Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles

Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer.     

Insulin Resistance of Puberty

Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity.     

Predictors of electromechanical dissociation during cardiac arrest

ECG patterns observed during cardiac arrest were analyzed in 261 comatose cardiac arrest survivors. Forty-seven patients (18%) exhibited electromechanical dissociation (EMD) at some point before restoration of stable spontaneous circulation. These patients had a higher mortality (P = .05) and a lower rate of cerebral recovery (P = .01) during the one-year follow-up than study patients who did not exhibit EMD. Patients who developed EMD subsequent to defibrillation had better outcome than patients presenting with EMD. Multivariate analysis revealed that age more than 70 years old (P = .007), pulmonary disease (P less than .001), diabetes (P = .013, in-hospital arrests only), and prearrest hypoxemia (P = .013, outside-hospital arrests only) were independently predictive of the occurrence of EMD. Although the generalizability of these findings is limited, they may offer new clues to the pathophysiology of EMD.     

Interventions to support recovery after domestic and sexual violence in primary care

Abstract

Experiences of domestic and sexual violence are common in patients attending primary care. Most often they are not identified due to barriers to asking by health practitioners and disclosure by patients. Women are more likely than men to experience such violence and present with mental and physical health symptoms to health practitioners. If identified through screening or case finding as experiencing violence they need to be supported to recover from these traumas. This paper draws on systematic reviews published in 2013–2015 and a further literature search undertaken to identify recent intervention studies relevant to recovery from domestic and sexual violence in primary care. There is limited evidence as to what interventions in primary care assist with recovery from domestic violence; however, they can be categorized into the following areas: first line response and referral, psychological treatments, safety planning and advocacy, including through home visitation and peer support programmes, and parenting and mother–child interventions. Sexual violence interventions usually include trauma informed care and models to support recovery. The most promising results have been from nurse home visiting advocacy programmes, mother–child psychotherapeutic interventions, and specific psychological treatments (Cognitive Behaviour Therapy, Trauma informed Cognitive Behaviour Therapy and, for sexual assault, Exposure and Eye Movement Desensitization and Reprocessing Interventions). Holistic healing models have not been formally tested by randomized controlled trials, but show some promise. Further research into what supports women and their children on their trajectory of recovery from domestic and sexual violence is urgently needed.     

Effectiveness of seatbelts in mitigating traumatic brain injury severity

INTRODUCTION Over the past few decades,traumatic brain injuries(TBIs)have become one of the leading causes of death and the leading cause of injury-related death in the USA.[1,2]It is estimated that 1.70 million people are subject to TBIs each year.[2]Males are more likely to sustain TBIs(59%);the most common age groups are 0–5 years,15–19 years,and>65 years.[2]Approximately 1.36 million people present to the emergency department(ED),275,000 are admitted to the hospital,and 52,000 people die from TBIs.[2]The leading causes of TBIs are falling(35.2%),motor vehicle collisions(MVCs,17.3%),struck by/against an object(16.5%),and assault(10.0%).[2]These statistics combine to make TBIs the leading cause of injury-related death in the USA at 30.5%.[2]It has been estimated that,with specifi c guidelines from the Brain Trauma Foundation,up to 50.0%of the 52,000 TBIrelated deaths may be prevented.[3]     

Cellular and molecular pathophysiology in the progression of Parkinson’s disease

Metabolic Brain Disease - Parkinson’s disease (PD) is a neurodegenerative disorder etiologically linked to the loss of substantia nigra (SN) dopaminergic neurons in the mid-brain. The...