Dissecting the contribution of knee joint NGF to spinal nociceptive sensitization in a model of OA pain in the rat

Objective: Although analgesic approaches targeting nerve growth factor (NGF) for the treatment of osteoarthritis (OA) pain remain of clinical interest, neurophysiological mechanisms by which NGF contribute to OA pain remain unclear. We investigated the impact of local elevation of knee joint NGF on knee joint, vs remote (hindpaw), evoked responses of spinal neurones in a rodent model of OA pain. Design: In vivo spinal electrophysiology was carried out in anaesthetised rats with established pain behaviour and joint pathology following intra-articular injection of monosodium iodoacetate (MIA), vs injection of saline. Neuronal responses to knee joint extension and flexion, mechanical punctate stimulation of the peripheral receptive fields over the knee and at a remote site (ipsilateral hind paw) were studied before, and following, intra-articular injection of NGF (10 mg/50 ml) or saline. Results: MIA-injected rats exhibited significant local (knee joint) and remote (lowered hindpaw withdrawal thresholds) changes in pain behaviour, and joint pathology. Intra-articular injection of NGF significantly (P<0.05) increased knee extension-evoked firing of spinal neurones and the size of the peripheral receptive fields of spinal neurones (100% increase) over the knee joint in MIA rats, compared to controls. Intra-articular NGF injection did not significantly alter responses of spinal neurones following noxious stimulation of the ipsilateral hind paw in MIA-injected rats. Conclusion: The facilitatory effects of intra-articular injection of NGF on spinal neurones receiving input from the knee joint provide a mechanistic basis for NGF mediated augmentation of OA knee pain, however additional mechanisms may contribute to the spread of pain to remote site

The anti-NGF antibody muMab 911 both prevents and reverses pain behaviour and subchondral osteoclast numbers in a rat model of osteoarthritis pain

Objective: Nerve growth factor (NGF) has a pivotal role in peripheral hyperalgesia and inflammation; anti-NGF antibodies attenuate pain responses in inflammatory pain models, and in people with osteoarthritis (OA) or low back pain. The aim of this study was to characterise the peripheral mechanisms contributing to the analgesic effects of anti-NGF antibody treatment in an established model of joint pain, which mimics key clinical features of OA. Design: Effects of preventative vs therapeutic treatment with an anti-NGF antibody (monoclonal antibody 911: muMab 911 (10 mg/kg, s.c.)) on pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWT)), cartilage damage, synovitis and numbers of subchondral osteoclasts were investigated in the monosodium iodoacetate (MIA) model. Potential direct effects of NGF on receptor activator of nuclear factor kappa-B ligand (RANKL) mediated osteoclastogenesis were investigated in cultured human osteoclasts. Results: Intra-articular MIA injection resulted in significant pain behaviour, cartilage damage, synovitis and increased numbers of subchondral osteoclasts. Both preventative and therapeutic treatment with muMab 911 significantly prevented, or reversed, MIA-induced pain behaviour, but did not alter cartilage or synovial pathology quantified at the end of the treatment period. NGF did not facilitate RANKL driven osteoclast differentiation in vitro, but preventative or therapeutic muMab 911 reduced numbers of TRAP positive osteoclasts in the subchondral bone. Conclusions: We demonstrate that anti-NGF antibody treatment attenuates OA pain behaviour despite permitting cartilage damage and synovitis. Indirec

Anemia prevalence in women of reproductive age in low- and middle-income countries between 2000 and 2018

Anemia is a globally widespread condition in women and is associated with reduced economic productivity and increased mortality worldwide. Here we map annual 2000–2018 geospatial estimates of anemia prevalence in women of reproductive age (15–49 years) across 82 low- and middle-income countries (LMICs), stratify anemia by severity and aggregate results to policy-relevant administrative and national levels. Additionally, we provide subnational disparity analyses to provide a comprehensive overview of anemia prevalence inequalities within these countries and predict progress toward the World Health Organization’s Global Nutrition Target (WHO GNT) to reduce anemia by half by 2030. Our results demonstrate widespread moderate improvements in overall anemia prevalence but identify only three LMICs with a high probability of achieving the WHO GNT by 2030 at a national scale, and no LMIC is expected to achieve the target in all their subnational administrative units. Our maps show where large within-country disparities occur, as well as areas likely to fall short of the WHO GNT, offering precision public health tools so that adequate resource allocation and subsequent interventions can be targeted to the most vulnerable populations.Peer reviewe

Cross-national analysis of the associations between traumatic events and suicidal behavior: findings from the WHO World Mental Health Surveys

Background: Community and clinical data have suggested there is an association between trauma exposure and suicidal behavior (i.e., suicide ideation, plans and attempts). However, few studies have assessed which traumas are uniquely predictive of: the first onset of suicidal behavior, the progression from suicide ideation to plans and attempts, or the persistence of each form of suicidal behavior over time. Moreover, few data are available on such associations in developing countries. The current study addresses each of these issues. Methodology/Principal Findings: Data on trauma exposure and subsequent first onset of suicidal behavior were collected via structured interviews conducted in the households of 102,245 (age 18+) respondents from 21 countries participating in the WHO World Mental Health Surveys. Bivariate and multivariate survival models tested the relationship between the type and number of traumatic events and subsequent suicidal behavior. A range of traumatic events are associated with suicidal behavior, with sexual and interpersonal violence consistently showing the strongest effects. There is a dose-response relationship between the number of traumatic events and suicide ideation/attempt; however, there is decay in the strength of the association with more events. Although a range of traumatic events are associated with the onset of suicide ideation, fewer events predict which people with suicide ideation progress to suicide plan and attempt, or the persistence of suicidal behavior over time. Associations generally are consistent across high-, middle-, and low-income countries. Conclusions/Significance: This study provides more detailed information than previously available on the relationship between traumatic events and suicidal behavior and indicates that this association is fairly consistent across developed and developing countries. These data reinforce the importance of psychological trauma as a major public health problem, and highlight the significance of screening for the presence and accumulation of traumatic exposures as a risk factor for suicide ideation and attempt