Improved survival for adolescents and young adults with Hodgkin lymphoma and continued high survival for children in the Netherlands: a population-based study during 1990–2015

Population-based studies that assess long-term patterns of incidence, major aspects of treatment and survival are virtually lacking for Hodgkin lymphoma (HL) at a younger age. This study assessed the progress made for young patients with HL (<25 years at diagnosis) in the Netherlands during 1990–2015. Patient and tumour characteristics were extracted from the population-based Netherlands Cancer Registry. Time trends in incidence and mortality rates were evaluated with average annual percentage change (AAPC) analyses. Stage at diagnosis, initial treatments and site of treatment were studied in relation to observed overall survival (OS). A total of 2619 patients with HL were diagnosed between 1990 and 2015. Incidence rates increased for 18–24-year-old patients (AAPC + 1%, P = 0·01) only. Treatment regimens changed into less radiotherapy and more ‘chemotherapy only’, different for age group and stage. Patients aged 15–17 years were increasingly treated at a paediatric oncology centre. The 5-year OS for children was already high in the early 1990s (93%). For patients aged 15–17 and 18–24 years the 5-year OS improved from 84% and 90% in 1990–1994 to 96% and 97% in 2010–2015, respectively. Survival for patients aged 15–17 years was not affected by site of treatment. Our present data demonstrate that significant progress in HL treatment has been made in the Netherlands since 1990.     

Embryology and variations of the recurrent artery of Heubner

The recurrent artery of Heubner (RAH) is a very fascinating artery for various reasons. The first one is its early development in the embryologic and phylogenic life. The second one is the discrepancy between its diameter and its functional importance and the last but not least reason is the many variations of origin and course of this artery. For more than a century, numerous studies furnished important information about variations in origin, course, and parenchymal territory of the RAH. The most important anomaly concerning the RAH is the accessory middle cerebral artery and well-illustrates the complexity of its embryologic development. For these reasons, authors provide a review of anatomical variations of this artery that could be encountered with a particular attention given to the history and embryological knowledge.     

Plasma homocysteine,dietary B vitamins,betaine, and choline and risk of peripheral artery disease

Objective

Few studies have examined the roles of homocysteine and related nutrients in the development of peripheral artery disease (PAD). We examined the associations between plasma homocysteine, dietary B vitamins, betaine, choline, and supplemental folic acid use and incidence of PAD.

Methods

We used two cohort studies of 72,348 women in the Nurses' Health Study (NHS, 1990–2010) and 44,504 men in the Health Professionals Follow-up Study (HPFS, 1986–2010). We measured plasma homocysteine in nested matched case–control studies of clinically recognized PAD within both cohorts, including 143 PAD cases and 424 controls within the NHS (1990–2010) and 143 PAD cases and 428 controls within the HPFS (1994–2008). We examined the association between diet and risk of incident PAD in the cohorts using a food frequency questionnaire and 790 cases of PAD over 3.1 million person-years of follow-up.

Results

Higher homocysteine levels were positively associated with risk of PAD in men (adjusted IRR 2.17; 95% CI, 1.08–4.38 for tertile 3 vs. 1). There was no evidence of an association in women (adjusted IRR 1.14; 95% CI, 0.61–2.12). Similarly, higher folate intake, including supplements, was inversely associated with risk of PAD in men (adjusted HR 0.90; 95% CI, 0.82–0.98 for each 250 μg increase) but not women (HR 1.01, 95% CI, 0.88–1.15). Intakes of the other B vitamins, betaine, and choline were not consistently associated with risk of PAD in men or women.

Conclusion

Homocysteine levels were positively associated and dietary folate intake was inversely associated with risk of PAD in men but not in women.     

Central role for hydrogen peroxide in P2Y1 ADP receptor-mediated cellular responses in vascular endothelium

ADP activates a family of cell surface receptors that modulate signaling pathways in a broad range of cells. ADP receptor antagonists are widely used to treat cardiovascular disease states. These studies identify a critical role for the stable reactive oxygen species hydrogen peroxide (H₂O₂) in mediating cellular responses activated by the G protein-coupled P2Y1 receptor for ADP. We found that ADP-dependent phosphorylation of key endothelial signaling proteins—including endothelial nitric oxide synthase, AMP-activated protein kinase, and the actin-binding MARCKS protein—was blocked by preincubation with PEG-catalase, which degrades H₂O₂. ADP treatment promoted the H₂O₂-dependent phosphorylation of c-Abl, a nonreceptor tyrosine kinase that modulates the actin cytoskeleton. Cellular imaging experiments using fluorescence resonance energy transfer-based biosensors revealed that ADP-stimulated activation of the cytoskeleton-associated small GTPase Rac1 was independent of H₂O₂. However, Rac1-dependent activation of AMP-activated protein kinase, the signaling phospholipid phosphatidylinositol-(4, 5)-bisphosphate, and the c-Abl–interacting protein CrkII are mediated by H₂O₂. We transfected endothelial cells with differentially targeted HyPer2 H₂O₂ biosensors and found that ADP promoted a marked increase in H₂O₂ levels in the cytosol and caveolae, and a smaller increase in mitochondria. We performed a screen for P2Y1 receptor-mediated receptor tyrosine kinase transactivation and discovered that ADP transactivates Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase expressed in these cells. Our observation that P2Y1 receptor-mediated responses involve Flt3 transactivation may identify a unique mechanism whereby cancer chemotherapy with receptor tyrosine kinase inhibitors promotes vascular dysfunction. Taken together, these findings establish a critical role for endogenous H₂O₂ in control of ADP-mediated signaling responses in the vascular wall.Beyond their established roles in intracellular energy flux and nucleic acid metabolism, purine nucleotides also serve as intercellular messenger molecules that regulate signal transduction pathways in a broad range of cells and tissues (1–3). The purine nucleotide ADP binds to G protein-coupled P2Y purinergic cell surface receptors, which are expressed in diverse mammalian cells, including blood platelets and vascular endothelial cells (reviewed in refs. 2 and 4). ADP is a critical determinant of platelet aggregation, blood vessel tone, and vascular wall integrity. Platelet granules contain high concentrations of ADP, which is released during platelet aggregation. The released ADP binds to P2Y12 and P2Y1 cell surface receptors for ADP on platelets and further potentiates platelet aggregation. P2Y receptor antagonists play a central role in cardiovascular therapeutics (2, 4): The P2Y12 blocker clopidogrel is one of the most commonly prescribed drugs in the United States, and other P2Y1 and P2Y12 blockers are being actively developed and tested for treatment of cardiovascular and cerebrovascular disease states. ADP also binds to P2Y1 receptors in vascular endothelial cells and rapidly activates endothelial nitric oxide synthase (eNOS) (5). Endothelium-generated nitric oxide (NO) inhibits platelet aggregation (3, 6) and provides an important feedback loop between endothelial cells and platelets that serves to attenuate the direct proaggregatory effects of ADP on platelets. ADP may also be released from the vascular endothelium and act in an autocrine or paracrine fashion to exert longer-term effects on vascular cell migration and barrier function (1, 3, 7–9). Clearly, a deeper understanding of P2Y receptor pharmacodynamics could inform current efforts in the development of novel purinergic antagonist drugs.Purinergic receptors for ADP can be classified by their structure and mode of action into two distinct receptor families, P2X and P2Y. P2X receptors are ligand-gated ion channels, whereas members of the P2Y receptor family are G protein-coupled receptors. ADP signaling pathways in platelets have been extensively characterized, yet the roles of ADP in the modulation of endothelial responses are less well understood. The current studies have focused on exploring the signaling pathways activated by P2Y1 receptors in vascular endothelial cells. We have shown (6) that ADP acts via P2Y1 receptors to activate the endothelial isoform of nitric oxide synthase (eNOS) in cultured endothelial cells and also modulates the activation of key signaling protein kinases including the AMP-activated protein kinase (AMPK). We also found that ADP promotes the P2Y1 ADP receptor-dependent endothelial cell migration through activation of the small GTPase Rac1 (6, 10). Discovering the involvement of Rac1 provided an important clue to the mechanisms whereby ADP exerts its influence on endothelial cell responses.Rac1 is an actin-binding cytoskeletal regulatory protein and is a member of the Rho GTPase protein family. The activation of eNOS by P2Y1 receptors for ADP depends on Rac1 (1, 6). Rac1 has been identified as a critical determinant of endothelial cell migration and barrier function, at least in part by modulating the levels of intracellular NO and hydrogen peroxide (H₂O₂) (11–15). H₂O₂ is a stable reactive oxygen species (ROS) that has been identified in recent years as a physiologically important intracellular messenger molecule (11–14), belying the classical concept of ROS functioning solely as deleterious molecules responsible for pathological states such as aging and neurodegeneration (14, 16). We reported (17, 18) that endogenous H₂O₂ regulates endothelial cell migration via dynamic signaling pathways involving the MARCKS protein, a ubiquitous phosphoprotein that translocates from the cell membrane to the actin cytoskeleton. The MARCKS protein also reversibly sequesters the signaling phospholipid phosphatidylinositol-(4, 5)-bisphosphate (PIP₂). PIP₂ is an important activator of proteins that initiate actin nucleation, including the phosphoprotein c-Abl, a nonreceptor tyrosine kinase that has been implicated in the dynamic cytoskeletal rearrangements that modulate endothelial barrier function. Endogenous H₂O₂ induces changes in cellular phospholipid metabolism via the phosphorylation and translocation of MARCKS in endothelial cells, yet the connections between receptor activation and intracellular modulation of H₂O₂ levels are incompletely understood.The roles of H₂O₂ as a physiological intracellular messenger molecule were initially discovered through studies of growth factor-dependent activation of their cognate receptor tyrosine kinases (19, 20), which then signal to redox-regulated phosphoprotein phosphatases via H₂O₂ (20). In contrast to the widespread involvement of H₂O₂ in receptor tyrosine kinase signaling, only a handful of G protein-coupled receptors have been shown to directly modulate H₂O₂ levels (11, 16, 21, 22). Indeed, the roles of H₂O₂ in modulation of physiological responses have not yet been clearly defined for G protein-coupled receptors. In these studies, we present observations that establish that the G protein-coupled P2Y1 receptor for ADP modulates key H₂O₂-dependent signaling responses in the vascular endothelium via transactivation of the receptor tyrosine kinase Flt3.     

Maximizing the benefits of antiretroviral therapy for key affected populations

Introduction

Scientific research has demonstrated the clinical benefits of earlier initiation of antiretroviral treatment (ART), and that ART can markedly reduce HIV transmission to sexual partners. Ensuring universal access to ART for those who need it has long been a core principle of the HIV response, and extending the benefits of ART to key populations is critical to increasing the impact of ART and the overall effectiveness of the HIV response. However, this can only be achieved through coordinated efforts to address political, social, legal and economic barriers that key populations face in accessing HIV services.

Discussion

Recent analyses show that HIV prevalence levels among key populations are far higher than among the general population, and they experience a range of biological and behavioural factors, and social, legal and economic barriers that increase their vulnerability to HIV and have resulted in alarmingly low ART coverage. World Health Organization 2014 consolidated guidance on HIV among key populations offers the potential for increased access to ART by key populations, following the same principles as for the general adult population. However, it should not be assumed that key populations will achieve greater access to ART unless stigma, discrimination and punitive laws, policies and practices that limit access to ART and other HIV interventions in many countries are addressed.

Conclusions

Rights-based approaches and investments in critical enablers, such as supportive legal and policy environments, are essential to enable wider access to ART and other HIV interventions for key populations. The primary objective of ART should always be to treat the person living with HIV; prevention is an important, additional benefit. ART should be provided only with informed consent. The preventive benefits of treatment must not be used as a pretext for failure to provide other necessary HIV programming for key populations, including comprehensive harm reduction and other prevention interventions tailored to meet the needs of key populations. An end to AIDS is only possible if we overcome the barriers of criminalization, stigma and discrimination that remain key drivers of the HIV epidemics among key populations.     

Repeated Nitrogen Dioxide Exposures and Eosinophilic Airway Inflammation in Asthmatics: A Randomized Crossover Study

Background: Nitrogen dioxide (NO₂), a ubiquitous atmospheric pollutant, may enhance the asthmatic response to allergens through eosinophilic activation in the airways. However, the effect of NO₂ on inflammation without allergen exposure is poorly studied.Objectives: We investigated whether repeated peaks of NO₂, at various realistic concentrations, induce changes in airway inflammation in asthmatics.Methods: Nineteen nonsmokers with asthma were exposed at rest in a double-blind, crossover study, in randomized order, to 200 ppb NO₂, 600 ppb NO₂, or clean air once for 30 min on day 1 and twice for 30 min on day 2. The three series of exposures were separated by 2 weeks. The inflammatory response in sputum was measured 6 hr (day 1), 32 hr (day 2), and 48 hr (day 3) after the first exposure, and compared with baseline values measured twice 10–30 days before the first exposure.Results: Compared with baseline measurements, the percentage of eosinophils in sputum increased by 57% after exposure to 600 ppb NO₂ (p = 0.003) but did not change significantly after exposure to 200 ppb. The slope of the association between the percentage of eosinophils and NO₂ exposure level was significant (p = 0.04). Eosinophil cationic protein in sputum was highly correlated with eosinophil count and increased significantly after exposure to 600 ppb NO₂ (p = 0.001). Lung function, which was assessed daily, was not affected by NO₂ exposure.Conclusions: We observed that repeated peak exposures of NO₂ performed without allergen exposure were associated with airway eosinophilic inflammation in asthmatics in a dose-related manner.Citation: Ezratty V, Guillossou G, Neukirch C, Dehoux M, Koscielny S, Bonay M, Cabanes PA, Samet JM, Mure P, Ropert L, Tokarek S, Lambrozo J, Aubier M. 2014. Repeated nitrogen dioxide exposures and eosinophilic airway inflammation in asthmatics: a randomized crossover study. Environ Health Perspect 122:850–855; http://dx.doi.org/10.1289/ehp.1307240