Abstract
Brain oedema is a life-threatening complication of various neurological conditions. Understanding molecular mechanisms of brain volume regulation is critical for therapy development. Unique ...insight comes from monogenic diseases characterized by chronic brain oedema, of which megalencephalic leukoencephalopathy with subcortical cysts (MLC) is the prototype. Variants in MLC1 or GLIALCAM, encoding proteins involved in astrocyte volume regulation, are the main causes of MLC. In some patients, the genetic cause remains unknown.
We performed genetic studies to identify novel gene variants in MLC patients, diagnosed by clinical and MRI features, without MLC1 or GLIALCAM variants. We determined subcellular localization of the related novel proteins in cells and in human brain tissue. We investigated functional consequences of the newly identified variants on volume regulation pathways using cell volume measurements, biochemical analysis and electrophysiology.
We identified a novel homozygous variant in AQP4, encoding the water channel aquaporin-4, in two siblings, and two de novo heterozygous variants in GPRC5B, encoding the orphan G protein-coupled receptor GPRC5B, in three unrelated patients. The AQP4 variant disrupts membrane localization and thereby channel function. GPRC5B, like MLC1, GlialCAM and aquaporin-4, is expressed in astrocyte endfeet in human brain. Cell volume regulation is disrupted in GPRC5B patient-derived lymphoblasts. GPRC5B functionally interacts with ion channels involved in astrocyte volume regulation.
In conclusion, we identify aquaporin-4 and GPRC5B as old and new players in genetic brain oedema. Our findings shed light on the protein complex involved in astrocyte volume regulation and identify GPRC5B as novel potentially druggable target for treating brain oedema.
Passchier et al. identify novel pathogenic variants in two genes, AQP4 and GPRC5B, in patients with genetic brain oedema. They provide the first description of a genetic disease linked to dysfunction of the water channel aquaporin-4, and identify GPRC5B as a potentially druggable target for the treatment of brain oedema.
See Oegema (https://doi.org/10.1093/brain/awad230) for a scientific commentary on this article.
A two-step radiolabelling protocol of a cancer relevant cRGD peptide is described where the fluorinase enzyme is used to catalyse a transhalogenation reaction to generate ...(18)F-5'-fluoro-5'-deoxy-2-ethynyladenosine, (18)FFDEA, followed by a 'click' reaction to an azide tethered cRGD peptide. This protocol offers efficient radiolabelling of a biologically relevant peptide construct in water at pH 7.8, 37 °C in 2 hours, which was metabolically stable in rats and retained high affinity for αVβ3 integrin.
Objective
In cancer care, optimal communication between patients and their physicians is, among other things, dependent on physicians' emotion regulation, which might be related to physicians' as ...well as patients' characteristics. In this study, we investigated physicians' emotion regulation during communication with advanced cancer patients, in relation to physicians' (stress, training, and alexithymia) and patients' (sadness, anxiety, and alexithymia) characteristics.
Methods
In this study, 134 real‐life consultations between 24 physicians and their patients were audio‐recorded and transcribed. The consultations were coded with the “Defence Mechanisms Rating Scale—Clinician.” Physicians completed questionnaires about stress, experience, training, and alexithymia, while patients completed questionnaires about sadness, anxiety, and alexithymia. Data were analysed using linear mixed effect models.
Results
Physicians used several defence mechanisms when communicating with their patients. Overall defensive functioning was negatively related to physicians' alexithymia. The number of defence mechanisms used was positively related to physicians' stress and alexithymia as well as to patients' sadness and anxiety. Neither physicians' experience and training nor patients' alexithymia were related to the way physicians regulated their emotions.
Conclusions
This study showed that physicians' emotion regulation is related to both physician (stress and alexithymia) and patient characteristics (sadness and anxiety). The study also generated several hypotheses on how physicians' emotion regulation relates to contextual variables during health care communication in cancer care.
Objective
To investigate which characteristics of the physician and of the consultation are related to patient satisfaction with communication and working alliance.
Methods
Real‐life consultations ...(N = 134) between patients (n = 134) and their physicians (n = 24) were audiotaped. All of the patients were aware of their cancer diagnosis and consulted their physician to discuss the results of tests (CT scans, magnetic resonance imaging, or tumor markers) and the progression of their cancer. The consultations were transcribed and coded with the “Defense Mechanisms Rating Scale—Clinician.” The patients and physicians completed questionnaires about stress, satisfaction, and alliance, and the data were analyzed using robust linear modeling.
Results
Patient satisfaction with communication and working alliance was high. Both were significantly (negatively) related to the physician's neurotic and action defenses—in particular to the defenses of displacement, self‐devaluation, acting out, and hypochondriasis—as well as to the physician's stress level. The content of the consultation was not significantly related to the patient outcomes.
Conclusions
Our study shows that patient satisfaction with communication and working alliance is not influenced by the content of the consultation but is significantly associated with the physician's self‐regulation (defense mechanisms) and stress. The results of this study might contribute to optimizing communication skills training and to improving communication and working alliance in cancer care.
The Capricorn Orogen in central Western Australia records the Palaeoproterozoic collision of the Archaean Pilbara and Yilgarn Cratons. Until recently only one orogenic event was thought to be the ...cause of this collision, the 1830–1780
Ma Capricorn Orogeny. However, recent work has uncovered an older event, the Glenburgh Orogeny that occurred between 2000 and 1960
Ma. The Glenburgh Orogeny reflects the collision of a late Archaean to Palaeoproterozoic microcontinent (the Glenburgh Terrane) with the Archaean Yilgarn Craton and is therefore tectonically distinct as well as significantly older than the widespread 1900–1800
Ma tectonothermal events recorded in northern Australia.
The Glenburgh Terrane preserves a different history from either the Yilgarn or Pilbara Cratons. Granitic gneiss protoliths dated at ca. 2550
Ma were intruded by widespread granite magmatism dated at 2005–1970
Ma, accompanied by high-grade metamorphism and deformation throughout the terrane. At ca. 1960
Ma silicic granite of the Bertibubba Supersuite intruded the northern margin of the Yilgarn Craton along the Errabiddy Shear Zone, a crustal-scale shear zone that today marks the contact of the Glenburgh Terrane and Yilgarn Craton. At ca. 1950
Ma silicic dykes intruded the southernmost part of the Glenburgh Terrane, marking the end of the Glenburgh Orogeny. East of the Glenburgh Terrane the Glenburgh Orogeny resulted in the cessation of mafic volcanism in the Bryah Basin, and the basin’s eventual closure. Siliciclastic, carbonate and chemical sedimentary rocks were deposited in the Padbury Basin that formed a retro-arc foreland basin on top of the Bryah Basin, and probably records the later stages of the Glenburgh Orogeny collision.
Integrating mental health care into HIV services is critical to addressing the high unmet treatment needs for people living with HIV and comorbid major depressive disorder. Introducing routine mental ...health screening at the primary health care level is a much needed diagonal approach to enhancing HIV care. In low-resource settings with a shortage of mental health care providers, eMental Health may provide a novel opportunity to attenuate this treatment gap and strengthen the health system.
To conduct formative health systems research on the implementation of routine depression screening using a digital tool - Mood in Retroviral Positive Individuals Application Monitoring (MIR + IAM) - in an HIV primary care setting in South Africa.
A Theory of Change (ToC) approach was utilised through individual and group session interviews to design an intervention that is embedded in the local context. Ten experts and local stakeholders were selected from the UK and South Africa. Data were analysed thematically using Atlas.ti to identify interventions, assumptions, barriers and facilitators of implementation.
The participants considered digital depression screening in HIV care services relevant for the improvement of mental health in this population. The six main themes identified from the ToC process were: (1) user experience including acceptability by patients, issues of patient privacy and digital literacy, and the need for a patient-centred tool; (2) benefits of the digital tool for data collection and health promotion; (3) availability of treatment after diagnosis; (4) human and physical resource capacity of primary health care; (5) training for lay health care workers; and (6) demonstration of the intervention's usefulness to generate interest from decision-makers.
Digital depression screening coupled with routine mental health data collection and analysis in HIV care is an applicable service that could improve the mental and physical health outcomes of this population. Careful consideration of the local health system capacity, including both workers and patients, is required. Future research to refine this intervention should focus on service users, government stakeholders and funders.
Major ice loss in the Amundsen Sea sector of the West Antarctic Ice Sheet (WAIS) is hypothesized to have triggered ice sheet collapses during past warm periods such as those in the Pliocene. ...International Ocean Discovery Program (IODP) Expedition 379 recovered continuous late Miocene to Holocene sediments from a sediment drift on the continental rise, allowing assessment of sedimentation processes in response to climate cycles and trends since the late Miocene. Via seismic correlation to the shelf, we interpret massive prograding sequences that extended the outer shelf by 80 km during the Pliocene through frequent advances of grounded ice. Buried grounding zone wedges indicate prolonged periods of ice‐sheet retreat, or even collapse, during an extended mid‐Pliocene warm period from ∼4.2–3.2 Ma inferred from Expedition 379 records. These results indicate that the WAIS was highly dynamic during the Pliocene and major retreat events may have occurred along the Amundsen Sea margin.
Plain Language Summary
Collapses of the West Antarctic Ice Sheet (WAIS) during past warm times are suggested to begin in the Amundsen Sea sector. During a drilling expedition of the International Ocean Discovery Program (IODP), deep‐sea sediments were retrieved from the Amundsen Sea. These sediment cores contain records of colder and warmer periods in the Pliocene (5.3–2.6 million years ago) which relate to the behavior of the WAIS. By analyzing seismic images that allow correlation of sediment layers from the drill sites to the continental shelf, we show that the shelf grew oceanward by 80 km due to the erosion of sediments below the WAIS and their deposition at the shelf break as the result of frequent Pliocene advances of grounded ice across the shelf. The shelf sediment layers contain grounding zone wedges predominantly formed during ice sheet retreat. The preservation of these grounding zone wedges testifies that they were not eroded by subsequent ice advances, with their burial requiring periods of prolonged WAIS retreat during warm intervals. This interpretation is consistent with our IODP drill core observations of a prominent decrease in terrigenous sedimentation between 4.2 and 3.2 million years ago, which indicates a highly dynamic WAIS during the Pliocene.
Key Points
Seismic stratigraphic continental rise‐to‐shelf link from International Ocean Discovery Program (IODP) Expedition 379 drill sites on the Amundsen Sea rise
Major prograding shelf growth in the Amundsen Sea Embayment by frequent grounded ice advances in the early Pliocene
Extended period of ice sheet retreat in mid‐Pliocene (4.2–3.2 Ma) from buried grounding zone wedges on shelf and core records from rise
Congestion is a major problem in large, urbanized areas. Intelligent transport solutions aim to reduce this problem. In general, traffic is monitored with the use of sensors, the resulting data are ...processed, a traffic state is estimated, and a control measure is computed and implemented. The availability and the quality of the data and the processing time of the algorithms are possible limiting factors in this pattern. The study reported in this paper examined the data requirements for various traffic control measures. In particular, the relationship between the spatial scale of the control measure and the time delay between the measurement and the control action, that is, the latency, was examined. A set of 17 applications showed that the larger the spatial scale of the control measure, the larger the latency could be. This relationship can be used to determine the latency quality criteria for a certain application. Alternatively, the relationship can be used to analyze which types of applications are possible when data with a specific quality can be collected. The latter analysis was carried out in the province of Delft, Netherlands. The analysis also showed the difference between the availability with respect to information and communication technology and useful data for applications. In particular, if no vehicles passed, information and communication technology systems were available, but no realistic measurements were produced.
A two-step radiolabelling protocol of a cancer relevant cRGD peptide is described where the fluorinase enzyme is used to catalyse a transhalogenation reaction to generate
18
...F-5′-fluoro-5′-deoxy-2-ethynyladenosine,
18
FFDEA, followed by a 'click' reaction to an azide tethered cRGD peptide. This protocol offers efficient radiolabelling of a biologically relevant peptide construct in water at pH 7.8, 37 °C in 2 hours, which was metabolically stable in rats and retained high affinity for α
V
β
3
integrin.
Fluorine-18 radiolabelling of a peptide is conducted in water (pH 7.8 and 37 °C) using the fluorinase enzyme and a 'click' reaction.
A two-step radiolabelling protocol of a cancer relevant cRGD peptide is described where the fluorinase enzyme is used to catalyse a transhalogenation reaction to generate ...super(18)F-5'-fluoro-5'-deoxy-2 -ethynyladenosine, super(18)FFDEA, followed by a 'click' reaction to an azide tethered cRGD peptide. This protocol offers efficient radiolabelling of a biologically relevant peptide construct in water at pH 7.8, 37 degree C in 2 hours, which was metabolically stable in rats and retained high affinity for alpha sub(V) beta sub(3) integrin.
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