Neuropathic pain as a process: reversal of chronification in an animal model

Peripheral neuropathic pain arises from trauma to sensory nerves. Other types of acute neurotrauma such as stroke and spinal cord injury are treated immediately, largely to prevent secondary damage. To pursue the possibility that neuropathic pain may also be amenable to early treatment, a rat model of neuropathic pain was induced using a 2-mm polyethylene cuff implanted around one sciatic nerve. Within 24 hours, hypersensitivity to von Frey hair stimulation appeared, as indicated by decreased paw withdrawal thresholds. When the cuff was removed 24 hours after implantation, readings returned to pre-implantation levels starting as early as day 18. When the cuff was removed after 4 days, there was a period of initial hypersensitivity, and then an increase toward baseline at two time points near the end of the study; therefore, only a partial recovery toward pre-implantation values occurred. Having established that a temporal reversal can occur, the next step examined possible pharmacological reversal. The tachykinin NK1 receptor antagonist, CP-96,345, produced a minor increase in withdrawal thresholds in animals with the cuff left permanently implanted. To determine the effect of early and repeated administration of CP-96,345, it was given daily on days 1–4. The cuff was removed on day 4. Six days later, readings showed reversal of tactile hypersensitivity. We suggest that persistent neuropathic pain occurs from processes that develop over several hours and days, and that some of these processes may be prevented by early medical intervention. Thus, nerve injury in the context of chronic neuropathic pain should be treated in a similar manner to nerve injury resulting from stroke, spinal cord injury, and other types of neurotrauma. We suggest that effective medical intervention within the first few hours after nerve injury may spare a patient from a chronic debilitating pain that may be refractory to later therapies

Perceptions of and responses to coastal erosion risks:The case of Cotonou in Benin

Intensive erosion has affected the coastal zone of Cotonou for several decades. An analysis of satellite images showed an average coastline retreat of 115 m in the study area over the period 2002–2013 with several hundred houses destroyed. Since 2014, a stabilisation of the coastline is observed. This study aimed at identifying the atrisk population and at analysing the perceptions of people who experience and those who manage coastal erosion risk, as well as the responses adopted. Based on four criteria and their hierarchy, we identified five profiles of inhabitants in this risk zone. (1) Wealthy people who leave the zone when they are affected or (2) fall into the category of people in danger in case they cannot migrate. (3) Fishermen who deliberately stay near the sea. (4) The most precarious people, trapped in the risk zone. Finally, (5) poor newcomers who continually increase the at-risk population. With the recent stabilisation of the coastline, the national authorities manage the “hazard” component of the risk. However, the majority of the population is not serene. The anthropogenic stress linked to evictions gradually replaced the stress to be engulfed by the sea. We conclude that the “vulnerability” component of the risk is not yet resolved. All categories of the population in this sensitive area need to be secured. Cooperation among multiple levels of governance, the application of land use planning regulations and of the Kampala Convention and the involvement of local communities are all measures which will enable to meet this objective

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Health, wellbeing and nutrition: Domain report

The escalation of global political, economic and ecological crises and associated price surges has contributed to interdependent forms of malnutrition – undernutrition, overweight and obesity – with enduring societal consequences. This study investigates the factors influencing the adoption of healthy diets in five African cities – Bukavu, DRC, Freetown, Sierra Leone, Kampala, Uganda, Lilongwe, Malawi and Nairobi, Kenya. It explores the engagement of policymakers, consumers, private actors and further stakeholders in food and health systems. Across all cities, rising food insecurity and the prevalence of non-communicable diseases (NCDs) linked to unhealthy dietary patterns, notably around consumption of ultra-processed foods, are observed. Despite urban residents generally experiencing lower food insecurity than rural counterparts, people with low incomes, particularly those living in informal settlements, remain vulnerable. Additional axes of vulnerability that intersect with low incomes are gender, age, disability and migrant/refugee status. Socioeconomic drivers that exacerbate food and nutrition insecurity include the high cost of nutritious diets, inadequate market, road, water and sanitation infrastructures, and the proliferation of unhealthy processed foods. Policy responses predominantly prioritise food quantity over quality, overlooking the importance of healthy diets. Additionally, profit-driven dynamics, within food and healthcare systems, and inconsistent resident knowledge of healthy, balanced diets, perpetuate the cycle of ill-health driven by poor nutrition, while informal food vendors, vital for low-income urbanites, face neglect or harassment. However, city governments possess avenues for intervention, such as awareness campaigns, social security mechanisms, and social and technical infrastructure support for water and sanitation, markets and street vendors. Primary healthcare services and community health workers play crucial roles in addressing malnutrition, youth development and adolescent health. Multisectoral collaboration is advocated for broadening the impact of strategic interventions from neighbourhood to city level. Reform efforts necessitate broad coalitions, encompassing governments, civil society and the private sector

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Russell Body Dermatitis Due to Syphilis.

status: publishe