Phase 1 Safety and Tolerability Study of BMP-7 in Symptomatic Knee Osteoarthritis

BACKGROUND: There are no proven therapies that modify the structural changes associated with osteoarthritis (OA). Preclinical data suggests that intra-articular recombinant human BMP-7 (bone morphogenetic protein-7) has reparative effects on cartilage, as well as on symptoms of joint pain. The objective of this study was to determine the safety and tolerability as well as dose-limiting toxicity and maximal tolerated dose of intra-articular BMP-7. The secondary objectives were to determine the effect on symptomatic responses through 24 weeks. METHODS: This was a Phase 1, double-blind, randomized, multi-center, placebo-controlled, single-dose escalation safety study consisting of 4 dosing cohorts in participants with knee OA. Each cohort was to consist of 8 treated participants, with treatment allocation in a 3:1 active (intra-articular BMP-7) to placebo ratio. Eligible participants were persons with symptomatic radiographic knee OA over the age of 40. The primary objective of this study was to determine the safety and tolerability of BMP-7 including laboratory assessments, immunogenicity data and radiographic assessments. Secondary objectives were to determine the proportion of participants with a 20%, 50%, and 70% improvement in the WOMAC pain and function subscales at 4, 8, 12, and 24 weeks. Other secondary outcomes included the change from baseline to 4, 8, 12, and 24 weeks for the OARSI responder criteria. RESULTS: The mean age of participants was 60 years and 73% were female. All 33 participants who were enrolled completed the study and most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. The 1 mg BMP-7 group showed a higher frequency of injection site pain and there was no ectopic bone formation seen on plain x-rays. By week 12, most participants in both the BMP-7 and placebo groups experienced a 20% improvement in pain and overall the BMP-7 group was similar to placebo with regard to this measurement. In the participants who received 0.1 mg and 0.3 mg BMP-7, there was a trend toward greater symptomatic improvement than placebo. The other secondary endpoints showed similar trends including the OARSI responder criteria for which the BMP-7 groups had more responders than placebo. CONCLUSIONS: There was no dose limiting toxicity identified in this study. The suggestion of a symptom response, together with the lack of dose limiting toxicity provide further support for the continued development of this product for the treatment of osteoarthritis.ARC Future Fellowship; Stryker Biotec

Movements and Population Structure of Humpback Whales in the North Pacific

Despite the extensive use of photographic identification methods to investigate humpback whales in the North Pacific, few quantitative analyses have been conducted. We report on a comprehensive analysis of interchange in the North Pacific among three wintering regions (Mexico, Hawaii, and Japan) each with two to three subareas, and feeding areas that extended from southern California to the Aleutian Islands. Of the 6,413 identification photographs of humpback whales obtained by 16 independent research groups between 1990 and 1993 and examined for this study, 3,650 photographs were determined to be of suitable quality. A total of 1,241 matches was found by two independent matching teams, identifying 2,712 unique whales in the sample (seen one to five times). Site fidelity was greatest at feeding areas where there was a high rate of resightings in the same area in different years and a low rate of interchange among different areas. Migrations between winter regions and feeding areas did not follow a simple pattern, although highest match rates were found for whales that moved between Hawaii and southeastern Alaska, and between mainland and Baja Mexico and California. Interchange among subareas of the three primary wintering regions was extensive for Hawaii, variable (depending on subareas) for Mexico, and low for Japan and reflected the relative distances among subareas. Interchange among these primary wintering regions was rare. This study provides the first quantitative assessment of the migratory structure of humpback whales in the entire North Pacific basin

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder