Detection of thyrotropin binding inhibitory activity in neonatal blood spots

Recent studies have suggested that maternal TSH receptor-blocking antibodies might be of primary etiological importance in some cases of transient congenital hypothyroidism (CH). Because these antibodies are extremely potent, we evaluated the feasibility of identifying babies at risk by using readily available newborn blood spots. Blood spots obtained from 84 normal babies (group 1) and from 354 infants whose initial T4 was less than the tenth percentile for the assay and whose TSH was 40 mU/L or more (group 2) were studied without knowledge of the diagnosis. Blood was eluted from spots overnight and evaluated for [125I]TSH binding inhibition (TBI) to solubilized porcine thyroid membranes. Four spots obtained from 3 group 2 babies, but none of those from the group 1 infants, exhibited TBI activity greater than 3 SD above the normal mean (33.9%). Four additional hypothyroxinemic infants whose mothers had Graves\u27 disease were also negative. Subsequent follow-up revealed that all 3 positive babies had transient CH, and all 3 mothers had primary myxedema. Potent TBI activity was confirmed in the serum of all 3 mothers and in the 2 babies in whom it was evaluated at birth. We conclude that newborn blood spots can be used to detect potent maternal TBI activity, and that this identifies a baby likely to have transient, rather than permanent, CH. Because of their stability and ease of collection and handling, newborn blood spots should offer a convenient tool for future studies aimed at defining in more detail the incidence and clinical characteristics of this unique syndrome

Frasier syndrome: a cause of focal segmental glomerulosclerosis in a 46,XX female

The description of Frasier syndrome until now has been restricted to XY females with gonadal dysgenesis, progressive glomerulopathy, and a significant risk of gonadoblastoma. Mutations in the donor splice site in intron 9 of the Wilms\u27 tumor (WT1) gene have been shown to cause Frasier syndrome and are distinct from WT1 exon mutations associated with Denys-Drash syndrome. The WT1 gene, which is essential for normal kidney and gonadal development, encodes a zinc finger transcription factor. The intron 9 alternative splice donor site mutation seen in Frasier syndrome leads to loss of three amino acids (+KTS isoform), thus disrupting the normal ratio of the +KTS/-KTS isoforms critical for proper gonadal and renal development. This study examines two sisters with identical intron 9 mutations. The proband carries a classic diagnosis of Frasier syndrome with 46,XY gonadal dysgenesis, whereas her sister has progressive glomerulopathy but a 46,XX karyotype and normal female development. This indicates that the proper WT1 isoform ratio is critical for renal and testicular development, but apparently does not affect either ovarian development or function. It is proposed that the clinical definition of Frasier syndrome should be broadened to include 46,XX females with normal genital development and focal segmental glomerulosclerosis associated with a WT1 intron 9 donor splice site mutation. Nephrologists need to consider the possibility of this heritable syndrome in evaluation of females with focal segmental glomerulosclerosis and to consider their risk for gonadal malignancy, as well as the risk for kidney disease, gonadal dysgenesis, and malignancy in their offspring

Autosomal dominant hypoparathyroidism associated with short stature and premature osteoarthritis

Familial hypoparathyroidism is an unusual and genetically heterogeneous group of disorders that may be isolated or may be associated with congenital or acquired abnormalities in other organs or glands. We have evaluated a family with a novel syndrome of autosomal dominant hypoparathyroidism, short stature, and premature osteoarthritis. A 74-yr-old female (generation I) presented with hypoparathyroidism, a movement disorder secondary to ectopic calcification of the cerebellum and basal ganglia, and a history of knee and hip replacements for osteoarthritis. Two members of generation II and one member of generation III were also documented with hypoparathyroidism, short stature, and premature osteoarthritis evident as early as 11 yr. Because of the known association between autosomal dominant hypoparathyroidism and activating mutations of the calcium-sensing receptor (CaR) gene, further studies were performed. Sequencing of PCR-amplified genomic DNA revealed a leucine to valine substitution at position 616 in the first transmembrane domain of the CaR, which cosegregated with the disorder. However, this amino acid sequence change did not affect the total accumulation of inositol phosphates as a function of extracellular calcium concentrations in transfected HEK-293 cells. In conclusion, a sequence alteration in the coding region of the CaR gene was identified, but is not conclusively involved in the etiology of this novel syndrome. The cosegregation of hypoparathyroidism, short stature, and osteoarthritis in this kindred does suggest a genetic abnormality involving a common molecular mechanism in parathyroid, bone, and cartilage

Paralinguistic processing in children with callosal agenesis: emergence of neurolinguistic deficits

Recent research revealed impaired processing of both nonliteral meaning and affective prosody in adults with agenesis of the corpus callosum (ACC) and normal intelligence. Since normal children have incomplete myelination of the corpus callosum, it was hypothesized that paralanguage deficits in children with ACC would be less apparent relative to their peers. The Familiar and Novel Language Comprehension Test (FANL-C) and Prosody Test were given to 18 children with ACC and normal intelligence and 17 controls matched for age (7-13 years), education, and IQ (83-122). When controlling for age, children with ACC were significantly poorer in comprehension of the precise meaning of both literal and nonliteral items on the FANL-C. Adults with ACC had previously been shown to have difficulty only on nonliteral items. The effect size for nonliteral comprehension in children with ACC was smaller than that seen in adults. There was only a trend for the child ACC group to perform worse on the recognition of affective prosody. Thus, while deficits in paralinguistic processing were apparent, children with ACC were not as clearly different from age peers as adults, and were equally deficient at comprehending literal and nonliteral expressions. The differences in results between adults and children with ACC are thought to reflect incomplete callosal development in normal children, and the importance of the corpus callosum in the early stages of the development of the ability to process literal language

Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies

To determine the incidence of transient congenital hypothyroidism due to TSH receptor-blocking antibodies, we screened dried blood specimens obtained from 788 neonates identified as having possible congenital hypothyroidism (from a total population of 1,614,166 babies) and 121 controls. A RRA was used. The potency of blood spot TSH binding inhibitory activity was compared with the severity of congenital hypothyroidism to assess the possible etiological relationship. Maternal serum was studied to confirm the presence of blocking antibodies by both RRA and bioassay. Blood spots obtained from 9 infants contained potent TSH receptor-blocking activity. Samples from 2 additional babies, studied because of clinical suspicion of the disease, were also positive. Long term outcome was known in 8 of the 11 babies, and all had transient disease. Neonates with TSH receptor-blocking activity greater than 132 U/L had a significantly lower T4 level (P \u3c 0.05) and higher TSH (P \u3c 0.005) than those in whom TSH binding-inhibitory activity was less than 132 U/L. All 9 mothers had autoimmune thyroid disease, and 3 had more than 1 affected child. Potent blocking activity was present in 7 maternal serum samples as long as 7 yr after the births of their affected babies. We conclude that measurement of TSH binding-inhibitory activity in dried neonatal blood specimens is a simple and effective method to predict the occurrence of transient congenital hypothyroidism. The incidence of this disorder in North America is 1 in 180,000 normal infants, or approximately 2% of babies with congenital hypothyroidism

The merger-driven evolution of massive galaxies

We explore the rate and impact of galaxy mergers on the massive galaxy population using the amplitude of the two-point correlation function on small scales for M > 5e10 M_sun galaxies from the COSMOS and COMBO-17 surveys. Using a pair fraction derived from the Sloan Digital Sky Survey as a low-redshift benchmark, the large survey area at intermediate redshifts allows us to determine the evolution of the close pair fraction with unprecedented accuracy for a mass-selected sample: we find that the fraction of galaxies more massive than 5e10M_sun in pairs separated by less than 30 kpc in 3D space evolves as F(z) = (0.0130+/-0.0019)x(1+z)^1.21+/-0.25 between z = 0 and z = 1.2. Assuming a merger time scale of 0.5 Gyrs, the inferred merger rate is such that galaxies with mass in excess of 1e11 M_sun have undergone, on average, 0.5 (0.7) mergers involving progenitor galaxies both more massive than 5e10 M_sun since z = 0.6 (1.2). We also study the number density evolution of massive red sequence galaxies using published luminosity functions and constraints on the M/L evolution from the fundamental plane. Moreover, we demonstrate that the measured merger rate of massive galaxies is sufficient to explain this observed number density evolution in massive red sequence galaxies since z = 1.Comment: Accepted in Ap

Beauty surveillance: the digital self-monitoring cultures of neoliberalism

This paper argues that ‘beauty apps’ are transforming the arena of appearance politics and foregrounds a theoretical architecture for critically understanding them. Informed by a feminist-Foucaultian framework, it argues that beauty apps offer a technology of gender which brings together digital self-monitoring and postfeminist modalities of subjecthood to produce an hitherto unprecedented regulatory gaze upon women that is marked by the intensification, extensification and psychologization of surveillance. The paper is divided into four sections. First it introduces the literature on digital self-tracking. Secondly it sets out our understanding of neoliberalism and postfeminism. Thirdly it looks at beauty and surveillance, before offering, in the final section, a typology of appearance apps. This is followed by a discussion of the modes of address/authority deployed in these apps – especially what we call ‘surveillant sisterhood’ - and the kinds of entrepreneurial subjectivity they constitute. The paper seeks to make a contribution to feminist surveillance studies and argues that much more detailed research is needed to critically examine beauty apps

Topological relationships between perivascular spaces and progression of white matter hyperintensities:A pilot study in a sample of the Lothian Birth Cohort 1936

Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the associations and proposed mechanistic link between PVS and WMH, they are hypothesized to also have topological proximity. However, this and the influence of their spatial proximity on WMH progression are unknown. We analyzed longitudinal MRI data from 29 out of 32 participants (mean age at baseline = 71.9 years) in a longitudinal study of cognitive aging, from three waves of data collection at 3-year intervals, alongside semi-automatic segmentation masks for PVS and WMH, to assess relationships. The majority of deep WMH clusters were found adjacent to or enclosing PVS (waves−1: 77%; 2: 76%; 3: 69%), especially in frontal, parietal, and temporal regions. Of the WMH clusters in the deep white matter that increased between waves, most increased around PVS (waves−1–2: 73%; 2–3: 72%). Formal statistical comparisons of severity of each of these two SVD markers yielded no associations between deep WMH progression and PVS proximity. These findings may suggest some deep WMH clusters may form and grow around PVS, possibly reflecting the consequences of impaired interstitial fluid drainage via PVS. The utility of these relationships as predictors of WMH progression remains unclear

Relationship Between Venules and Perivascular Spaces in Sporadic Small Vessel Diseases

Background and Purpose— Perivascular spaces (PVS) around venules may help drain interstitial fluid from the brain. We examined relationships between suspected venules and PVS visible on brain magnetic resonance imaging. Methods— We developed a visual venular quantification method to examine the spatial relationship between venules and PVS. We recruited patients with lacunar stroke or minor nondisabling ischemic stroke and performed brain magnetic resonance imaging and retinal imaging. We quantified venules on gradient echo or susceptibility-weighted imaging and PVS on T2-weighted magnetic resonance imaging in the centrum semiovale and then determined overlap between venules and PVS. We assessed associations between venular count and patient demographic characteristics, vascular risk factors, small vessel disease features, retinal vessels, and venous sinus pulsatility. Results— Among 67 patients (69% men, 69.0±9.8 years), only 4.6% (range, 0%–18%) of venules overlapped with PVS. Total venular count increased with total centrum semiovale PVS count in 55 patients after accounting for venule-PVS overlap (β=0.468 [95% CI, 0.187–0.750]) and transverse sinus pulsatility (β=0.547 [95% CI, 0.309–0.786]) and adjusting for age, sex, and systolic blood pressure. Conclusions— Despite increases in both visible PVS and suspected venules, we found minimal spatial overlap between them in patients with sporadic small vessel disease, suggesting that most magnetic resonance imaging-visible centrum semiovale PVS are periarteriolar rather than perivenular

Circadian and Brain State Modulation of Network Hyperexcitability in Alzheimer’s Disease

Abstract Network hyperexcitability is a feature of Alzheimer’ disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (hAPP) (J20), to a knock-in model expressing APP at physiological levels (APPNL/F). We recorded continuous long-term electrocorticogram (ECoG) activity from mice, and studied modulation by circadian cycle, behavioral, and brain state. We report that while J20s exhibit frequent interictal spikes (IISs), APPNL/F mice do not. In J20 mice, IISs were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM (NREM) sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD