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Background Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. Method Utilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity. Result NfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers. Conclusion In presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN-related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. Utilizing T1 and task-free functional magnetic resonance imaging (tf-fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel-wise whole brain degree and GRN-relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity. NfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN-FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers. In presymptomatic carriers, the co-occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf-fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

ObjectiveBile acid diarrhoea (BAD), which includes bile acid malabsorption, causes a variety of digestive symptoms. Diagnostic rates and management vary considerably. We conducted a survey of current practice to review expert opinion and provide guidance on diagnosis and management.Design/methodAn online survey was conducted of clinical members of the UK Bile Acid Related Diarrhoea Network, who had all published research on BAD (n=21). Most were National Health Service consultants who had diagnosed over 50 patients with the condition.ResultsThe preferred terminology was to use BAD, with primary and secondary to classify causes. A wide range of presenting symptoms and associated conditions were recognised. SeHCAT (tauroselcholic acid) was the preferred diagnostic test, and 50% of respondents thought general practitioners should have access to this. Patients who met the Rome IV diagnostic criteria for functional diarrhoea, irritable bowel syndrome (IBS) with predominant diarrhoea or postcholecystectomy diarrhoea were usually investigated by SeHCAT, which was used sometimes in other types of IBS. Treatment with a bile acid sequestrant was offered to patients with low SeHCAT values, with expected response rates >70% in the most severe. Colestyramine was the usual sequestrant, starting between 2 g and 8 g daily; colesevelam was an alternative. In patients who had an incomplete response, increasing the dose, changing to an alternative sequestrant, use of loperamide and a low fat diet were suggested. Recommendations for follow-up and to improve the overall patient experience were made.ConclusionThis expert survey indicates current best practice in the diagnosis and management of BAD.

Issue Title: Topical Issue: The Reuven Ramaty High-Energy Solar Spectroscopic Imager (RHESSI) - Mission Description and Early Results RHESSI is the sixth in the NASA line of Small Explorer (SMEX) missions and the first managed in the Principal Investigator mode, where the PI is responsible for all aspects of the mission except the launch vehicle. RHESSI is designed to investigate particle acceleration and energy release in solar flares, through imaging and spectroscopy of hard X-ray/gamma-ray continua emitted by energetic electrons, and of gamma-ray lines produced by energetic ions. The single instrument consists of an imager, made up of nine bi-grid rotating modulation collimators (RMCs), in front of a spectrometer with nine cryogenically-cooled germanium detectors (GeDs), one behind each RMC. It provides the first high-resolution hard X-ray imaging spectroscopy, the first high-resolution gamma-ray line spectroscopy, and the first imaging above 100 keV including the first imaging of gamma-ray lines. The spatial resolution is as fine as 2.3 arc sec with a full-Sun (1°) field of view, and the spectral resolution is 1-10 keV FWHM over the energy range from soft X-rays (3 keV) to gamma-rays (17 MeV). An automated shutter system allows a wide dynamic range (>10^sup 7^) of flare intensities to be handled without instrument saturation. Data for every photon is stored in a solid-state memory and telemetered to the ground, thus allowing for versatile data analysis keyed to specific science objectives. The spin-stabilized (15 rpm) spacecraft is Sun-pointing to within 0.2° and operates autonomously. RHESSI was launched on 5 February 2002, into a nearly circular, 38° inclination, 600-km altitude orbit and began observations a week later. The mission is operated from Berkeley using a dedicated 11-m antenna for telemetry reception and command uplinks. All data and analysis software are made freely and immediately available to the scientific community.[PUBLICATION ABSTRACT]

Primitive neuroectodermal tumors (PNETs) are composed of immature neuronal precursor cells and sometimes more mature neuronal cell types. Medulloblastomas, occuring in the cerebellum, represent the most common PNET and are broadly classified into two subgroups: classical and desmoplastic. Desmoplastic medulloblastomas exhibit a slightly better prognosis than classical medulloblastomas. However, there are currently no good molecular markers available to distinguish clinical outcome and similar treatment is used for most patients with associated complications. It has been shown that neoplastic cells in these tumors recapitulate stages in maturation of normal human neuroblasts; therefore, embryological studies of the earliest events in the development of the cerebellum may provide useful information about the molecular behavior of the tumor. Transcription factors such as Sox proteins involved in neural development may also play a role in the etiology of brain tumors. Sox4 in particular has been implicated in the biology of several other types of cancer. We have studied the expression of Sox4, and the closely related Sox11 gene, in medulloblastomas. Sox4 and Sox11 were strongly expressed in most classical medulloblastomas but only weakly in desmoplastic medulloblastomas. The expression profile of these two genes in developing cerebellum was also analyzed. Our results suggest that strong Sox4 and Sox11 expression in classical medulloblastomas reflects their maturation-dependent expression during normal cerebellum development, and that they may therefore provide markers to divide tumors into clinically relevant subgroups.