Guidelines for the use of imaging in the management of patients with myeloma.

The role of imaging in myeloma has gained increasing importance over the past few years. The recently revised definition of myeloma from the International Myeloma Working Group (IMWG) includes cross sectional imaging as a method to define bone disease and also incorporates its use in the disease definition for patients with suspected smouldering myeloma. The National Institute for Health and Care Excellence myeloma guidelines also recommend cross sectional imaging for patients with suspected myeloma. There is also increasing use of imaging in disease assessments and the International Myeloma Working Group has recently incorporated imaging in defining new response categories of minimal residual disease negativity, with or without imaging-based evidence of disease. Plain X-rays have previously been the standard imaging modality included in a myeloma work up at presentation but evidence is mounting for use of cross-sectional modalities such as computed tomography (CT), magnetic resonance imaging (MRI) and 18 fluoro-deoxyglucose (18 F-FDG) positron emission tomography (PET)/CT. Funding and therefore availability of newer imaging techniques remains a barrier. Here, we propose an evidence-based approach to the use and technical application of the latest imaging modalities at diagnosis and in the follow-up of patients with myeloma and plasmacytoma.

Time to redefine Myeloma.

In November 2014 the International Myeloma Working Group (IMWG) revised the definition of multiple myeloma, such that asymptomatic patients with newly diagnosed multiple myeloma without any of the traditional 'CRAB' (hypercalcaemia, renal impairment, anaemia, bone disease) end organ damage criteria but with one of three new criteria would be recommended to start treatment. Previously, the standard of care for such patients was expectant management. These three new criteria are: greater than 60% clonal plasma cells on bone marrow biopsy, a serum free light chain (sFLC) ratio of >100 (the involved sFLC must be >100 mg/l) and greater than one unequivocal focal lesion on advanced imaging (low dose whole body computerized tomography, magnetic resonance imaging, (18) F fluorodeoxyglucose positron emission tomography). Although this would appear to affect a small number of patients, the impact of these changes are broad, leading to an increased use of advanced imaging, a debate around the management of patients previously diagnosed with smouldering myeloma, changed terminology and clinical trial design and an extension of the use of biomarkers. For the first time the philosophy of treatment in myeloma will change from treatment initiation only being triggered by overt end organ damage to an era where sub clinical risk factors will also be taken into account.

Optimizing the management of patients with spinal myeloma disease.

Myeloma is one of the most common malignancies that results in osteolytic lesions of the spine. Complications, including pathological fractures of the vertebrae and spinal cord compression, may cause severe pain, deformity and neurological sequelae. They may also have significant consequences for quality of life and prognosis for patients. For patients with known or newly diagnosed myeloma presenting with persistent back or radicular pain/weakness, early diagnosis of spinal myeloma disease is therefore essential to treat and prevent further deterioration. Magnetic resonance imaging is the initial imaging modality of choice for the evaluation of spinal disease. Treatment of the underlying malignancy with systemic chemotherapy together with supportive bisphosphonate treatment reduces further vertebral damage. Additional interventions such as cement augmentation, radiotherapy, or surgery are often necessary to prevent, treat and control spinal complications. However, optimal management is dependent on the individual nature of the spinal involvement and requires careful assessment and appropriate intervention throughout. This article reviews the treatment and management options for spinal myeloma disease and highlights the value of defined pathways to enable the proper management of patients affected by it.

mHealth in hyper-connected Hong Kong: examining attitudes and access to mobile devices and health information among older Chinese residents.

BACKGROUND: Hong Kong Special Administrative Region is one of the most technologically advanced and interconnected cities in the world in terms of ownership of internet-enabled mobile devices. mHealth programs that make use of mobile devices such as smart phones and tablets to maximise access to health information, have been identified as having great potential for ageing communities for the management of health and social care needs. This paper reports the findings of a two-stage exploratory research project which examined the experiences and perceptions of Hong Kong residents aged over 60 years in relation to mHealth technologies and health literacy. METHODS: This study collected data from older Hong Kong residents at a community centre. Data were collected at two stages in July and August 2019. Stage one involved a one-on-one interview at Centre A with each research participant. The self-report surveys included seven questions about mobile phone ownership and a 16-item gerontechnology survey previously used in Hong Kong. Stage two of the data collection involved three discussion groups with the research participants that were run over a 3-week period. RESULTS: (I) Providing health information via digital devices was considered promising and acceptable by most of our participants. (II) Major concerns that impeded the elders' use of digital devices were their lack of the necessary skills to use these gadgets and their loss of memory. (III) Many participants stated their concern that they found it difficult to recall information immediately after being taught. (IV) Most participants had problems in reading because of low literacy levels or some age-related eye-diseases. (V) Video instructions were preferred by participants as audio and visual input is more useful than rather than static written information with heavy reading requirements. CONCLUSIONS: Participants were interested in using mHealth technologies. Education and ongoing support in their use is necessary.

Effect of hyperthermia and anoxia on glucocorticoid and mineralocorticoid receptor expression in neonatal rat hippocampus.

Brief periods of neonatal asphyxia are frequently observed. Within the CNS, the hippocampus is known to be particularly vulnerable to the damaging effects of hypoxia/ischaemia. The hippocampus contains the highest concentration of both mineralocorticoid (MR) and glucocorticoid (GR) receptors and the balance between MR/GR activation influences cell birth and death. MR occupation appears to promote prosurvival actions, while GR overactivation favours neurodegeneration. It has been widely recognized that core body temperature is a critical determinant of the severity of hypoxic-ischemic brain injury; indeed, hyperthermia exacerbates the degree of damage. Therefore, the aim of the present investigation was to study the effect of elevated body temperature in newborn rats under control conditions or during neonatal exposure to a critical anoxia, on changes of MR and GR mRNA expression in the rat hippocampus. 2-day-old rats were exposed to anoxia in 100% nitrogen atmosphere. Rectal temperature was kept at 33 degrees C (typical for the rat neonates), or elevated to a level typical for febrile (39 degrees C) adults. Control rats were exposed to atmospheric air under the respective thermal conditions. The changes in MR and GR mRNA expression in hippocampus were examined 24h after exposure. Our data show that hyperthermia with or without added anoxia, causes induction of MR mRNA expression in neonatal rat hippocampus without any effect on GR mRNA expression. We suggest this elevation of MR plays an important role in modulating the survival of neurons in the injured hippocampus.

Long-term stabilisation of myeloma with curcumin.

Myeloma is a haematological malignancy which typically follows a relapsing-remitting course. While treatment can control the myeloma and improve quality of life for given periods of time, remissions generally become progressively shorter with subsequent relapses, and patients ultimately enter a final refractory phase. To help control symptoms and enhance quality of life, some patients use complementary therapies as an adjunct to their conventional therapy. Here, we describe a myeloma patient who started a daily dietary supplement of curcumin when approaching her third relapse. In the absence of further antimyeloma treatment, the patient plateaued and has remained stable for the last 5 years with good quality of life.

Overexpression of the mineralocorticoid receptor protects against injury in PC12 cells.

Mineralocorticoid receptor expression is increased following neuronal injury, and this is associated with increased neuronal survival. Here we demonstrate a causal link between overexpression of MR in PC12 cells and protection against death induced by staurosporine and oxygen-glucose deprivation. This survival effect is abrogated by MR antagonism. Drugs which upregulate MR may form the basis for a novel therapeutic approach in conditions such as stroke and head injury.

Obese Zucker rats have reduced mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type 1 expression in hippocampus-implications for dysregulation of the hypothalamic-pituitary-adrenal axis in obesity.

Obese Zucker rats have elevated basal corticosterone levels and an increased stress response suggestive of an increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. We hypothesized that altered central expression of glucocorticoid receptors (GR), mineralocorticoid receptors (MR), and/or 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) contribute to these changes. In brains from young adult male rats, in situ hybridization and Western blotting showed that obese rats had normal hippocampal GR mRNA and protein levels. In contrast, in obese rats, 11betaHSD1 mRNA levels were reduced in a subpopulation of hippocampal cells in the main neuronal layers (by 37-47%, P < 0.05), whereas 11betaHSD1 levels in sparse high-expressing cells did not differ. MR mRNA was decreased in all regions of the hippocampus (by 37-49%, P < 0.05 for CA1-2 and P < 0.01 for dentate gyrus) and in frontal cortex (by 16%, P < 0.05) in obese rats. In whole hippocampal homogenates, however, neither the protein concentration of MR by Western blot nor activity of 11betaHSD1 was measurably different between the phenotypes. To test the functional importance of lower central MR expression, groups of lean and obese rats were given spironolactone before restraint stress. In vehicle-treated animals, obese rats had higher plasma corticosterone levels than lean rats after stress (by ANOVA, P < 0.05). Spironolactone markedly increased the corticosterone response in both groups, but the incremental rise was smaller in the obese rats, so that spironolactone abolished the differences between groups. We conclude that lower levels of MR, but not GR, contribute to the increased HPA activity in the obese Zucker rats and that this seems more influential during stress than in the basal state. This may be exacerbated by impaired local regeneration of corticosterone by 11betaHSD1. These abnormalities could contribute to the subtle changes in the HPA axis in rodent and human obesity.

Injury-induced mineralocorticoid receptor expression involves differential promoter usage: a novel role for the rat MRbeta variant.

Neuronal injury results in increased mineralocorticoid receptor (MR) expression and is associated with increased neuronal survival, suggesting that enhancing MR signalling may have therapeutic implications. MR has a complex gene structure with at least three untranslated exons (alpha, beta, gamma) each with unique promoters and a common coding region. We examined whether distinct cellular stressors differentially regulate exon-specific MR transcripts. MRbeta transcript was specifically upregulated in rat primary cortical cultures undergoing hypothermic oxygen-glucose deprivation (OGD/H) through activation of its own promoter. This effect was mediated in part by ERK signalling as blockade with PD98059 inhibited OGD/H-induced MRbeta promoter activity. A specific increase in MRbeta transcript expression was also found in vivo in hypothermic anoxic neonatal rat hippocampus. These results demonstrate a novel key role for the MRbeta transcript in response to injury and suggest that some of the known neuroprotective effects of hypothermia may be mediated through increased MR expression.

Forebrain mineralocorticoid receptor overexpression enhances memory, reduces anxiety and attenuates neuronal loss in cerebral ischaemia.

The nuclear mineralocorticoid receptor (MR), a high-affinity receptor for glucocorticoids, is highly expressed in the hippocampus where it underpins cognitive, behavioural and neuroendocrine regulation. Increased neuronal MR expression occurs early in the response to cellular injury in vivo and in vitro and is associated with enhanced neuronal survival. To determine whether increased neuronal MR might be causal in protecting against ischaemic damage in vivo we generated a forebrain-specific MR-overexpressing transgenic mouse (MR-Tg) under the control of the CamKII alpha promoter, and subjected mice to transient cerebral global ischaemia induced by bilateral common carotid artery occlusion for 20 min. We also separately assessed the effects of MR overexpression on hypothalamic-pituitary-adrenal (HPA) axis activity and cognitive and affective functions in noninjured animals. Our results showed that MR-Tg mice had significantly reduced neuronal death following transient cerebral global ischaemia compared to wild-type littermates. This effect was not associated with alterations in basal or poststress HPA axis function or in arterial blood pressure. MR-Tg mice also demonstrated improved spatial memory retention, reduced anxiety and altered behavioural response to novelty. The induction of neuronal MR appears to offer a protective response which has potential therapeutic implications in cerebral ischaemia and cognitive and affective disorders.

Mineralocorticoid receptor expression and increased survival following neuronal injury.

Glucocorticoids, acting via the mineralocorticoid receptor, are required for granule neuronal survival in the rat dentate gyrus. Whether this mineralocorticoid receptor-mediated neuroprotective effect has more general applicability is unknown. Here we report increased mineralocorticoid receptor expression in rat hippocampal and cortical neurons exposed in vitro to low levels of staurosporine and in rat hippocampal pyramidal neurons exposed in vivo to hypothermic transient global ischaemia. In both the cell culture system and the in vivo system increased mineralocorticoid receptor expression is associated with increased neuronal survival, and this increase is reversed by mineralocorticoid receptor antagonism. Modulation of mineralocorticoid receptor gene expression may therefore be an important target for reduction of brain injury in conditions caused by cerebral ischaemia including brain damage following cardiac arrest and stroke.