The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

The present historical moment may seem a particularly inopportune time to review Bowling Alone, Robert Putnam's latest exploration of civic decline in America. After all, the outpouring of volunteerism, solidarity, patriotism, and self-sacrifice displayed by Americans in the wake of the September 11 terrorist attacks appears to fly in the face of Putnam's central argument: that \"social capital\" -defined as \"social networks and the norms of reciprocity and trustworthiness that arise from them\" (p. 19)'has declined to dangerously low levels in America over the last three decades. However, Putnam is not fazed in the least by the recent effusion of solidarity. Quite the contrary, he sees in it the potential to \"reverse what has been a 30to 40-year steady decline in most measures of connectedness or community.\"' As an example of how the current \"war on terrorism\" could generate a durable civic renewal, Putnam points to the burst in civic practices that occurred during and after World War II, which he says \"permanently marked\" the generation that lived through it and had a \"terrific effect on American public life over the last half-century.\" 3 If Americans can follow this example and channel their current civic

Bowling alone: The collapse and revival of American community

In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at

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EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Rheumatoid arthritis is the most common inflammatory arthritis and is a major cause of disability. It existed in early Native American populations several thousand years ago but might not have appeared in Europe until the 17th century. Early theories on the pathogenesis of rheumatoid arthritis focused on autoantibodies and immune complexes. T-cell-mediated antigen-specific responses, T-cell-independent cytokine networks, and aggressive tumour-like behaviour of rheumatoid synovium have also been implicated. More recently, the contribution of autoantibodies has returned to the forefront. Based on the pathogenic mechanisms, specific therapeutic interventions can be designed to suppress synovial inflammation and joint destruction in rheumatoid arthritis.

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Evolving concepts of rheumatoid arthritis

The four Visegrad states — Poland, the Czech Republic, Slovakia (until 1993 Czechoslovakia) and Hungary — form a compact area between Germany and Austria in the west and the states of the former USSR in the east. They are bounded by the Baltic in the north and the Danube river in the south. They are cut by the Sudeten and Carpathian mountain ranges, which divide Poland off from the other states. Poland is an extension of the North European plain and like the latter is drained by rivers that flow from south to north west — the Oder, the Vlatava and the Elbe, the Vistula and the Bug. The Danube is the great exception, flowing from its source eastward, turning through two 90-degree turns to end up in the Black Sea, forming the barrier and often the political frontier between central Europe and the Balkans. Hungary to the east of the Danube is also an open plain. The region is historically and culturally part of western Europe, but its eastern Marches now represents a vital strategic zone between Germany and the core of the European Union to the west and the Russian zone to the east.

Economy and Society

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(00)05112-6.pdf

Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births.

Angiogenesis and inflammation are closely integrated processes in osteoarthritis (OA) and may affect disease progression and pain. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation. Angiogenesis can also promote chondrocyte hypertrophy and endochondral ossification, contributing to radiographic changes in the joint. Inflammation sensitizes nerves, leading to increased pain. Innervation can also accompany vascularization of the articular cartilage, where compressive forces and hypoxia may stimulate these new nerves, causing pain even after inflammation has subsided. Inhibition of inflammation and angiogenesis may provide effective therapeutics for the treatment of OA by improving symptoms and retarding joint damage. This review aims to summarize (i) the evidence that angiogenesis and inflammation play an important role in the pathophysiology of OA and (ii) possible directions for future research into therapeutics that could effectively treat this disease.

Osteoarthritis, angiogenesis and inflammation

Regional differences in population levels of alcohol-related harm exist across Great Britain, but these are not entirely consistent with differences in population levels of alcohol consumption. This incongruence may be due to the use of self-report surveys to estimate consumption. Survey data are subject to various biases and typically produce consumption estimates much lower than those based on objective alcohol sales data. However, sales data have never been used to estimate regional consumption within Great Britain (GB). This ecological study uses alcohol retail sales data to provide novel insights into regional alcohol consumption in GB, and to explore the relationship between alcohol consumption and alcohol-related mortality. Alcohol sales estimates derived from electronic sales, delivery records and retail outlet sampling were obtained. The volume of pure alcohol sold was used to estimate per adult consumption, by market sector and drink type, across eleven GB regions in 2010–11. Alcohol-related mortality rates were calculated for the same regions and a cross-sectional correlation analysis between consumption and mortality was performed. Per adult consumption in northern England was above the GB average and characterised by high beer sales. A high level of consumption in South West England was driven by on-trade sales of cider and spirits and off-trade wine sales. Scottish regions had substantially higher spirits sales than elsewhere in GB, particularly through the off-trade. London had the lowest per adult consumption, attributable to lower off-trade sales across most drink types. Alcohol-related mortality was generally higher in regions with higher per adult consumption. The relationship was weakened by the South West and Central Scotland regions, which had the highest consumption levels, but discordantly low and very high alcohol-related mortality rates, respectively. This study provides support for the ecological relationship between alcohol-related mortality and alcohol consumption. The synthesis of knowledge from a combination of sales, survey and mortality data, as well as primary research studies, is key to ensuring that regional alcohol consumption, and its relationship with alcohol-related harms, is better understood.

https://link.springer.com/content/pdf/10.1186%2F1471-2458-15-1.pdf

Regional alcohol consumption and alcohol-related mortality in Great Britain: novel insights using retail sales data.

Television viewing has been associated with greater sub- sequent attention problems in children. Few studies have examined the possibility of a similar association between video games and attention problems, and none of these has used a longitudinal design. METHODS: A sample of 1323 middle childhood participants were as- sessed during a 13-month period by parent- and child-reported televi- sion and video game exposure as well as teacher-reported attention problems. Another sample of 210 late adolescent/early adult partici- pants provided self-reports of television exposure, video game expo- sure, and attention problems. RESULTS: Exposure to television and video games was associated with greater attention problems. The association of television and video games to attention problems in the middle childhood sample remained significant when earlier attention problems and gender were statisti- cally controlled. The associations of screen media and attention prob- lems were similar across media type (television or video games) and age (middle childhood or late adolescent/early adult). CONCLUSIONS: Viewing television and playing video games each are associated with increased subsequent attention problems in child- hood. It seems that a similar association among television, video games, and attention problems exists in late adolescence and early adulthood. Research on potential risk factors for attention problems should be expanded to include video games in addition to television. Pediatrics 2010;126:214-221

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Television and Video Game Exposure and the Development of Attention Problems

During osteoarthritis (OA), angiogenesis is increased in the synovium, osteophytes and menisci and leads to ossification in osteophytes and the deep layers of articular cartilage. Angiogenic and antiangiogenic factors might both be upregulated in the osteoarthritic joint; however, vascular growth predominates, and the articular cartilage loses its resistance to vascularization. In addition, blood vessel growth is increased at--and disrupts--the osteochondral junction. Angiogenesis in this location is dependent on the creation of channels from subchondral bone spaces into noncalcified articular cartilage. Inflammation drives synovial angiogenesis through macrophage activation. Blood vessel and nerve growth are linked by common pathways that involve the release of proangiogenic factors, such as vascular endothelial growth factor, β-nerve growth factor and neuropeptides. Proangiogenic factors might also stimulate nerve growth, and molecules produced by vascular cells could both stimulate and guide nerve growth. As sensory nerves grow along new blood vessels in osteoarthritic joints, they eventually penetrate noncalcified articular cartilage, osteophytes and the inner regions of menisci. Angiogenesis could, therefore, contribute to structural damage and pain in OA and provide potential targets for new treatments.

David A. Walsh

Papers

Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births.

Osteoarthritis, angiogenesis and inflammation

Regional alcohol consumption and alcohol-related mortality in Great Britain: novel insights using retail sales data.

Television and Video Game Exposure and the Development of Attention Problems

Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis