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.     

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.     

Pim kinases in hematological malignancies: where are we now and where are we going?

The proviral insertion in murine (PIM) lymphoma proteins are a serine/threonine kinase family composed of three isoformes: Pim-1, Pim-2 and Pim-3. They play a critical role in the control of cell proliferation, survival, homing and migration. Recently, overexpression of Pim kinases has been reported in human tumors, mainly in hematologic malignancies. In vitro and in vivo studies have confirmed their oncogenic potential. Indeed, PIM kinases have shown to be involved in tumorgenesis, to enhance tumor growth and to induce chemo-resistance, which is why they have become an attractive therapeutic target for cancer therapy. Novel molecules inhibiting Pim kinases have been evaluated in preclinical studies, demonstrating to be effective and with a favorable toxicity profile. Given the promising results, some of these compounds are currently under investigation in clinical trials. Herein, we provide an overview of the biological activity of PIM-kinases, their role in hematologic malignancies and future therapeutic opportunities.     

Leptin in farm animals: where are we and where can we go?

Fat affects meat quality, value and production efficiency as well as providing energy reserves for pregnancy and lactation in farm livestock. Leptin, the adipocyte product of the obese (ob) gene, was quickly seen as a predictor of body fat content in animals approaching slaughter and an aid to assessing reproductive readiness in females. Its participation in inflammation and immune responses that help animals survive infection and trauma has clear additional relevance to meat and milk production. Furthermore, almost a decade of discoveries of nucleotide polymorphisms in the leptin and leptin receptor genes has suggested useful applications relating to feed intake regulation, the efficiency of feed use, the composition of growth, the timing of puberty, mammogenesis and mammary gland function and fertility in cattle, pigs and poultry. The current review attempts to summarise where research has taken us in each of these aspects and speculates on where future research might lead.     

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.     

Two Decades of Molecular Ecology: where are we and where are we heading?

The twentieth anniversary of the journal Molecular Ecology was celebrated with a symposium on the current state and the future directions of the field. The event, organized by Tim Vines and Loren Rieseberg, took place on the opening day of the First Joint Congress on Evolutionary Biology organized by the American Society of Naturalists (ASN), the Canadian Society for Ecology and Evolution (CSEE), the European Society for Evolutionary Biology (ESEB), the Society for the Study of Evolution (SSE) and the Society of Systematic Biologists (SSB) in Ottawa (Canada) from 6–10 July 2012. The get together of these five societies created a truly international and exciting “Evolution conference” and the ideal framework for the Molecular Ecology symposium. Its thirteen talks were grouped into the five different subject areas of the journal: Speciation and Hybridization; Landscape Genetics, Phylogeography and Conservation; Ecological Genomics and Molecular Adaptation; Kinship, Parentage and Behaviour; Ecological Interactions. Each session was followed by a panel discussion on the future direction of the subfield. That more than 300 colleagues registered for this special symposium illustrates the broad interest in, and appreciation of, molecular ecology – both the field and the journal.     

Teaching history-taking: where are we?

Knowledge in history-taking has increased rapidly over the last twenty years. Currently the principles to be taught include "conduct," "content," and "diagnostic reasoning." However, inattentiveness of medical schools, reluctance of busy faculty to be involved, and increasing enrollments have resulted in difficulties in teaching these skills. Studies have shown a beneficial short-term effect of teaching these materials on interview performance but it is unknown whether this effect is long-lasting. The methods for instruction include the bedside and videotape models utilizing the concept of the fifteen-minute interview technique, programmed instruction, patient instructors, and direct student feedback. Future research should focus on identifying strategies in diagnostic reasoning, developing graduated competency criteria for trainees at different levels of their education, refining methods to evaluate large numbers of students, measuring outcomes of effective training such as compliance, and comparing costs and effectiveness of various methods. In addition, there remains the need to establish an association of course directors.     

Oxidative stress and neurodegeneration: where are we now?

The brain and nervous system are prone to oxidative stress, and are inadequately equipped with antioxidant defense systems to prevent 'ongoing' oxidative damage, let alone the extra oxidative damage imposed by the neurodegenerative diseases. Indeed, increased oxidative damage, mitochondrial dysfunction, accumulation of oxidized aggregated proteins, inflammation, and defects in protein clearance constitute complex intertwined pathologies that conspire to kill neurons. After a long lag period, therapeutic and other interventions based on a knowledge of redox biology are on the horizon for at least some of the neurodegenerative diseases.     

Insurance and genetic testing: where are we now?

Basic research will spur development of genetic tests that are capable of presymptomatic prediction of disease, disability, and premature death in presently asymptomatic individuals. Concerns have been expressed about potential harms related to the use of genetic test results, especially loss of confidentiality, eugenics, and discrimination. Existing laws and administrative policies may not be sufficient to assure that genetic information is used fairly. To provide factual information and conceptual principles upon which sound social policy can be based, the Human Genome Initiative established an Ethical, Legal, and Social Issues Program. Among the first areas to be identified as a priority for study was insurance. This paper provides a review of life, health, and disability insurance systems, including basic principles, risk classification, and market and regulatory issues, and examines the potential impact of genetic information on the insurance industry.     

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.