Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis

Objective: To assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1 alpha/beta dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA). Methods: Patients with >= 1 erosive and >= 3 tender and/or swollen hand joints were randomised to placebo or lutikizumab 200 mg subcutaneously every 2 weeks for 24 weeks. The primary endpoint was change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints. Continuous endpoints were assessed using analysis of covariance models, with treatment and country as main factors and baseline measurements as covariates. Results: Of 132 randomised subjects, 1 received no study drug and 110 completed the study (placebo, 61/67 (91%); lutikizumab, 49/64 (77%)). AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16 (least squares mean difference, 1.5 (95% CI -1.9 to 5.0)). Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1 alpha and IL-1 beta levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropaenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67). Conclusion: Despite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA compared with placebo

Introduction of Genetically Engineered Organisms - Draft Programmatic Environmental Impact Statement—July 2007

The U.S. Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS) regulates the environmental introduction of genetically engineered (GE) organisms, including crop and noncrop plants, vertebrate and invertebrate animals, and micro-organisms. APHIS regulations are grounded in the most up-to-date science and are designed to provide a level of oversight appropriate for the safe introduction of GE organisms. APHIS is considering whether revisions to its regulations are necessary. One purpose of such revisions would be to address current and future technological trends resulting in GE plants with which the agency is less familiar, such as plants with environmental stress tolerance or enhanced nutrition, and plants engineered for new purposes such as biofuels or for production of pharmaceutical or industrial compounds. Additionally, the regulations would be revised to ensure a high level of environmental protection, to create regulatory processes that are transparent to stakeholders and the public, to consider the efficient use of agency resources, to ensure that the level of oversight is commensurate with the risk, and to ensure conformity with obligations under international treaties and agreements, such as World Trade Organization (WTO) agreements. To this end, this draft environmental impact statement (DEIS) was prepared to provide agency decisionmakers with a full range of regulatory alternatives and assist them in selecting a preferred alternative

Ecologically Appropriate Xenobiotics Induce Cytochrome P450s in Apis mellifera

BACKGROUND: Honey bees are exposed to phytochemicals through the nectar, pollen and propolis consumed to sustain the colony. They may also encounter mycotoxins produced by Aspergillus fungi infesting pollen in beebread. Moreover, bees are exposed to agricultural pesticides, particularly in-hive acaricides used against the parasite Varroa destructor. They cope with these and other xenobiotics primarily through enzymatic detoxificative processes, but the regulation of detoxificative enzymes in honey bees remains largely unexplored. METHODOLOGY/PRINCIPAL FINDINGS: We used several approaches to ascertain effects of dietary toxins on bee susceptibility to synthetic and natural xenobiotics, including the acaricide tau-fluvalinate, the agricultural pesticide imidacloprid, and the naturally occurring mycotoxin aflatoxin. We administered potential inducers of cytochrome P450 enzymes, the principal biochemical system for Phase 1 detoxification in insects, to investigate how detoxification is regulated. The drug phenobarbital induces P450s in many insects, yet feeding bees with phenobarbital had no effect on the toxicity of tau-fluvalinate, a pesticide known to be detoxified by bee P450s. Similarly, no P450 induction, as measured by tau-fluvalinate tolerance, occurred in bees fed xanthotoxin, salicylic acid, or indole-3-carbinol, all of which induce P450s in other insects. Only quercetin, a common pollen and honey constituent, reduced tau-fluvalinate toxicity. In microarray comparisons no change in detoxificative gene expression was detected in phenobarbital-treated bees. However, northern blot analyses of guts of bees fed extracts of honey, pollen and propolis showed elevated expression of three CYP6AS P450 genes. Diet did not influence tau-fluvalinate or imidacloprid toxicity in bioassays; however, aflatoxin toxicity was higher in bees consuming sucrose or high-fructose corn syrup than in bees consuming honey. CONCLUSIONS/SIGNIFICANCE: These results suggest that regulation of honey bee P450s is tuned to chemicals occurring naturally in the hive environment and that, in terms of toxicological capacity, a diet of sugar is not equivalent to a diet of honey

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

A field investigation of Depressaria (Elachistidae) host plants and ecology in the Western United States

Depressaria Haworth is a relatively species-rich group of moths with a Holarctic distribution. In western North America there has been a striking radiation of Apiaceae-feeding members of the genus. To understand patterns of Depressaria distribution, host usage, and natural history in the western United States, we surveyed select potential host plants for larvae. Particular emphasis was placed on surveying plants in the genus Lomatium Raf. because most published Depressaria host plant records are from this genus. Surveys took place throughout the western United States from Utah and Wyoming to the Pacific Ocean, and from the Canadian border in Washington State to California and northern Arizona. Approximately 32,000 km of roadway were covered. When larvae were encountered they were collected and reared to adulthood. Ten species of Depressaria were reared. Two additional potentially undescribed species, represented only by female specimens, were also reared. Our data support previously published accounts of Depressaria biology, host usage, and distribution, consistent with the fact that known host plant genera were targeted in the surveys. Substantial changes in land use have occured in some parts of the western United States since the work of J. F. G. Clarke, an early student of Depressaria. Several of his published collection localities, including the type locality for D. whitmani Clarke and most collection localities near the Pacific Coast and in dry grasslands, have been destroyed or seriously degraded by agriculture, grazing, roadway improvements, and other forms of development