COX-2: Where are we in 2003? - Be strong and resolute: continue to use COX-2 selective inhibitors at recommended dosages in appropriate patients

Cyclooxygenase (COX)-2 selective inhibitors have been shown to have comparable efficacy to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Large outcome studies have shown that patients with OA and RA not taking low-dose aspirin have fewer symptomatic and complicated upper GI events when treated with COX-2 selective inhibitors than with nonselective NSAIDs. When used in recommended dosages, there is no convincing evidence that patients treated with COX-2 selective inhibitors have an increased incidence of cardiovascular thrombotic events, including non-fatal myocardial infarction, than patients treated with either placebo or nonselective NSAIDs other than naproxen. Co-therapy with low-dose aspirin is recommended in patients with OA and RA at increased risk for cardiovascular events; the need for gastroprotective therapy in such patients is controversial.     

COX-2: Where are we in 2003? - Specific cyclooxygenase-2 inhibitors and aspirin-exacerbated respiratory disease

The use of analgesic anti-inflammatory agents in patients with asthma is clinically challenging because of the prevalence (10-20%) of aspirin hypersensitivity. Aspirin-exacerbated respiratory disease (AERD), or aspirin-induced asthma, is characterized by asthma and rhinitis triggered by the ingestion of aspirin and non-steroidal anti-inflammatory drugs. AERD is associated with upper and lower respiratory-tract mucosal inflammation, progressive sinusitis, nasal polyposis, and asthma regardless of whether patients avoid triggering drugs. The mechanism underlying the propensity of aspirin and non-steroidal anti-inflammatory drugs to cause this reaction is thought to involve inhibition of the synthesis of protective prostaglandins (PGs), resulting in an increase in the synthesis of cysteinyl leukotrienes by eosinophils and mast cells. Clinical data suggest that protective PGs are derived from cyclooxygenase (COX)-1 because studies have now confirmed that drugs specifically inhibiting COX-2 are not cross-reactive with aspirin in patients with AERD.     

COX-2: Where are we in 2003? - Specific cyclooxygenase-2 inhibitors and aspirin-exacerbated respiratory disease

The use of analgesic anti-inflammatory agents in patients with asthma is clinically challenging because of the prevalence (10–20%) of aspirin hypersensitivity. Aspirin-exacerbated respiratory disease (AERD), or aspirin-induced asthma, is characterized by asthma and rhinitis triggered by the ingestion of aspirin and non-steroidal anti-inflammatory drugs. AERD is associated with upper and lower respiratory-tract mucosal inflammation, progressive sinusitis, nasal polyposis, and asthma regardless of whether patients avoid triggering drugs. The mechanism underlying the propensity of aspirin and non-steroidal anti-inflammatory drugs to cause this reaction is thought to involve inhibition of the synthesis of protective prostaglandins (PGs), resulting in an increase in the synthesis of cysteinyl leukotrienes by eosinophils and mast cells. Clinical data suggest that protective PGs are derived from cyclooxygenase (COX)-1 because studies have now confirmed that drugs specifically inhibiting COX-2 are not cross-reactive with aspirin in patients with AERD.     

COX-2: Where are we in 2003? - Distinction from NSAIDs becoming blurred

The distinction between cyclooxygenase-2-selective inhibitors (CSIs) and nonsteroidal anti-inflammatory drugs ultimately must be clinical and must be clinically and economically relevant. This distinction needs to be demonstrated in a substantial and clinically relevant difference in the respective rates of serious adverse reactions of the upper gastrointestinal tract. Event-driven, randomized, blinded, controlled trials with sufficient power are required to resolve uncertainties concerning the relative risk of thrombotic cardiovascular events in patients taking CSIs who have risk factors for these events. Patients and situations more representative of those in primary-care practice - elderly, comorbidities, comedication - need to be included in larger studies to provide a better understanding of the risks and benefits of CSIs.     

Cox-2: where are we in 2003? - Cardiovascular risk and Cox-2 inhibitors

Selective cyclooxygenase-2 (COX-2) inhibitors were developed to reduce the gastrointestinal toxicity of conventional nonsteroidal anti-inflammatory agents. However, COX-2 inhibitors decrease prostacyclin production and may disrupt the normal homeostatic balance, leading to a prothrombotic state and offsetting the potential gastrointestinal benefits. Available clinical data and basic biological studies raise significant concern about the potential prothrombotic effect of this class of drugs. Two recent studies with a newer, more selective COX-2 inhibitor have added to the already existing concern about the cardiovascular safety of these agents. The widespread use of these agents mandates prospective, randomized evaluation of the cardiovascular safety of COX-2 inhibitors.     

Cox-2: where are we in 2003? - Cardiovascular risk and Cox-2 inhibitors

Selective cyclooxygenase-2 (COX-2) inhibitors were developed to reduce the gastrointestinal toxicity of conventional nonsteroidal anti-inflammatory agents. However, COX-2 inhibitors decrease prostacyclin production and may disrupt the normal homeostatic balance, leading to a prothrombotic state and offsetting the potential gastrointestinal benefits. Available clinical data and basic biological studies raise significant concern about the potential prothrombotic effect of this class of drugs. Two recent studies with a newer, more selective COX-2 inhibitor have added to the already existing concern about the cardiovascular safety of these agents. The widespread use of these agents mandates prospective, randomized evaluation of the cardiovascular safety of COX-2 inhibitors.     

Cox-2: Where are we in 2003? - The role of cyclooxygenase-2 in bone repair

Prostaglandins are important mediators of bone repair, and cyclooxygenases are required for prostaglandin production. Data from animal studies suggest that both non-specific and specific inhibitors of cyclooxygenases impair fracture healing but that this is due to the inhibition of COX-2 and not COX-1. Although these data raise concerns about the use of COX-2-specific inhibitors as anti-inflammatory or anti-analgesic drugs in patients undergoing bone repair, clinical reports have been inconclusive. Because animal data suggest that the effects of COX-2 inhibitors are both dose-dependent and reversible, in the absence of scientifically sound clinical evidence it is suggested that physicians consider short-term administration or other drugs in the management of these patients.     

Antibiotic use in animal agriculture: what have we learned and where are we going?

Antibiotics are enormously important for the humane and efficient production of food animals. These benefits are somewhat offset by the human and animal health antibiotic resistance risks posed by their use in animals. This article provides an overview of what we have learned about antibiotic resistance as an issue in animal agriculture and where that knowledge could lead us in the future. To preserve the effectiveness of antibiotics, more action is needed to ensure their prudent use, particularly in the case of antibiotic growth promoters and antibiotics deemed critically important for human and animal health.     

Neurochemical dementia diagnostics in Alzheimer's disease: where are we now and where are we going?

Neurochemical dementia diagnostics (NDD) is a routine laboratory tool used in the diagnostic process for patients with neurodegenerative disorders, such as Alzheimer's disease. Currently, two groups of biomarkers analyzed in the cerebrospinal fluid are considered - namely amyloid-β peptides and Tau proteins - along with the hyperphosphorylated forms of the latter (pTau). Current directions in the development of NDD include the following: search for novel biomarkers with improved analytical or diagnostic performance; optimization of the analysis of the biomarkers already available (e.g., by improved quality control and interlaboratory comparison of results); applications of novel technologies enabling better management of patient samples; and search for biomarkers in the blood. This article presents the state-of-the-art in the field of cerebrospinal fluid-based NDD, and also summarizes some of the hypotheses of how the future development of NDD tools might look.     

The use of nitrogen fertiliser in agriculture. Where do we go practically and ecolotically?

Nitrogen fertilisers were produced in 72 countries in 1982, total world capacity being 99 mt of N, having been 50 mt in 1970. Consumption was 31.8 mt in 1970, rising to 60.3 mt in 1980 (Av. annual growth rate 7%). Forecasts suggest N use of 90 mt in 1990 rising to between 111–134 mt by the year 2000.The large amount of N added to only some 11% of the earth's land surface as fertilisers, coupled with concurrent increases in biological N fixation, mainly by grain legumes, is bound to result in increases in the total N content of soils, waters, crop residues and municipal wastes. The need to use N to produce sufficient food and fibre for the 7 billion humans must be set against the need to maintain a good and safe environment. Nitrate levels are increasing in both surface and ground water supplies. The amount of ammonia and oxides of nitrogen in the atmosphere produced by volatilisation and denitrification from soils and animal excreta is also rising. Such increases may have detrimental environmental effects to human health and to the ecology of downstream or polluted non-agricultural ecosystems though the severity and extent of these effects requires verification. As yet, there is little hard evidence of direct damage to human health due to high levels of nitrate in diet or of NH₃ and NO_x in the atmosphere, but effects on natural and forest ecosystems in some areas are proven.With this background, strategies are examined which should help to increase the efficiency with which N is utilised by crops and animals and so decrease losses of nitrogen from farmland.These include the selection of optimum N fertiliser practices based on knowledge of plant requirements, soil N supply, and the use of carefully chosen times, methods and forms of N fertiliser application. Other technological approaches such as use of slow release fertilisers, chemicals that inhibit certain biological transfers of N in soils and amendments added to N fertilisers, to soils or to animal excreta to alter their chemical properties could be developed. Greater use of legumes and enhanced levels of N₂-fixation may also help to lessen the need for N fertiliser.To achieve further improvement in the ways of using N in agriculture, more precise knowledge is needed of the dynamics of nitrogen turnover in soils, of translocation and assimilation in plants, and of interactive flows between soil, plants and animals, and the atmosphere. Only with full understanding of the many biological processes that affect N in ecosystems obtained by multidisciplinary research will it be possible to determine the guidelines for environmentally kind, socially acceptable and economically sound management of nitrogen utilisation in agriculture.     

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

Introduction: Hypertension is a complex and multifactorial cardiovascular disorder. With different mechanisms contributing to a different extent to an individual’s blood pressure, the discovery of novel pathogenetic principles of hypertension is challenging. However, there is an urgent and unmet clinical need to improve prevention, detection, and therapy of hypertension in order to reduce the global burden associated with hypertension-related cardiovascular diseases.

Areas covered: Proteomic techniques have been applied in reductionist experimental models including angiotensin II infusion models in rodents and the spontaneously hypertensive rat in order to unravel mechanisms involved in blood pressure control and end organ damage. In humans proteomic studies mainly focus on prediction and detection of organ damage, particularly of heart failure and renal disease. While there are only few proteomic studies specifically addressing human primary hypertension, there are more data available in hypertensive disorders in pregnancy, such as preeclampsia. We will review these studies and discuss implications of proteomics on precision medicine approaches.

Expert commentary: Despite the potential of proteomic studies in hypertension there has been moderate progress in this area of research. Standardized large-scale studies are required in order to make best use of the potential that proteomics offers in hypertension and other cardiovascular diseases.     

Student report--the fight against cancer and angiogenesis inhibitors: are we entering a new era?

Chemoresistance is currently the main cause of failure in the treatment of cancer which, despite extensive research, remains unsolved. In this report the theoretical assumptions underlying antiangiogenic therapy are described and future perspectives and limits are discussed.     

Northern ragweed ecotypes flower earlier and longer in response to elevated CO2: what are you sneezing at?

Oecologia - Significant changes in plant phenology and flower production are predicted over the next century, but we know relatively little about geographic patterns of this response in many...     

Granivory and microhabitat use in Australian desert rodents: are seeds important?

The diet and microhabitat use of two species of native Australian desert rodents, the spinifex hoppingmouseNotomys alexis and sandy inland mousePseudomys hermannsburgensis, were studied in the Simpson Desert, south-western Queensland. Contrary to expectation, both species were confirmed from analyses of their stomach contents to be omnivorous. The diets of both species varied through time in a similar manner; seeds were important in summer and especially in winter, but in autumn invertebrates constituted nearly 50% and 60% of the diet ofN. alexis andP. hermannsburgensis, respectively. Other plant material (root, leaf, floral part, stem) was found in appreciable amounts in the stomach contents of both species, and fungi were identified from a small number of individuals. Both species showed a high degree of overlap in the broad types of food they ingested (seed, plant material, invertebrates); however, there was considerably less overlap in the species of seeds eaten. Analysis of microhabitat use suggested that this difference was due to differential foraging between the species; the larger, bipedalN. alexis forages in the open more than the smaller, quadrupedalP. hermannsburgensis, which is found more commonly in or under hummocks of spinifex grass. Although our findings parallel patterns of morphological specialisation and differential foraging on seeds that have been described within communities of North American heteromyid rodents, we found little evidence that the foraging economics ofN. alexis orP. hermannsburgensis should depend solely or primarily on the distribution patterns of seeds. In the absence of dietary information, we suggest that ecological studies of desert rodents which focus solely on granivory, and neglect other important aspects of rodent foraging, can lead to a misinterpretation of species coexistence and community structure.     

Primary and Secondary Antifungal Prophylaxis in the Immunocompromised Child: Where do we Stand?

Invasive opportunistic fungal infections are important causes of morbidity and mortality in immunocompromised children undergoing chemotherapy or haematopoietic stem cell transplantation (HSCT). Primary and secondary chemoprophylaxis of invasive fungal infections targets high risk disease-related patients with acute myeloid leukaemia, high risk acute lymphoblastic leukaemias, recurrent leukaemias and those following allogeneic HSCT. The rationale for antifungal prophylaxis in high risk patients comes from two different aspects. On the one hand, is the difficulty of instant diagnosis and, on the other hand, the consequences of morbidity and mortality by invasive infectious diseases. Although we have limited pediatric data concerning antifungal prophylaxis, it has become part of infectious disease supportive care schemes in most of paediatric leukaemia and HSCT centres. This review has insights on the evidence concerning primary and secondary antifungal prophylaxis in immunocompromised children. Although our knowledge comes from large adult studies concerning antifungal agents, there is a great need for evidence of primary or secondary antifungal prophylaxis in large pediatric clinical trials in order to have a consensus in primary and secondary antifungal prophylaxis in immunocompromised children.