IntroductionThe epidemiology, pathogenetic mechanisms and clinical features of chronic cold agglutinin disease (CAD) have been quite extensively elucidated in the literature, 1-5 but therapy remains suboptimal. [6][7][8][9][10] Although most authors emphasize the importance of avoiding cold exposure, a population based study showed that drug therapy had been attempted in more than 70% of the patients, 9 indicating that counseling is insufficient as sole therapeutic measure in a majority. The requirement for effective pharmacologic treatment is also highlighted by hemoglobin (Hgb) levels less than 8.0 g/dL in one-third and cold-induced circulatory symptoms in more than 90% of unselected patients with CAD, whereas 50% of such patients were found to have received blood transfusions during the course of the disease. 9 Corticosteroids, conventional immunosuppressive drugs and alkylating agents are generally ineffective. 6,9 Treatment with the monoclonal anti-CD20 antibody rituximab is the only well-documented effective therapy, leading to partial responses (PRs) in 45%-60% of the patients, but complete responses (CRs) are rare. 9,11,12 A median response duration of 11 months (range, 2-42 months) has been reported. 11 Although rituximab therapy is effective in polyclonal autoimmune diseases, 13,14 part of the rationale for rituximab in CAD was the demonstration of a monoclonal, B-cell lymphoproliferative bone marrow disorder in more than 90% of patients traditionally classified as having primary CAD. 4,9,11 Histologic signs of nonHodgkin B-cell lymphoma were present in bone marrow biopsy specimens from 75% of unselected patients with CAD in a population based study. 9 The most frequent type was lymphoplasmacytic lymphoma (LPL), which was found in 50% of the patients.We wanted to improve on the results achieved by rituximab single-agent therapy in patients with primary CAD. The purine analogues, eg fludarabine and cladribine, are powerful therapeutic agents in a variety of lymphoproliferative diseases. Although therapy with fludarabine for CAD has not been studied systematically, successful treatment was reported in one patient. 15 Histologic remission of the bone marrow lymphoproliferative disorder was observed after cladribine therapy in a series of 5 patients, but clinical remission was not achieved. 8 Fludarabine therapy, alone or in combination with rituximab, has yielded high response rates in Waldenström macroglobulinemia (WM), which is considered a closely related entity. [16][17][18] Furthermore, treatment with the fludarabine and rituximab combination has been found feasible and efficient in follicular lymphoma. 19 In the present study we have investigated the potential of fludarabine and rituximab in combination in patients with CAD requiring treatment. Methods Study designWe conducted a prospective, uncontrolled multicenter trial of combination therapy with fludarabine and rituximab in patients with CAD requiring An Inside Blood analysis of this article appears at the front of this issue.The publication cos...

The polyunsaturated lipid mediator PD1n-3 DPA (5) was recently isolated from self-resolving inflammatory exudates of 5 and human macrophages. Herein, the first total synthesis of PD1n-3 DPA (5) is reported in 10 steps and 9% overall yield. These efforts, together with NMR data of its methyl ester 6, confirmed the structure of 5 to be (7Z,10R,11E,13E,15Z,17S,19Z)-10,17-dihydroxydocosa-7,11,13,15,19-pentaenoic acid. The proposed biosynthetic pathway, with the involvement of an epoxide intermediate, was supported by results from trapping experiments. In addition, LC-MS/MS data of the free acid 5, obtained from hydrolysis of the synthetic methyl ester 6, matched data for the endogenously produced biological material. The natural product PD1n-3 DPA (5) demonstrated potent anti-inflammatory properties together with pro-resolving actions stimulating human macrophage phagocytosis and efferocytosis. These results contribute new knowledge on the n-3 DPA structure-function of the growing numbers of specialized pro-resolving lipid mediators and pathways.

Agelasine E, previously isolated from the marine sponge Agelas nakamurai, has been synthesized for the first time, together with analogs with various terpenoid side chains. Treatment of N6-methoxy-9-methyl-9H-purin-6-amine with allylic bromides gave the desired 7,9-dialkylpurinium salts together with minor amounts of the N6-alkylated isomer. The N6-methoxy group was finally removed reductively. 1H-15N HMBC and 1H-15N HSQC NMR spectroscopy gave additional information on tautomerism and charge delocalization in the purine derivatives studied. The heterocyclic products were screened for activity against Mycobacterium tuberculosis and agelasine analogs carrying a relatively long terpenoid substituent in the purine 7-position and a methoxy group at N-6 were potent inhibitors of bacterial growth. Since agelasine analogs with the geranylgeranyl chain at N-7 exhibited antimicrobial activity, several strategies for synthesis of geometrically pure (2E,6E,10E)-geranylgeranyl bromide from geranyllinalool were evaluated.

To cite this article: Vik A, Mathiesen EB, Brox J, Wilsgaard T, Njølstad I, Jørgensen L, Hansen J.-B. Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: the Tromsø Study. J Thromb Haemost 2011; 9: 638-44.Summary. Background: Osteoprotegerin (OPG) concentration in serum is associated with the presence and severity of atherosclerosis. Objective: To investigate the association between serum osteoprotegerin and the risk of a future myocardial infarction, ischemic stroke and mortality in a general population. Patients/methods: OPG was measured in serum collected from 6265 subjects recruited from a general population without a prior myocardial infarction and ischemic stroke (the Tromsø Study). Incident myocardial infarction, ischemic stroke and mortality were registered during follow-up. Cox regression models were used to estimate crude and adjusted hazard ratios and 95% confidence intervals (HR; 95% CI). Results: There were 575 myocardial infarctions, 284 ischemic strokes and 824 deaths (146 deaths as a result of ischemic heart disease, 78 deaths because of stroke and 600 deaths due to other causes) in the cohort during a median of 10.6 years of followup. Serum OPG (per SD [1.13 ng mL ] increase in OPG) was associated with an increased risk of a myocardial infarction (1.20; 1.11-1.31), ischemic stroke (1.32; 1.18-1.47), total mortality (1.34; 1.26-1.42), death because of ischemic heart disease, (1.35; 1.18-1.54), stroke (1.44; 1.19-1.75) and nonvascular causes (1.31; 1.22-1.41) after adjustment for age, gender, current smoking, systolic blood pressure, body mass index, high density lipoprotein cholesterol, total cholesterol, creatinine, high sensitivity C-reactive protein (CRP) and diabetes mellitus or HbA1c > 6.1%. No association was detected between OPG and incident hemorrhagic stroke (1.02; 0.73-1.43). Conclusions: Serum OPG was associated with future risk of myocardial infarction, ischemic stroke, total mortality, mortality of ischemic heart disease, stroke and of non-vascular causes independent of traditional cardiovascular risk factors.

A western type diet and lifestyle play an important role in the development of chronic diseases, yet little insight into the precise cellular and biomolecular mechanisms has emerged. It is known that an unbalanced diet may result in obesity and diabetes. Sufficient amounts and proper balance of omega-6 and omega-3 polyunsaturated fatty acids is key for maintenance of health. The resolution of inflammation is now held to be a biosynthetically actively driven process precisely regulated and controlled by a superfamily of specialized pro-resolving mediators. Specialized pro-resolving mediators are biosynthesized from both omega-6 and omega-3 polyunsaturated fatty acids and are resolution agonists acting on distinct G-coupled protein receptors. These mediators display potent anti-inflammatory and pro-resolving bioactions with EC50-values in the low nanomolar to picomolar range. The protectin (PD) family of specialized pro-resolving mediators is biosynthesized from the two omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and n–3 docosapentaenoic acid (n–3 DPA). All of the PDs display interesting bioactions as anti-inflammatory and pro-resolving agents. This review covers the bioactions, G-coupled protein receptors pharmacology, biosynthesis, and medicinal chemistry of the PD family of specialized pro-resolving mediators with an emphasis on obesity and anti-diabetic effects. In order to enable drug development and medicinal chemistry efforts against these diseases, stereoselective total organic synthesis of each of these mediators is required for confirmation of structure, stereochemical biosynthesis, and their functions. We provide an overview of our ongoing efforts and the current knowledge.

The association between myocardial infarction (MI) and future risk of incident cancer is scarcely investigated. Therefore, we aimed to study the risk of cancer after a first time MI in a large cohort recruited from a general population. Participants in a large population-based study without a previous history of MI or cancer (n=28763) were included and followed from baseline to date of cancer, death, migration or study end. Crude incidence rates (IRs) and hazard ratios (HRs) for cancer after MI were calculated. During a median follow-up of 15.7 years, 1747 subjects developed incident MI, and of these, 146 suffered from a subsequent cancer. In the multivariableadjusted model (adjusted for age, sex, BMI, systolic blood pressure, diabetes mellitus, HDL cholesterol, smoking, physical activity and education level), MI patients had 46% (HR 1.46; 95% CI: 1.21-1.77) higher hazard ratio of cancer compared to those without MI. The increased cancer incidence was highest during the first 6 months after the MI, with a 2.2-fold higher HR (2.15; 95% CI: 1.29-3.58) compared with subjects without MI. After a 2-year period without higher incidence rate, MI patients displayed 60% (HR 1.60; 95% CI: 1.27-2.03) higher HR of future cancer more than 3 years after the event. The increased incidence rates were higher in women than men. Patients with MI had a higher short-and long-term incidence rate of cancer compared to subjects without MI. Our findings suggest that occult cancer and shared risk factors of MI and cancer may partly explain the association.

An improved synthesis of (+)-agelasine D (10) from (+)-manool is reported together with cytotoxic and antibacterial data for agelasine D and structurally close synthetic analogues. These compounds display a broad spectrum of antibacterial activities including effects on M. tuberculosis and Gram-positive and Gram-negative bacteria (both aerobes and anaerobes). They exhibit profound cytotoxic activity against several cancer cells, including a multidrug-resistant cell line. (+)-Agelasine D (10) has been isolated earlier from a marine sponge (Agelas sp.).

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