¹⁸F-fluoride PET as a noninvasive imaging biomarker for determining treatment efficacy of bone active agents at the hip: a prospective, randomized, controlled clinical study.

The functional imaging technique of ¹⁸F-fluoride positron emission tomography (¹⁸F-PET) allows the noninvasive quantitative assessment of regional bone formation at any skeletal site, including the spine and hip. The aim of this study was to determine if ¹⁸F-PET can be used as an early biomarker of treatment efficacy at the hip. Twenty-seven treatment-naive postmenopausal women with osteopenia were randomized to receive teriparatide and calcium and vitamin D (TPT group, n = 13) or calcium and vitamin D only (control group, n = 14).

Downregulation of 18F-FDG uptake in PET as an early pharmacodynamic effect in treatment of non-small cell lung cancer with the mTOR inhibitor everolimus.

Unlabelled: Everolimus downregulates glucose metabolism-associated genes in preclinical models. Inhibition of glucose metabolism measured by (18)F-FDG PET was postulated to serve as a pharmacodynamic marker in everolimus-treated non-small cell lung cancer (NSCLC) patients.

Methods: In 8 NSCLC patients treated with everolimus, the percentage change in (18)F-FDG PET uptake (days 8 and 28 relative to baseline) was determined using a variety of summed standardized uptake value (SUV) measures.

Discovery of potent, selective, and orally active carboxylic acid based inhibitors of matrix metalloproteinase-13.

The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE).

Colorectal liver metastases: contrast agent diffusion coefficient for quantification of contrast enhancement heterogeneity at MR imaging.

Purpose: To describe and determine the reproducibility of a simplified model to quantitatively measure heterogeneous intralesion contrast agent diffusion in colorectal liver metastases.

Materials And Methods: This HIPAA-compliant retrospective study received institutional review board approval, and written informed consent was obtained from 14 patients (mean age, 61 years +/- 9 [standard deviation]; range, 41-78 years), including 10 men (mean age, 65 years +/- 8; range, 47-78 years) and four women (mean age, 54 years +/- 9; range, 41-59 years), with colorectal liver metastases. Magnetic resonance (MR) imaging was performed twice (first baseline MR image [B(1)] and second baseline MR image [B(2)]) in a single target lesion prior to therapy.

In vivo MRI of cartilage pathogenesis in surgical models of osteoarthritis.

Objective: To examine in vivo time-course changes in macromolecular composition of articular cartilage in two surgical models of osteoarthritis (goat: meniscal transection and cartilage incision; rabbit: medial meniscectomy).

Design: Collagen integrity and proteoglycan (PG) content were evaluated in both models by magnetization transfer (MT) and contrast-enhanced MRI, respectively. The MT rate k(m) for the exchange process between the bulk water and water bound to collagen was determined as a marker of the collagen network.

Pain related behaviour in two models of osteoarthritis in the rat knee.

Osteoarthritis (OA) is a major healthcare burden, with increasing incidence. Pain is the predominant clinical feature, yet therapy is ineffective for many patients. While there are considerable insights into the mechanisms underlying tissue remodelling, there is poor understanding of the link between disease pathology and pain.

In vivo assessment of macromolecular content in articular cartilage of the goat knee.

Loss of proteoglycans (PGs) from the extracellular matrix of cartilage is an early event of osteoarthritis. The capability of Gd(DTPA)(2-)-enhanced MRI to quantitatively assess PG content was explored in a goat model of cartilage degeneration. Partial to total PG depletion was induced by an intraarticular injection of papain 1 day prior to the MRI session.

Qualitative and quantitative in vivo assessment of articular cartilage using magnetic resonance imaging.

The molecular organization and biochemical composition that give cartilage the viscoelasticity necessary for load distribution also convey unique magnetic resonance (MR) properties. In that context, MR imaging has the potential to detect cartilage degeneration and regeneration. Magnetization transfer (MT) imaging probes the exchange of magnetization between the bulk water pool and the water pool bound to macromolecules such as collagen and hence MT may be applied for evaluation of collagen integrity.

Quantitative and qualitative assessment of articular cartilage in the goat knee with magnetization transfer imaging.

We investigated the role of collagen in the magnetization transfer (MT) effect in contrast to other macromolecules. By means of phantoms made of collagen, chondroitin sulfate (CS) and albumin, MR parameters have been optimized in order to reduce the acquisition time and improve the sensitivity, as well as to minimize the contributions from CS and albumin to the MT induced signal attenuation. The same method was used to study cartilage ex vivo (bovine articular and nasal cartilage plugs) and in vivo (goat knee femoral chondyle).

Fluorescently labeled mesenchymal stem cells (MSCs) maintain multilineage potential and can be detected following implantation into articular cartilage defects.

Several studies have reported enhanced repair of damaged cartilage following implantation of mesenchymal stem cells (MSCs) into full-thickness cartilage defects suggesting that the cells in the repair tissue were derived from the implant. However, it cannot be excluded that the enhanced tissue repair is derived from host cells recruited to the defect in response to the implant, rather than the re-population of the tissue by the implanted MSCs. Our objective was to study the short-term fate of fluorescently labeled MSCs after implantation into full-thickness cartilage defects in vivo.

Recombinant human complement C5a receptor antagonist reduces infarct size after surgical revascularization.

Objectives: This study tested the hypothesis that a recombinant human C5a antagonist, CGS 32359, attenuates neutrophil activation and reduces infarct size in a porcine model of surgical revascularization.

Methods: CGS 32359 (0.16-16 micromol/L) dose-dependently inhibited superoxide production by human C5a-activated porcine neutrophils (18 +/- 3.

C5a receptor antagonists.

The anaphylatoxin C5a is an extremely potent proinflammatory peptide produced during activation of the complement system. The structure of C5a includes a core region (N-terminal residues 1-63) consisting of four, antiparallel alpha-helices held together by three disulfide linkages and a structured C-terminal tail (residues 64-74). The C5a receptor belongs to the large class of seven transmembrane, G-protein-linked receptors.

Novel C5a receptor antagonists regulate neutrophil functions in vitro and in vivo.

Novel recombinant human C5a receptor antagonists were discovered through modification of the C terminus of C5a. The C5a1-71T1M,C27S,Q71C monomer, (C5aRAM; CGS 27913), was a pure and potent functional antagonist. The importance of a C-terminal cysteine at position 71 to antagonist properties of C5aRAM was confirmed by studying C5a1-71 derivatives with replacements of Q71, C5a derivatives of various lengths (70-74) with C-terminal cysteines, and C5a derivatives of various lengths (71-74) with Q71C replacements.

Residues 21-30 within the extracellular N-terminal region of the C5a receptor represent a binding domain for the C5a anaphylatoxin.

The functions of the C5a anaphylatoxin are expressed through its interaction with a cell-surface receptor with seven transmembrane helices. The interaction of C5a with the receptor has been explained by a two-site model whereby recognition and effector sites on C5a bind, respectively, to recognition and effector domains on the receptor, leading to receptor activation (Chenoweth, D. E.

LTB4-induced transient neutropenia in the rat: a model for evaluating efficacy and bioavailability of LTB4 receptor antagonists.

An animal model of leukotriene B4- (LTB4) induced neutropenia has been developed to evaluate LTB4 receptor antagonists in vivo. LTB4, a potent chemotactic inflammatory mediator, when administered intravenously, induces a profound, rapid, and transient redistribution of blood neutrophils from the circulating pool to the marginated pool. This phenomenon is applied in the neutropenia model whereby circulating blood neutrophil counts prior to and after intravenous infusion of LTB4 are compared.

Germ-cell deficient (gcd), an insertional mutation manifested as infertility in transgenic mice.

A genetic analysis is necessary to gain a greater understanding of the complex developmental processes in mammals. Toward this end, an insertional transgenic mouse mutant has been isolated that results in abnormal germ-cell development. This recessive mutation manifests as infertility in both males and females and is specific for the reproductive organs, since all other tissues examined were histologically normal.

Migration pathways of recirculating murine B cells and CD4+ and CD8+ T lymphocytes.

Migration pathways of B cell and CD4+ and CD8+ T cell subsets of murine thoracic duct lymphocytes (TDL) were mapped. Per weight, the spleen accumulated more TDL than any other organ, regardless of lymphocyte subset. Spleen autoradiographs showed early accumulations of TDL in marginal zone and red pulp.

Deep splenic lymphatic vessels in the mouse: a route of splenic exit for recirculating lymphocytes.

A study of pathways of lymphocyte migration through mouse spleen revealed lymphatic channels closely following arteries in trabeculae and white pulp. Because there is no detailed record of the layout of deep splenic lymphatics in the mouse, or other species, we present our observations in this paper, relating our findings to normal migratory pathways of lymphocytes through the spleen. Lymphatics draining the spleen are so inconspicuous that they often are not mentioned in anatomical discussions.