Iron Deposition in the Brain After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: After aneurysmal subarachnoid hemorrhage (SAH), thrombus forms over the cerebral cortex and releases hemoglobin. When extracellular, hemoglobin is toxic to neurones. High local hemoglobin concentration overwhelms the clearance capacity of macrophages expressing the hemoglobin-haptoglobin scavenger receptor CD163. We hypothesized that iron is deposited in the cortex after SAH and would associate with outcome. METHODS: Two complementary cross-sectional studies were conducted. Postmortem brain tissue from 39 SAH (mean postictal interval of 9 days) and 22 control cases was studied with Perls' staining for iron and immunolabeling for CD163, ADAM17 (a disintegrin and metallopeptidase domain 17), CD68, and Iba1 (ionized calcium binding adaptor molecule 1). In parallel, to study the persistence of cortical iron and its relationship to clinical outcome, we conducted a susceptibility-weighted imaging study of 21 SAH patients 6 months postictus and 10 control individuals. RESULTS: In brain tissue from patients dying soon after SAH, the distribution of iron deposition followed a gradient that diminished with distance from the brain surface. Iron was located intracellularly (mainly in macrophages, and occasionally in microglia, neurones, and glial cells) and extracellularly. Microglial activation and motility markers were increased after SAH, with a similar inward diminishing gradient. In controls, there was a positive correlation between CD163 and iron, which was lost after SAH. In SAH survivors, iron-sensitive imaging 6 months post-SAH confirmed persistence of cortical iron, related to the size and location of the blood clot immediately after SAH, and associated with cognitive outcome. CONCLUSIONS: After SAH, iron deposits in the cortical gray matter in a pattern that reflects proximity to the brain surface and thrombus and is related to cognitive outcome. These observations support therapeutic manoeuvres which prevent the permeation of hemoglobin into the cortex after SAH.

Examining the effects of acquired limb loss on the family network: a grounded theory study.

BACKGROUND: Individuals with acquired limb loss are faced with various challenges. Family networks become important in facilitating coping and recovery, but the limited research into their own experiences has so far only examined spousal and parental carers. AIMS: This research aimed to: understand the experiences of acquired limb loss from the perspective of the family network; and to develop a theoretical model to explain how they experience limb loss of the other. The use of 'network' was adopted to include kin self-identified as family. METHOD: Participants (n = 14) were recruited nationally. Interviews were conducted in a process moving from unstructured, semi-structured and structured interviews, using Grounded Theory method. FINDINGS: A theoretical model was developed around the interaction of five core categories. Families witness the difficulties faced by the person with limb loss, leading to a responsibility to provide support. Families subsequently experience various challenges of limb loss; together with numerous emotional reactions. Various forms of coping are used in order to resolve these experiences. CONCLUSIONS: Families are involved in the processes and challenges of an amputation in another family member, regardless of aetiology, gender or relationship structure. The theoretical model can be understood through the integration of existing research. The issues identified indicate potential considerations for services supporting such families.IMPLICATIONS FOR REHABILITATIONThe challenges and emotions experienced by family members have potential consequences for the support offered to the person with limb loss.This could ultimately influence the physical and psychological rehabilitation of the person with limb loss.Services should support families in witnessing difficulties in the person with limb loss, adjusting to relational changes and managing health care systems.

Psychosocial impact of paediatric demyelinating disorders: a scoping review.

AIM: To: (1) provide greater insight into the psychological and social impact of a range of demyelinating disorders, (2) explore differences between disorders, and (3) provide direction for future research. METHOD: Studies were identified by searching online databases. Studies that explored the psychological, emotional, or social impact of a range of demyelinating disorders in childhood, including acute disseminated encephalomyelitis (ADEM), optic neuritis, transverse myelitis, and multiple sclerosis, were included and screened independently by three authors. Data on the design, sample characteristics, psychosocial measures, key findings, and methodological strengths and limitations were extracted. Twenty-five studies were included in the narrative synthesis. RESULTS: Demyelinating disorders are associated with lower quality of life, affecting young people's emotional, social, school, and behavioural functioning. There is a high prevalence of psychiatric disorders and fatigue, particularly in multiple sclerosis. Subtle differences exist in the psychological presentation between different demyelinating disorders, with clear gaps in the research for the long-term psychosocial impact of monophasic conditions. INTERPRETATION: The difference between the impact of monophasic and relapsing demyelinating disorders on psychosocial functioning is unclear. Future research should aim to identify the psychosocial impact across disorders and over time, ensure that services are capturing those patients who may benefit from tailored interventions. WHAT THIS PAPER ADDS: Prevalence of psychiatric diagnoses in paediatric demyelinating disorders is higher than controls. Depression and emotional concerns are elevated in paediatric demyelinating disorders. Demyelinating disorders impact children's quality of life across school, social, and physical functioning.

Hearing impairment after subarachnoid hemorrhage.

Background: Subarachnoid hemorrhage (SAH) survivors experience significant neurological disability, some of which is under-recognized by neurovascular clinical teams. We set out to objectively determine the occurrence of hearing impairment after SAH, characterize its peripheral and/or central origin, and investigate likely pathological correlates. Methods: In a case-control study (n = 41), participants were asked about new onset hearing difficulty 3 months post-SAH, compared with pre-SAH. Formal audiological assessment included otoscopy, pure tone audiometry, a questionnaire identifying symptoms of peripheral hearing loss and/or auditory processing disorder, and a test of speech understanding in noise. A separate cohort (n = 21) underwent quantitative susceptibility mapping (QSM) of the auditory cortex 6 months after SAH, for correlation with hearing difficulty. Results: Twenty three percent of SAH patients reported hearing difficulty that was new in onset post-SAH. SAH patients had poorer pure tone thresholds compared to controls. The proportion of patients with peripheral hearing loss as defined by the World Health Organization and British Audiological Society was however not increased, compared to controls. All SAH patients experienced symptoms of auditory processing disorder post-SAH, with speech-in-noise test scores significantly worse versus controls. Iron deposition in the auditory cortex was higher in patients reporting hearing difficulty versus those who did not. Conclusion: This study firmly establishes hearing impairment as a frequent clinical feature after SAH. It primarily consists of an auditory processing disorder, mechanistically linked to iron deposition in the auditory cortex. Neurovascular teams should inquire about hearing, and refer SAH patients for audiological assessment and management.

Second-generation CK2α inhibitors targeting the αD pocket.

CK2 is a critical cell cycle regulator that also promotes various anti-apoptotic mechanisms. Development of ATP-non-competitive inhibitors of CK2 is a very attractive strategy considering that the ATP binding site is highly conserved among other kinases. We have previously utilised a pocket outside the active site to develop a novel CK2 inhibitor, CAM4066. Whilst CAM4066 bound to this new pocket it was also interacting with the ATP site: herein, we describe an example of a CK2α inhibitor that binds completely outside the active site. This second generation αD-site binding inhibitor, compound CAM4712 (IC50 = 7 µM, GI50 = 10.0 ± 3.6 µM), has numerous advantages over the previously reported CAM4066, including a reduction in the number of rotatable bonds, the absence of amide groups susceptible to the action of proteases and improved cellular permeability. Unlike with CAM4066, there was no need to facilitate cellular uptake by making a prodrug. Moreover, CAM4712 displayed no drop off between its ability to inhibit the kinase in vitro (IC50) and the ability to inhibit cell proliferation (GI50).

A subarachnoid haemorrhage-specific outcome tool.

Functional outcome after subarachnoid haemorrhage has traditionally been assessed using scales developed for other neurological conditions. The modified Rankin score and Glasgow Outcome Scale are most commonly used. Employment of these scales in subarachnoid haemorrhage is hampered by well recognized limitations. We set out to develop and validate a new condition-specific subarachnoid haemorrhage outcome tool (SAHOT). Items addressing diverse aspects of the impact of subarachnoid haemorrhage were collected during focus groups involving patients, next-of-kin and multidisciplinary professionals involved in subarachnoid haemorrhage management. After a series of iterative revisions, the resultant questionnaire was applied to patients and their next-of-kin at 1, 3 and 6 months post-subarachnoid haemorrhage. Rasch methodology was used to finalize the structure of the questionnaire and explore the extent to which SAHOT scores met Rasch-based criteria of successful measurement. The SAHOT was further assessed using traditional scale evaluation techniques, and validated in a second separate subarachnoid haemorrhage patient cohort. The final SAHOT included 56 items dealing with cognitive, physical, and behavioural/psychological consequences of subarachnoid haemorrhage. Rasch analysis indicated the scale successfully measured functional outcome post-subarachnoid haemorrhage. Three item scoring categories produced the best scale performance. There was no evidence of differential item functioning between patients and next-of-kin. The SAHOT was found to be acceptable, have good convergent and divergent validity, good discrimination and excellent responsiveness. It was successfully validated in a second subarachnoid haemorrhage patient cohort. The SAHOT offers the first subarachnoid haemorrhage-specific scientifically robust outcome measure with potential utility in neurovascular clinical services and research studies.

ECG changes in hyperemesis gravidarum.

This is a case report of a 30-year-old patient presenting at advanced gestation with hyperemesis, who developed a prolonged QT interval secondary to electrolyte imbalance during recovery. This potentially fatal complication should be considered in all patients with hyperemesis gravidarum, especially after a prolonged period of starvation. We hope to highlight the importance of ECG monitoring and careful prescribing in such cases, something that is not considered in current guidelines.

Partially Saturated Bicyclic Heteroaromatics as an sp(3) -Enriched Fragment Collection.

Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp(2) -rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp(3) character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters.

The effects of verbal information and approach-avoidance training on children's fear-related responses.

BACKGROUND AND OBJECTIVES: This study examined the effects of verbal information and approach-avoidance training on fear-related cognitive and behavioural responses about novel animals. METHODS: One hundred and sixty children (7-11 years) were randomly allocated to receive: a) positive verbal information about one novel animal and threat information about a second novel animal (verbal information condition); b) approach-avoidance training in which they repeatedly pushed away (avoid) or pulled closer (approach) pictures of the animals (approach-avoidance training), c) a combined condition in which verbal information was given prior to approach-avoidance training (verbal information + approach-avoidance training) and d) a combined condition in which approach-avoidance training was given prior to verbal information (approach-avoidance training + verbal information). RESULTS: Threat and positive information significantly increased and decreased fear beliefs and avoidance behaviour respectively. Approach-avoidance training was successful in training the desired behavioural responses but had limited effects on fear-related responses. Verbal information and both combined conditions resulted in significantly larger effects than approach-avoidance training. We found no evidence for an additive effect of these pathways. LIMITATIONS: This study used a non-clinical sample and focused on novel animals rather than animals about which children already had experience or established fears. The study also compared positive information/approach with threat information/avoid training, limiting specific conclusions regarding the independent effects of these conditions. CONCLUSIONS: The present study finds little evidence in support of a possible causal role for behavioural response training in the aetiology of childhood fear. However, the provision of verbal information appears to be an important pathway involved in the aetiology of childhood fear.

The morphology and symptom history of the Achilles tendons of figure skaters: an observational study.

This cross-sectional study assessed the prevalence of Achilles tendinopathy symptoms and ultrasound (US) abnormalities in male and female ice skaters, and compared this to age-matched controls. The 20 skaters of mean (sd) age 17.3 (7.9) were recruited from British figure skating clubs. The 17 non-skaters of mean age 18.0 (3.7) were recruited from a secondary school and university. Each group had 12 females. All participants completed a questionnaire, and Achilles tendons were ultrasound-scanned for thickening, hypoechoic areas, paratenon blurring and neovascularization. Skaters experienced significantly more lifetime symptoms (p=0.012) than the control group but there were no differences in present symptoms. Mid-tendon longitudinal thickness and the coefficient of variation (CoV) for longitudinal tendon thickness were significantly greater in the skaters (p=0.001 and p=0.017 respectively). No other ultrasound abnormalities were detected in either group. Figure skaters may be at a greater risk of Achilles tendon problems than the general population and have adaptive changes in their tendons.