The clinically important MAM blood group antigen is present on haematopoietic cells of all humans except rare MAM-negative individuals. Its molecular basis is unknown. By whole-exome sequencing we ...identify EMP3, encoding epithelial membrane protein 3 (EMP3), as a candidate gene, then demonstrate inactivating mutations in ten known MAM-negative individuals. We show that EMP3, a purported tumour suppressor in various solid tumours, is expressed in erythroid cells. Disruption of EMP3 by CRISPR/Cas9 gene editing in an immortalised human erythroid cell line (BEL-A2) abolishes MAM expression. We find EMP3 to associate with, and stabilise, CD44 in the plasma membrane. Furthermore, cultured erythroid progenitor cells from MAM-negative individuals show markedly increased proliferation and higher reticulocyte yields, suggesting an important regulatory role for EMP3 in erythropoiesis and control of cell production. Our data establish MAM as a new blood group system and demonstrate an interaction of EMP3 with the cell surface signalling molecule CD44.
Abstract Background Functional somatic symptoms (FFS) and bodily distress disorders are highly prevalent across all medical settings. Services for these patients are dispersed across the health care ...system with minimal conceptual and operational integration, and patients do not currently access therapeutic offers in significant numbers due to a mismatch between their and professionals’ understanding of the nature of the symptoms. New service models are urgently needed to address patients’ needs and to align with advances in aetiological evidence and diagnostic classification systems to overcome the body–mind dichotomy. Method A panel of clinical experts from different clinical services involved in providing aspects of health care for patients with functional symptoms reviewed the current care provision. This review and the results from a focus group exploration of patients with lived experience of functional symptoms were explored by the multidisciplinary expert group, and the conclusions are summarised as recommendations for best practice. Results The mapping exercise and multidisciplinary expert consultation revealed five themes for service improvement and pathway development: time/access, communication, barrier-free care, choice and governance. Service users identified four meta-themes for best practice recommendations: focus on healthcare professional communication and listening skills as well as professional attributes and knowledge base to help patients being both believed and understood in order to accept their condition; systemic and care pathway issues such as stronger emphasis on primary care as the first point of contact for patients, resources to reduce the length of the patient journey from initial assessment to diagnosis and treatment. Conclusion We propose a novel, integrated care pathway for patients with ‘functional somatic disorder’, which delivers care according to and working with patients’ explanatory beliefs. The therapeutic model should operate based upon an understanding of the embodied nature of patient’s complaints and provide flexible access points to the care pathway.
Tetraspanins are thought to facilitate the formation of multiprotein complexes at cell surfaces, but evidence illuminating the biologic importance of this role is sparse. Tetraspanin CD151 forms very ...stable laminin-binding complexes with integrins α3β1 and α6β1 in kidney and α3β1 and α6β4 in skin. It is encoded by a gene at the same position on chromosome 11p15.5 as the MER2 blood group gene. We show that CD151 expresses the MER2 blood group antigen and is located on erythrocytes. We examined CD151 in 3 MER2-negative patients (2 are sibs) of Indian Jewish origin with end-stage kidney disease. In addition to hereditary nephritis the sibs have sensorineural deafness, pretibial epidermolysis bullosa, and β-thalassemia minor. The 3 patients are homozygous for a single nucleotide insertion (G383) in exon 5 of CD151, causing a frameshift and premature stop signal at codon 140. The resultant truncated protein would lack its integrin-binding domain. We conclude that CD151 is essential for the proper assembly of the glomerular and tubular basement membrane in kidney, has functional significance in the skin, is probably a component of the inner ear, and could play a role in erythropoiesis.
Comparison of normal erythroblasts and erythroblasts from persons with the rare In(Lu) type of Lu(a-b-) blood group phenotype showed increased transcription levels for 314 genes and reduced levels ...for 354 genes in In(Lu) cells. Many erythroid-specific genes (including ALAS2, SLC4A1) had reduced transcript levels, suggesting the phenotype resulted from a transcription factor abnormality. A search for mutations in erythroid transcription factors showed mutations in the promoter or coding sequence of EKLF in 21 of 24 persons with the In(Lu) phenotype. In all cases the mutant EKLF allele occurred in the presence of a normal EKLF allele. Nine different loss-of-function mutations were identified. One mutation abolished a GATA1 binding site in the EKLF promoter (−124T>C). Two mutations (Leu127X; Lys292X) resulted in premature termination codons, 2 (Pro190LeufsX47; Arg319GlufsX34) in frameshifts, and 4 in amino acid substitution of conserved residues in zinc finger domain 1 (His299Tyr) or domain 2 (Arg328Leu; Arg328His; Arg331Gly). Persons with the In(Lu) phenotype have no reported pathology, indicating that one functional EKLF allele is sufficient to sustain human erythropoiesis. These data provide the first description of inactivating mutations in human EKLF and the first demonstration of a blood group phenotype resulting from mutations in a transcription factor.
With advancements in the science of detection and attribution studies, the influence of climate change over many events has now been quantified. Because of the rapidly increasing temperatures, ...vulnerable populations (adults older than 65 years, and children younger than one year of age) were exposed to 3·7 billion more heatwave days in 2021 than annually in 1986–2005 (indicator 1.1.2), and heat-related deaths increased by 68% between 2000–04 and 2017–21 (indicator 1.1.5), a death toll that was significantly exacerbated by the confluence of the COVID-19 pandemic. Despite the local cooling and overall health benefits of urban greenspaces, only 277 (27%) of 1038 global urban centres were at least moderately green in 2021 (indicator 2.2.3), and the number of households with air conditioning increased by 66% from 2000 to 2020, a maladaptive response that worsens the energy crisis and further increases urban heat, air pollution, and greenhouse gas emissions. ...millions of people do not have access to the energy needed to keep their homes at healthy temperatures, preserve food and medication, and meet the seventh Sustainable Development Goal (to ensure access to affordable, reliable, sustainable, and modern energy for all). Aggravating this situation even further, governments continue to incentivise fossil fuel production and consumption: 69 (80%) of 86 countries reviewed had net-negative carbon prices (ie, provided a net subsidy to fossil fuels) for a net total of US$400 billion
In 2022, the Lancet Countdown warned that people's health is at the mercy of fossil fuels and stressed the transformative opportunity of jointly tackling the concurrent climate change, energy, ...cost-of-living, and health crises for human health and wellbeing. Harnessing the rapidly advancing science of detection and attribution, new analysis shows that over 60% of the days that reached health-threatening high temperatures in 2020 were made more than twice as likely to occur due to anthropogenic climate change (indicator 1.1.5); and heat-related deaths of people older than 65 years increased by 85% compared with 1990–2000, substantially higher than the 38% increase that would have been expected had temperatures not changed (indicator 1.1.5). ...those countries that have historically contributed the least to climate change are bearing the brunt of its health impacts—both a reflection and a direct consequence of the structural inequities that lie within the root causes of climate change. The 2022 Lancet Countdown report highlighted the opportunity to accelerate the transition away from health-harming fossil fuels in response to the global energy crisis.
Background & Aims: Infection with Helicobacter pylori causes chronic gastritis, and this confers a risk of gastric cancer. Short alleles of the membrane-bound mucin MUC1, which has a large ...extracellular highly glycosylated domain and is highly polymorphic due to variation in the number of tandemly repeated (TR) 20–amino acid units, have been shown to be associated with gastric cancer. Our aim was to investigate the involvement of MUC1 in chronic gastritis and, by implication, gastric cancer. Methods: Immunohistochemical analysis was performed on endoscopic biopsy specimens from 95 patients. Gastritis was classified using the Sydney System, and H. pylori status was determined. MUC1 was detected with antibodies against different epitopes of the TR region and the cytoplasmic tail. Southern blot analysis of the MUC1 gene was performed on 57 Northern European patients to determine TR allele lengths. Results: With the TR antibodies, apical staining and some perinuclear staining was seen in 34 of 41 biopsy specimens classified as histologically normal and H. pylori negative. None of the 36 biopsy specimens with gastritis and current H. pylori infection showed apical staining. In contrast, the cytoplasmic tail antibody detected apical staining in both groups. Comparison of the MUC1 allele length distributions between Northern European patients with H. pylori infection and those without H. pylori gastritis showed a statistically significant difference in distribution, with shorter alleles associated with H. pylori gastritis. Conclusions: Our results suggest that H. pylori interacts with MUC1 and that there are functional allelic differences that affect susceptibility to gastritis.
GASTROENTEROLOGY 2002;123:41-49
This paper examines portfolio allocation behavior of the elderly, investigating whether their behavior conforms to Arrow's postulate of increasing relative risk aversion. Additionally, the effects on ...risk aversion of age, race, gender, education, health status, and the number of children are examined. The source of data is the AHEAD data set that is comprised of households with at least one member aged 70 or over. In the preferred specification, evidence supports a finding of modestly decreasing relative risk aversion and statistical significance for the personal characteristics examined. Implications are drawn for the likely security markets effects of an aging population.
PDF
