese Patients with Congenital Hypothyroidism Attributable to TG Defects.

CONTEXT: Thyroglobulin (Tg), encoded by TG, is essential for thyroid hormone synthesis. TG defects result in congenital hypothyroidism (CH). Most reported patients were born before the introduction of newborn screening (NBS). OBJECTIVE: We aimed to clarify the phenotypic features of patients with TG defects diagnosed and treated since the neonatal period. SUBJECTS AND METHODS: We screened 1061 patients with CH for thirteen CH-related genes and identified thirty patients with TG defects. One patient was diagnosed due to hypothyroidism-related symptoms and the rest were diagnosed via NBS. Patients were divided into two groups according to their genotypes, and clinical characteristics were compared. We evaluated the functionality of the seven missense variants using HEK293 cells. RESULTS: Twenty-seven rare TG variants were detected, including fifteen nonsense, three frameshift, two splice-site, and seven missense variants. Patients were divided into two groups: thirteen patients with biallelic truncating variants and seventeen patients with monoallelic/biallelic missense variants. Patients with missense variants were more likely to develop thyroid enlargement with TSH stimulation than patients with biallelic truncating variants. Patients with biallelic truncating variants invariably required full hormone replacement, whereas patients with missense variants required variable doses of levothyroxine. Loss of function of the seven missense variants was confirmed in vitro. CONCLUSION: To our knowledge, this is the largest investigation on the clinical presentation of TG defects diagnosed in the neonatal period. Patients with missense variants showed relatively mild hypothyroidism with compensative goiter. Patients with only truncating variants showed minimal or no compensative goiter and required full hormone replacement.

Human Stiffness Perception and Learning in Interacting With Compliant Environments.

Humans are capable of adjusting their posture stably when interacting with a compliant surface. Their whole-body motion can be modulated in order to respond to the environment and reach to a stable state. In perceiving an uncertain external force, humans repetitively push it and learn how to produce a stable state. Research in human motor control has led to the hypothesis that the central nervous system integrates an internal model with sensory feedback in order to generate accurate movements. However, how the brain understands external force through exploration movements, and how humans accurately estimate a force from their experience of the force, is yet to be fully understood. To address these questions, we tested human behaviour in different stiffness profiles even though the force at the goal was the same. We generated one linear and two non-linear stiffness profiles, which required the same force at the target but different forces half-way to the target; we then measured the differences in the learning performance at the target and the differences in perception at the half-way point. Human subjects learned the stiffness profile through repetitive movements in reaching the target, and then indicated their estimation of half of the target value (position and force separately). This experimental design enabled us to probe how perception of the force experienced in different profiles affects the participants' estimations. We observed that the early parts of the learning curves were different for the three stiffness profiles. Secondly, the position estimates were accurate independent of the stiffness profile. The estimation in position was most likely influenced by the external environment rather than the profile itself. Interestingly, although visual information about the target had a large influence, we observed significant differences in accuracy of force estimation according to the stiffness profile.

What kind of network is the brain?

The different areas of the cerebral cortex are linked by a network of white matter, comprising the myelinated axons of pyramidal cells. Is this network a neural net, in the sense that representations of the world are embodied in the structure of the net, its pattern of nodes, and connections? Or is it a communications network, where the same physical substrate carries different information from moment to moment? This question is part of the larger question of whether the brain is better modeled by connectionism or by symbolic artificial intelligence (AI), but we review it in the specific context of the psychophysics of stimulus comparison and the format and protocol of information transmission over the long-range tracts of the brain.

An infant with X-linked anhidrotic ectodermal dysplasia with immunodeficiency presenting with Pneumocystis pneumonia: A case report.

Pneumocystis jirovecii pneumonia associated with primary immunodeficiency should be considered in infants with slowly progressing cyanosis, even without fever or respiratory symptoms. Genetic counseling is crucial for incontinentia pigmenti families in advance of pregnancy because lethal infections can occur before the diagnosis of X-linked anhidrotic ectodermal dysplasia with immunodeficiency.

Chromosomal copy number analysis of products of conception by conventional karyotyping and next-generation sequencing.

PURPOSE: Chromosomal abnormalities are a major cause of spontaneous abortion, and conventional G-banded karyotyping (G-banding) is mainly utilized for chromosomal analysis. Recently, next-generation sequencing (NGS) has been introduced for chromosomal analysis. Here, we aimed to investigate the applicability and utility of NGS-based chromosomal analysis of products of conception (POC) on chorionic villus samples from spontaneous abortion. METHODS: The results of chromosomal analysis of 7 chorionic villus samples from spontaneous abortion were compared between conventional G-banding and NGS-based chromosomal copy number analysis. Age dependency and frequency of each chromosomal aneuploidy were evaluated for 279 cases analyzed by NGS. RESULTS: Excluding two cases (culture failure and maternal cell contamination), the results were consistent between G-banding and NGS. For cases analyzed by NGS, the rate of chromosomal abnormality increased in a maternal age-dependent manner. The frequency of each chromosomal aneuploidy detected by NGS was almost the same as that previously reported. Finally, NGS analysis was possible for difficult cases by G-banding analysis, such as culture failure, maternal cell contamination, long-term storage cases, and low cell number. CONCLUSIONS: Chromosome analysis using NGS not only obtains comparable results to conventional G-banding, but also can analyze POC more accurately and efficiently.

Separation in the visual field has divergent effects on discriminating the speed and the direction of motion.

Local motion in a visual scene allows the detection of prey or predator and predicts their future positions. Relative motion segregates objects and reveals their 3D relationships. 'Optic flow' - the motion of texture across the field - guides locomotion and balance. Given these several uses of visually perceived motion, it is unsurprising that many species have evolved hard-wired neural mechanisms to extract motion as a primitive feature of the visual world [1]. In the cortex (e.g. [2-4]), and even the retina [5], of primates, cells are found that respond selectively according to direction of motion. In visual areas V1 and MT, some directionally selective cells are also tuned for the second attribute of motion, speed [3]. It might be thought that the brain derives a single velocity signal from the activity in this population of neurons - since speed and direction must often be combined to predict an object's future position or to derive a 3D structure. However, we report here a striking difference in discrimination of the two attributes: Thresholds for direction, but not those for speed, increase with the spatial separation of the stimuli.

Rituximab-induced serum sickness in a 6-year-old boy with steroid-dependent nephrotic syndrome.

Rituximab (RTX) is a murine-human chimeric monoclonal antibody against CD20 that has been proven effective for preventing relapse in frequently-relapsing or steroid-dependent nephrotic syndrome (NS). Serum sickness, a type-3 hypersensitivity reaction resulting from injection of foreign proteins, has been reported in patients treated with RTX. Herein, we describe a case of RTX-induced serum sickness (RISS) in a 6-year-old boy with steroid-dependent NS. He presented to the hospital with fever and polyarthralgia at 10 days after his fourth dose of RTX. Although he was started on empiric intravenous antibiotics, there was no evidence of septic arthritis and his symptoms resolved over the course of 4 days. He was diagnosed with RISS based on the chronology of RTX administration and the acute-onset self-limiting course of the polyarthritis. His serum human anti-chimeric antibody (HACA) level on day 53 exceeded the limit of quantification (5000 ng/mL). The pathogenesis of RISS and the role of HACAs remain unclear. It is important for clinicians to recognize RISS, because further infusions of RTX may cause more severe reactions in patients with a history of RISS.

Evidence for distinct clusters of diverse anomalous experiences and their selective association with signs of elevated cortical hyperexcitability.

Visual cortical hyperexcitability is now known to be an underlying factor for aberrant visual experience, including hallucinations, and pattern or light induced visual discomfort. Such factors have also been observed in neurological and non-clinical groups (albeit in attenuated form) - consistent with the notion of a continuum of anomalous experiences. Utilizing an exploratory factor analysis (EFA) approach (n = 300), Study 1 developed a revised proxy screening measure for visual cortical hyperexcitability - the Cortical Hyperexcitability index - II(CHi-II). The EFA revealed a stable 3-factor solution which can be characterised as; (i) Heightened Visual Sensitivity and Discomfort (HVSD); (ii) Aura-like Hallucinatory Experience (AHE); and, (iii) Distorted Visual Perception (DVP). Study 2 tested both a self-reported migraine group and a control group on the CHi-II in conjunction with a computerised pattern-glare task that is known to reflect visual cortical hyperexcitability. The migraine group produced significantly elevated scores on both the AHE and HVSD factors of the CHi-II, relative to controls. Among the non-migraine group, subjects who scored higher in the pattern-glare task also produced significantly elevated scores on the AHE factor compared to those with low pattern-glare task scores. Collectively, these findings support the utility of the CHi-II as an indirect proxy measure for signs of cortical hyperexcitability and reveal new categorical distinctions for the nature of the anomalous perceptions. These perceptions may well reflect diverse neurocognitive underpinnings leading to advancements in our understanding of aberrations in conscious experience.

Novel DHCR7 mutation in a case of Smith-Lemli-Opitz syndrome showing 46,XY disorder of sex development.

Smith-Lemli-Opitz syndrome is an autosomal recessive disease caused by mutations in 7-dehydrocholesterol reductase (DHCR7), which is rarely observed in Japan. We report a Japanese case with 46,XY disorder of sex development and Y-shaped 2-3 toe syndactyly. DHCR7 gene analysis revealed compound heterozygous mutations including the novel mutation H442R. Early diagnosis led to starting cholesterol treatment at an early age.

Optimal visual-haptic integration with articulated tools.

When we feel and see an object, the nervous system integrates visual and haptic information optimally, exploiting the redundancy in multiple signals to estimate properties more precisely than is possible from either signal alone. We examined whether optimal integration is similarly achieved when using articulated tools. Such tools (tongs, pliers, etc) are a defining characteristic of human hand function, but complicate the classical sensory 'correspondence problem' underlying multisensory integration. Optimal integration requires establishing the relationship between signals acquired by different sensors (hand and eye) and, therefore, in fundamentally unrelated units. The system must also determine when signals refer to the same property of the world-seeing and feeling the same thing-and only integrate those that do. This could be achieved by comparing the pattern of current visual and haptic input to known statistics of their normal relationship. Articulated tools disrupt this relationship, however, by altering the geometrical relationship between object properties and hand posture (the haptic signal). We examined whether different tool configurations are taken into account in visual-haptic integration. We indexed integration by measuring the precision of size estimates, and compared our results to optimal predictions from a maximum-likelihood integrator. Integration was near optimal, independent of tool configuration/hand posture, provided that visual and haptic signals referred to the same object in the world. Thus, sensory correspondence was determined correctly (trial-by-trial), taking tool configuration into account. This reveals highly flexible multisensory integration underlying tool use, consistent with the brain constructing internal models of tools' properties.

Stimulating the aberrant brain: Evidence for increased cortical hyperexcitability from a transcranial direct current stimulation (tDCS) study of individuals predisposed to anomalous perceptions.

Findings from neurological and clinical groups have shown that increased predisposition to anomalous experience/aura reflects an elevation in aberrant neural processes in the brain. However, studies of anomalous experiences in non-clinical/non-neurological groups are less clear on this matter and are more typically confined to subjective questionnaire measures alone. The current investigation, the first to our knowledge, carried out a transcranial Direct Current Stimulation (tDCS) study of cortical hyperexcitability, and its association with anomalous experience in non-clinical/non-neurological groups. Sixty participants completed; (i) both excitatory (anodal) and inhibitory (cathodal) brain stimulation conditions of the visual cortex; (ii) a computerised pattern-glare task, where observers reported phantom visual distortions from viewing highly irritable visual patterns (a metric of cortical hyperexcitability), and; (iii) questionnaire measures of predisposition to anomalous perceptions. There were no reliable signs of cortical hyperexcitability (via pattern-glare tasks) when collapsed across the whole sample. However, a significant positive correlation between predisposition to anomalous experience and elevated signs of cortical hyperexcitability was observed. Crucially, there was a significant negative correlation between tDCS stimulatory conditions. A visual cortex that reacted more strongly to excitatory stimulation, responded less well to inhibitory suppression, and this pattern was related to predisposition to anomalous perceptions. Both findings are consistent with the presence of a hyperexcitable cortex. Collectively the present findings provide objective evidence that the brains of individuals predisposed to anomalous experiences/hallucinations can be hyperexcitable - even in the non-clinical/non-neurological population. These data are consistent with continuum models of anomalous experience and have important implications for contemporary theories of aberrations in self-consciousness.

The Cortical Hyperexcitability Index (CHi): a new measure for quantifying correlates of visually driven cortical hyperexcitability.

INTRODUCTION: Aberrations of visual experience, including visual hallucinations and visual distortions, are known to be associated with increased cortical hyperexcitability. As a consequence, the presence, intensity and frequency of certain experiences may well be indicative of an underlying increase in cortical hyperexcitability. METHODS: The current study presents a new proxy measure of cortical hyperexcitability, the Cortical Hyperexcitability Index (CHi). Two hundred and fifty healthy participants completed the CHi with the results subjected to exploratory factor analysis (EFA). RESULTS: The EFA revealed a three-factor model as the most parsimonious solution. The three factors were defined as: (1) heightened visual sensitivity and discomfort; (2) negative aura-type visual aberrations; and (3) positive aura-type visual aberrations. The identification of three factors suggests that multiple mechanisms underlie the notion of cortical hyperexcitability, providing researchers with new and greater precision in delineating these underlying features. CONCLUSIONS: The factorial structure of the CHi and the increased precision could aid the interpretation of findings from neuroscientific (i.e., brain imaging/stimulation) examinations of cortical processes underlying aberrant perceptions across a host of clinical, neurological and pathological conditions. As a consequence, the CHi is a useful and comprehensive proxy measure of cortical hyperexcitability with considerable scientific and clinical utility.

[The investigation of understanding and comfort of patients taking Divigel(®) 1 mg].

Hormone replacement therapy (HRT) given by injection or administered orally or topically can improve the QOL of patients with menopausal symptoms. Because patient comfort is influenced largely by the dosage form, pharmacists should understand the properties of each dosage form and provide appropriate information to individual patients. In this study, we investigated the understanding of medicines and diseases of patients receiving HRT and discuss the approaches pharmacists can take to improve patients' adherence. Thirty-seven patients (mean age 51.7±3.6 years) taking estradiol gel (Divigel(®) 1 mg) completed a questionnaire asked by their pharmacist. Responses indicated 70% of patients failed to use the gel as prescribed, and they had poor knowledge of both the sites where the gel shouldn't be applied and appropriate measures to take if having forgotten to apply the gel (43% and 11% correct understanding, respectively). Since the duration of HRT treatment for menopausal symptom is 2-5 years, patients should be administered the minimum effective dose in the shortest amount of time. Hence it is important to maintain patients' adherence particularly in this limited administration period. HRT guidelines define HRT outcome as not only improvement of menopausal symptoms but also suppression of bone resorption, improvement of glucose and lipid metabolism, and reduced prevalence of Alzheimer's disease. Accordingly, pharmacists should facilitate proper adherence to HRT to improve and maintain women's QOL in the perimenopausal period, necessitating they actively provide pharmaceutical care such as preparing useful instructions patients can repeatedly use and periodically checking patients' understanding of their HRT medications.

Visual-haptic integration with pliers and tongs: signal "weights" take account of changes in haptic sensitivity caused by different tools.

When we hold an object while looking at it, estimates from visual and haptic cues to size are combined in a statistically optimal fashion, whereby the "weight" given to each signal reflects their relative reliabilities. This allows object properties to be estimated more precisely than would otherwise be possible. Tools such as pliers and tongs systematically perturb the mapping between object size and the hand opening. This could complicate visual-haptic integration because it may alter the reliability of the haptic signal, thereby disrupting the determination of appropriate signal weights. To investigate this we first measured the reliability of haptic size estimates made with virtual pliers-like tools (created using a stereoscopic display and force-feedback robots) with different "gains" between hand opening and object size. Haptic reliability in tool use was straightforwardly determined by a combination of sensitivity to changes in hand opening and the effects of tool geometry. The precise pattern of sensitivity to hand opening, which violated Weber's law, meant that haptic reliability changed with tool gain. We then examined whether the visuo-motor system accounts for these reliability changes. We measured the weight given to visual and haptic stimuli when both were available, again with different tool gains, by measuring the perceived size of stimuli in which visual and haptic sizes were varied independently. The weight given to each sensory cue changed with tool gain in a manner that closely resembled the predictions of optimal sensory integration. The results are consistent with the idea that different tool geometries are modeled by the brain, allowing it to calculate not only the distal properties of objects felt with tools, but also the certainty with which those properties are known. These findings highlight the flexibility of human sensory integration and tool-use, and potentially provide an approach for optimizing the design of visual-haptic devices.

Fractionating the unitary notion of dissociation: disembodied but not embodied dissociative experiences are associated with exocentric perspective-taking.

It has been argued that hallucinations which appear to involve shifts in egocentric perspective (e.g., the out-of-body experience, OBE) reflect specific biases in exocentric perspective-taking processes. Via a newly devised perspective-taking task, we examined whether such biases in perspective-taking were present in relation to specific dissociative anomalous body experiences (ABE) - namely the OBE. Participants also completed the Cambridge Depersonalization Scale (CDS; Sierra and Berrios, 2000) which provided measures of additional embodied ABE (unreality of self) and measures of derealization (unreality of surroundings). There were no reliable differences in the level of ABE, emotional numbing, and anomalies in sensory recall reported between the OBE and control group as measured by the corresponding CDS subscales. In contrast, the OBE group did provide significantly elevated measures of derealization ("alienation from surroundings" CDS subscale) relative to the control group. At the same time we also found that the OBE group was significantly more efficient at completing all aspects of the perspective-taking task relative to controls. Collectively, the current findings support fractionating the typically unitary notion of dissociation by proposing a distinction between embodied dissociative experiences and disembodied dissociative experiences - with only the latter being associated with exocentric perspective-taking mechanisms. Our findings - obtained with an ecologically valid task and a homogeneous OBE group - also call for a re-evaluation of the relationship between OBEs and perspective-taking in terms of facilitated disembodied experiences.

Signs of increased cortical hyperexcitability selectively associated with spontaneous anomalous bodily experiences in a nonclinical population.

INTRODUCTION: The current study examined the presence of cortical hyperexcitability, in nonclinical hallucinators, reporting different forms of anomalous bodily experiences (ABEs). Groups reporting visual out-of-body experiences and nonvisual sensed-presence experiences were examined. It was hypothesised that only those hallucinators whose experiences contained visual elements would show increased signs of visual cortical hyperexcitability. METHODS: One hundred and eighty-two participants completed the "Pattern-glare task" (involving the viewing of striped gratings with spatial frequencies irritable to visual cortex)-a task known to reflect degrees of cortical hyperexcitability associated with hallucinatory/aura experiences in neurological samples. Participants also completed questionnaire measures of anomalous "temporal-lobe experience" and predisposition to anomalous visual experiences. RESULTS: Those reporting increased levels of anomalous bodily experiences provided significantly elevated scores on measures of temporal-lobe experience. Only the visual OBE group reported significantly elevated levels of cortical hyperexcitability as assessed by the pattern-glare task. CONCLUSIONS: Collectively, the results are consistent with there being an increased degree of background cortical hyperexcitability in the cortices of individuals predisposed to some ABE-type hallucinations, even in the nonclinical population. The present study also establishes the clinical utility of the pattern-glare task for examining signs of aberrant visual connectivity in relation to visual hallucinations.

Hyaluronan-enriched transfer medium improves outcome in patients with multiple embryo transfer failures.

PURPOSE: To ascertain whether the use of hyaluronan-enriched transfer medium (HETM) improves pregnancy and implantation rates among embryo transfer patients with a history of multiple implantation failures. METHODS: Patients (n = 314) under the age of 40 and with a history of multiple unsuccessful embryo transfers were enrolled. There were three groups of patients: those undergoing fresh embryo transfer (fresh ET [n = 111]), those undergoing vitrified-warmed ET in the natural cycle (WET-N [n = 101]) and those undergoing WET in a hormone replacement cycle (WET-H [n = 102]). On the day of ET, patients were randomized to HETM (0.5 mg/ml hyaluronan) or control medium containing no hyaluronan. Only patients with good quality embryos on day 3 were included. RESULTS: For all three patients groups (fresh ET, WET-N and WET-H) pregnancy rates (37.5 %, 31.4 % and 41.2 %, respectively) were significantly higher when using HETM compared with control medium (10.9 %, 10.0 % and 15.7 %, respectively; p < 0.05), and implantation rates when using HETM were also significantly higher compared with control medium (p < 0.05). Miscarriage rates were similar in both groups. CONCLUSION: HETM significantly increased pregnancy and implantation rates among embryo transfer patients with a history of multiple unsuccessful implantations-regardless of method used to prepare the endometrium.

A programmed schedule of oocyte retrieval using mild ovarian stimulation (clomiphene citrate and recombinant follicle-stimulating hormone).

PURPOSE: The purpose was to establish a mild ovarian stimulation protocol that would help assisted reproductive technology (ART) units to avoid scheduling on weekends. METHODS: This protocol directed patients to take 50 mg/day of clomiphene citrate between days 3 and 7 of the menstrual cycle: 225 IU of recombinant follicle-stimulating hormone (rec-FSH) were administered on days 3, 5 and 7; human chorionic gonadotropin (hCG) was administered on day 9; and, oocyte pick-up (OPU) was planned for day 11. From October 2008 through October 2009, 514 women underwent ART treatment with mild stimulation at the Sugiyama Clinic, and we evaluated whether OPU was accomplished on the planned day. RESULTS: Of all the treatment cycles, 419 (81.5%) underwent OPU on day 11 (scheduled group). Additional rec-FSH administration was needed in 83 cycles, in which case OPU was performed on day 12 or later. In 12 cycles, OPU was canceled. The unscheduled group (n = 95) consisted of delayed OPU cycles and canceled cycles. Of all treatment cycles, 332 cycles in the scheduled group and 68 cycles in the unscheduled group underwent embryo transfer, with 81 and 16, respectively, resulting in pregnancies. CONCLUSIONS: Using this protocol, OPU was performed on the scheduled day in about 80% of the cycles. Most weekend scheduling of OPU can be avoided using this mild stimulation.