Hypothalamic disease in craniopharyngioma patients.

Craniopharyngioma (CP) patients suffer from high rates of morbidity and mortality. The aim of this study was to describe hypothalamic morbidityand establish the standardised mortality ratio for CP patients attendingthe national neurosurgical unit in Ireland; to investigate abnormalities ofthirst, sleep disorders and somnolence, glucose tolerance and abnormalhormonal responses to food intake, in CP patients. The standardised mortality ratio for craniopharyngioma patients in this study was 8.75, with a predominance of deaths due to cardiovascular andrespiratory disease. Over 80% of CP patients had panhypopituitarism, including diabetes insipidus. Four patients with diabetes insipidus had adipsia, which is associated in the published literature with increased morbidity and mortality. Tumour recurrence ocurred in 46%, and hydrocephalus was diagnosed in 40% of CPs. Sixty-six percent of CPs were obese and 26% were overweight. Seventy-one percent of CP patients suffered from somnolence and 46%were diagnosed with sleep apnoea; thus not all somnolence in CP wasexplained by sleep apnoea. Somnolence responded to treatment with continuous positive airway pressure therapy or modafinil. Abnormal glucose tolerance was identified in 40% of CP patients, who were insulin resistant and obese or overweight. The CP patients with abnormal glucose tolerance were older when diagnosed with CP than those with normal glucose tolerance. CP patients had similar ghrelin levels to normal weight controls, which suggested that excess ghrelin was not the explanation for obesity in CP. However serum ghrelin levels in CP patients suppressed after food ingestion and were lower in patients with apnoea than in those without apnoea, which suggested that the hypothalamus remained sensitive to ghrelin signalling. This study confirms the previous reports of high rates of morbidity and mortality in CP patients and identifies new targets for treatment of morbidity, such as dysnatraemia, somnolence and abnormal glucose tolerance

Deletion in chromosome 6 spanning alpha-synuclein and multimerin1 loci in the Rab27a/b double knockout mouse

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Pattanayak, R., Underwood, R., Crowley, M. R., Crossman, D. K., Morgan, J. R., & Yacoubian, T. A. Deletion in chromosome 6 spanning alpha-synuclein and multimerin1 loci in the Rab27a/b double knockout mouse. Scientific Reports, 12(1), (2022): 9837, https://doi.org/10.1038/s41598-022-13557-8.We report an incidental 358.5 kb deletion spanning the region encoding for alpha-synuclein (αsyn) and multimerin1 (Mmrn1) in the Rab27a/Rab27b double knockout (DKO) mouse line previously developed by Tolmachova and colleagues in 2007. Western blot and RT-PCR studies revealed lack of αsyn expression at either the mRNA or protein level in Rab27a/b DKO mice. PCR of genomic DNA from Rab27a/b DKO mice demonstrated at least partial deletion of the Snca locus using primers targeted to exon 4 and exon 6. Most genes located in proximity to the Snca locus, including Atoh1, Atoh2, Gm5570, Gm4410, Gm43894, and Grid2, were shown not to be deleted by PCR except for Mmrn1. Using whole genomic sequencing, the complete deletion was mapped to chromosome 6 (60,678,870–61,037,354), a slightly smaller deletion region than that previously reported in the C57BL/6J substrain maintained by Envigo. Electron microscopy of cortex from these mice demonstrates abnormally enlarged synaptic terminals with reduced synaptic vesicle density, suggesting potential interplay between Rab27 isoforms and αsyn, which are all highly expressed at the synaptic terminal. Given this deletion involving several genes, the Rab27a/b DKO mouse line should be used with caution or with appropriate back-crossing to other C57BL/6J mouse substrain lines without this deletion.This study was supported by NIH [R56NS115767 (TAY), RF1NS115767-01A1 (TAY), P50NS108675 (TAY), and NINDS/NIA RF1NS078165 (JRM)]

Hepatic and adipose phenotype in Alström syndrome

BACKGROUND AND AIMS: Alström syndrome (AS) is a recessive monogenic syndrome characterized by obesity, extreme insulin resistance and multi-organ fibrosis. Despite phenotypically being high risk of non-alcoholic fatty liver disease (NAFLD), there is a lack of data on the extent of fibrosis in the liver and its close links to adipose in patients with AS. Our aim was to characterize the hepatic and adipose phenotype in patients with AS. METHODS: Observational cohort study with comprehensive assessment of metabolic liver phenotype including liver elastography (Fibroscan® ), serum Enhanced Liver Fibrosis (ELF) Panel and liver histology. In addition, abdominal adipose histology and gene expression was assessed. We recruited 30 patients from the UK national AS clinic. A subset of six patients underwent adipose biopsies which was compared with control tissue from nine healthy participants. RESULTS: Patients were overweight/obese (BMI 29.3 (25.95-34.05) kg/m2 ). A total of 80% (24/30) were diabetic; 74% (20/27) had liver ultrasound scanning suggestive of NAFLD. As judged by the ELF panel, 96% (24/25) were categorized as having fibrosis and 10/21 (48%) had liver elastography consistent with advanced liver fibrosis/cirrhosis. In 7/8 selected cases, there was evidence of advanced NAFLD on liver histology. Adipose tissue histology showed marked fibrosis as well as disordered pro-inflammatory and fibrotic gene expression profiles. CONCLUSIONS: NAFLD and adipose dysfunction are common in patients with AS. The severity of liver disease in our cohort supports the need for screening of liver fibrosis in AS.Alström UKThis is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/liv.1316

Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome : the utility of serum androstenedione

CONTEXT: Polycystic ovary syndrome (PCOS) is a triad of anovulation, insulin resistance, and hyperandrogenism. Androgen excess may correlate with metabolic risk and PCOS consensus criteria define androgen excess on the basis of serum T. Here we studied the utility of the androgen precursor serum androstenedione (A) in conjunction with serum T for predicting metabolic dysfunction in PCOS. PATIENTS AND METHODS: Eighty-six PCOS patients fulfilling Rotterdam diagnostic consensus criteria and 43 age- and body mass index-matched controls underwent measurement of serum androgens by tandem mass spectrometry and an oral glucose tolerance test with homeostatic model assessment of insulin resistance and insulin sensitivity index calculation. We analyzed 24-hour urine androgen excretion by gas chromatography/mass spectrometry. RESULTS: PCOS patients had higher levels of serum androgens and urinary androgen metabolites than controls (all P < .001). Within the PCOS cohort, both serum A and T were positively correlated with the free androgen index (T × 100/SHBG) and total androgen metabolite excretion (all P < .001). All subjects with T above the normal reference range [high T (HT)] also had high A (HA/HT group, n = 56). However, the remaining 30 patients had normal T levels, either in the presence of HA (HA/NT; n = 20) or normal A (NA/NT; n = 10). The groups did not differ in age or BMI. The HA/HT and HA/NT groups had higher total androgen excretion than NA/NT (P < .01 and P < .05, respectively). Multiple linear regression showed a strong negative association between serum androstenedione and insulin sensitivity. The incidence of dysglycemia according to an oral glucose tolerance test increased with the severity of androgen phenotype (NA/NT, 0%; HA/NT, 14%; HA/HT, 25%, P = .03). CONCLUSION: Simultaneous measurement of serum T and A represents a useful tool for predicting metabolic risk in PCOS women. HA levels are a sensitive indicator of PCOS-related androgen excess

Increased central adiposity and decreased subcutaneous adipose tissue 11β-hydroxysteroid dehydrogenase type 1 are associated with deterioration in glucose tolerance-A longitudinal cohort study

Objective and Context. Increasing adiposity, ageing and tissue‐specific regeneration of cortisol through the activity of 11β‐hydroxysteroid dehydrogenase type 1 have been associated with deterioration in glucose tolerance. We undertook a longitudinal, prospective clinical study to determine if alterations in local glucocorticoid metabolism track with changes in glucose tolerance. Design, Patients, and Measurements. Sixty‐five overweight/obese individuals (mean age 50.3 ± 7.3 years) underwent oral glucose tolerance testing, body composition assessment, subcutaneous adipose tissue biopsy and urinary steroid metabolite analysis annually for up to 5 years. Participants were categorized into those in whom glucose tolerance deteriorated (“deteriorators”) or improved (“improvers”). Results. Deteriorating glucose tolerance was associated with increasing total and trunk fat mass and increased subcutaneous adipose tissue expression of lipogenic genes. Subcutaneous adipose tissue 11β‐HSD1 gene expression decreased in deteriorators, and at study completion, it was highest in the improvers. There was a significant negative correlation between change in area under the curve glucose and 11β‐HSD1 expression. Global 11β‐HSD1 activity did not change and was not different between deteriorators and improvers at baseline or follow‐up. Conclusion. Longitudinal deterioration in metabolic phenotype is not associated with increased 11β‐HSD1 activity, but decreased subcutaneous adipose tissue gene expression. These changes may represent a compensatory mechanism to decrease local glucocorticoid exposure in the face of an adverse metabolic phenotype

The Atacama Cosmology Telescope: A Measurement of the DR6 CMB Lensing Power Spectrum and its Implications for Structure Growth

We present new measurements of cosmic microwave background (CMB) lensing over $9400$ sq. deg. of the sky. These lensing measurements are derived from the Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB dataset, which consists of five seasons of ACT CMB temperature and polarization observations. We determine the amplitude of the CMB lensing power spectrum at $2.3\%$ precision ($43\sigma$ significance) using a novel pipeline that minimizes sensitivity to foregrounds and to noise properties. To ensure our results are robust, we analyze an extensive set of null tests, consistency tests, and systematic error estimates and employ a blinded analysis framework. The baseline spectrum is well fit by a lensing amplitude of $A_{\mathrm{lens}}=1.013\pm0.023$ relative to the Planck 2018 CMB power spectra best-fit $\Lambda$CDM model and $A_{\mathrm{lens}}=1.005\pm0.023$ relative to the $\text{ACT DR4} + \text{WMAP}$ best-fit model. From our lensing power spectrum measurement, we derive constraints on the parameter combination $S^{\mathrm{CMBL}}_8 \equiv \sigma_8 \left({\Omega_m}/{0.3}\right)^{0.25}$ of $S^{\mathrm{CMBL}}_8= 0.818\pm0.022$ from ACT DR6 CMB lensing alone and $S^{\mathrm{CMBL}}_8= 0.813\pm0.018$ when combining ACT DR6 and Planck NPIPE CMB lensing power spectra. These results are in excellent agreement with $\Lambda$CDM model constraints from Planck or $\text{ACT DR4} + \text{WMAP}$ CMB power spectrum measurements. Our lensing measurements from redshifts $z\sim0.5$--$5$ are thus fully consistent with $\Lambda$CDM structure growth predictions based on CMB anisotropies probing primarily $z\sim1100$. We find no evidence for a suppression of the amplitude of cosmic structure at low redshiftsComment: 45+21 pages, 50 figures. Prepared for submission to ApJ. Also see companion papers Madhavacheril et al and MacCrann et a

The Atacama Cosmology Telescope: High-resolution component-separated maps across one-third of the sky

Observations of the millimeter sky contain valuable information on a number of signals, including the blackbody cosmic microwave background (CMB), Galactic emissions, and the Compton-$y$ distortion due to the thermal Sunyaev-Zel'dovich (tSZ) effect. Extracting new insight into cosmological and astrophysical questions often requires combining multi-wavelength observations to spectrally isolate one component. In this work, we present a new arcminute-resolution Compton-$y$ map, which traces out the line-of-sight-integrated electron pressure, as well as maps of the CMB in intensity and E-mode polarization, across a third of the sky (around 13,000 sq.~deg.). We produce these through a joint analysis of data from the Atacama Cosmology Telescope (ACT) Data Release 4 and 6 at frequencies of roughly 93, 148, and 225 GHz, together with data from the \textit{Planck} satellite at frequencies between 30 GHz and 545 GHz. We present detailed verification of an internal linear combination pipeline implemented in a needlet frame that allows us to efficiently suppress Galactic contamination and account for spatial variations in the ACT instrument noise. These maps provide a significant advance, in noise levels and resolution, over the existing \textit{Planck} component-separated maps and will enable a host of science goals including studies of cluster and galaxy astrophysics, inferences of the cosmic velocity field, primordial non-Gaussianity searches, and gravitational lensing reconstruction of the CMB.Comment: The Compton-y map and associated products will be made publicly available upon publication of the paper. The CMB T and E mode maps will be made available when the DR6 maps are made publi

The Atacama Cosmology Telescope: DR6 Gravitational Lensing Map and Cosmological Parameters

We present cosmological constraints from a gravitational lensing mass map covering 9400 sq. deg. reconstructed from CMB measurements made by the Atacama Cosmology Telescope (ACT) from 2017 to 2021. In combination with BAO measurements (from SDSS and 6dF), we obtain the amplitude of matter fluctuations $\sigma_8 = 0.819 \pm 0.015$ at 1.8% precision, $S_8\equiv\sigma_8({\Omega_{\rm m}}/0.3)^{0.5}=0.840\pm0.028$ and the Hubble constant $H_0= (68.3 \pm 1.1)\, \text{km}\,\text{s}^{-1}\,\text{Mpc}^{-1}$ at 1.6% precision. A joint constraint with CMB lensing measured by the Planck satellite yields even more precise values: $\sigma_8 = 0.812 \pm 0.013$, $S_8\equiv\sigma_8({\Omega_{\rm m}}/0.3)^{0.5}=0.831\pm0.023$ and $H_0= (68.1 \pm 1.0)\, \text{km}\,\text{s}^{-1}\,\text{Mpc}^{-1}$. These measurements agree well with $\Lambda$CDM-model extrapolations from the CMB anisotropies measured by Planck. To compare these constraints to those from the KiDS, DES, and HSC galaxy surveys, we revisit those data sets with a uniform set of assumptions, and find $S_8$ from all three surveys are lower than that from ACT+Planck lensing by varying levels ranging from 1.7-2.1$\sigma$. These results motivate further measurements and comparison, not just between the CMB anisotropies and galaxy lensing, but also between CMB lensing probing $z\sim 0.5-5$ on mostly-linear scales and galaxy lensing at $z\sim 0.5$ on smaller scales. We combine our CMB lensing measurements with CMB anisotropies to constrain extensions of $\Lambda$CDM, limiting the sum of the neutrino masses to $\sum m_{\nu} < 0.12$ eV (95% c.l.), for example. Our results provide independent confirmation that the universe is spatially flat, conforms with general relativity, and is described remarkably well by the $\Lambda$CDM model, while paving a promising path for neutrino physics with gravitational lensing from upcoming ground-based CMB surveys.Comment: 30 pages, 16 figures, prepared for submission to ApJ. Cosmological likelihood data is here: https://lambda.gsfc.nasa.gov/product/act/actadv_prod_table.html ; likelihood software is here: https://github.com/ACTCollaboration/act_dr6_lenslike . Also see companion papers Qu et al and MacCrann et al. Mass maps will be released when papers are publishe