Timothy J. Laing

Quantitative assessment of cartilage surface roughness in osteoarthritis using high frequency ultrasound

Osteoarthritis (OA) is a common disease which affects nearly 50% of people over age 60. Histologic evaluation suggests that fibrillations approximately 20-150 microns are among the earliest changes in the articular cartilage. We propose a technique to quantify these surface fibrillatory changes in osteoarthritic articular cartilage by considering the angular distribution of the envelope-detected backscattered pressure field from an incident 30-MHz focused transducer. The angular distribution of the scattered acoustic field from an inosonifying source will directly relate to the distribution of surface fibrillatory changes. Data are presented for three different grades (400, 500 and 600 grit) of commercially available emory paper and three samples of osteoarthritic femoral head articular cartilage, which were visually assessed as having smooth, intermediate and rough surfaces, respectively. Our preliminary results indicate a probable monotonic relationship between articular cartilage roughening and the degree of broadening in the angle-dependent pressure amplitude. When applied to the emory paper, the technique indicates sensitivity to differences as small as approximately 5-10 microns in mean roughness. This procedure may provide an extremely sensitive and reproducible means of quantifying and following the cartilage changes observed in early osteoarthritis.

The Use of Trained Patient Educators with Rheumatoid Arthritis to Teach Medical Students

OBJECTIVE To assess whether patients with rheumatoid arthritis (RA) trained as educators can enhance the integration of clinical and basic science education among second-year medical students during their rheumatology sequence. METHODS Twenty patients with RA and strong communication skills were extensively trained to teach students how to perform the whole-body joint examination. Each arthritis educator taught three 2-hour small group sessions and participated in a concluding 2-hour panel discussion with the entire class. Changes in student knowledge and attitudes were assessed in a pre-post evaluation design. RESULTS There were statistically and educationally significant gains in knowledge, confidence, and attitudes related to psychosocial aspects of arthritis in each of the 2 years the program was implemented. One-year followup data indicated substantial retention of these gains. CONCLUSIONS Patients trained in arthritis education can effectively teach fundamental musculoskeletal examination skills and encourage the development of sensitivity to the impact of chronic arthritis on the daily life of other patients.

Decreased natural and antibody-dependent cellular cytotoxic activities in intravenous drug abusers☆

Peripheral blood lymphocytes from 14 adult male patients admitted to the hospital with complications of intravenous drug abuse (IDA) were examined for natural killer (NK) and antibody-dependent cellular cytotoxic (ADCC) activities, lectin-dependent cellular cytotoxicity, and interferon (IFN)- and interleukin 2 (IL-2)-induced NK activity. Serum was also assayed for circulating interferon levels and soluble factor(s) capable of suppressing the cytotoxic potential of allogeneic lymphocytes from healthy donors. IDA patients demonstrated significantly decreased levels of NK and ADCC activities compared to age- and sex-matched healthy controls. The lectin, phytohemagglutinin, could significantly enhance the cytotoxicity of IDA lymphocytes; however, activity was not completely restored to normal levels. IDA sera demonstrated a significant inhibitory effect on the NK and ADCC activities of normal allogeneic lymphocytes, and these sera contained negligible levels of circulating IFN. Although the NK activity of IDA lymphocytes could not be restored completely to normal levels by either IFN-alpha or IL-2, the percentage enhancement of cytotoxicity was remarkably higher in IDA patients with significantly reduced NK activity than that observed using PBL from patients with near normal NK activity. The ability of IFN or IL-2 to enhance the decreased cytotoxicity of PBL from drug abusers suggests a novel therapeutic approach to the management of the complications of IDA.

Ultrasonic characterization of in vitro osteoarthritic articular cartilage with validation by confocal microscopy.

The majority of adults over the age of 65 y develop osteoarthritis (OA), a joint disease characterized by degeneration of articular cartilage and subchondral sclerosis. Early in the disease, the articular cartilage surface begins to change histologically from a smooth to a rough or fibrillated appearance. A prerequisite for any chondroprotective pharmacological intervention is detection of OA in its preclinical phase. Current diagnostic imaging modalities, such as radiographs or (nuclear) magnetic resonance imaging, either cannot directly image the cartilage surface or lack sufficient resolution to detect surface fibrillations. We have developed an ultrasonic technique that can be used to characterize these surface fibrillations directly. We present our in vitro results with validation by laser-based confocal microscopic imaging.

Quantitative assessment of surface roughness using backscattered ultrasound: The effects of finite surface curvature

We have previously described a technique to quantify surface fibrillatory changes in osteoarthritic articular cartilage. In that study, the angular distribution of the scattered acoustic field from an insonifying source directly related to the distribution of surface fibrillatory changes. In the current study, we demonstrate a more sensitive method to quantify surface roughness, the effect of global surface curvature in estimating surface roughness and the utility of using focused transducers in circumventing this potential problem for in vivo work. Phantoms composed of acrylic rods with and without sandpaper grit (about 15 to 72 microns, mean particle size) applied to the surface were scanned. A more robust angular scattering technique to measure the angle dependent data was employed, in which the integrated squared pressure amplitude over a finite time window (mean power) was measured as a function of incident acoustic angle for varying surface roughnesses and radii of curvature. We show that the potential dynamic range for making roughness discriminations diminishes with decreasing radius of curvature of the acrylic rod phantoms using an unfocused transducer. This effect is minimized with use of a focused transducer. Roughness effects are most evident at sufficiently large angles where incoherent scattering dominates. We conclude that the roughness of cylindrically curved surfaces can be quantitatively assessed using a focused ultrasound beam at sufficiently large incident angles, given that the focal spot size is sufficiently smaller than the radius of curvature of the surface.

Physicochemical characterization and solubility analysis of thalidomide and its N-alkyl analogs

AbstractPurpose. The present study was primarily aimed at exploring the feasibility of improving percutaneous delivery via chemical manipulation of the thalidomide molecule to form analogs with improved physicochemical properties. N-Alkyl analogs were synthesized with the belief that these would be suitably hydrophobic and far less crystalline than the reference compound. This article presents their physicochemical properties. Methods. Thalidomide and three of its N-alkyl analogs were synthesized. Identification and levels of purity (>96%) were assured through element analysis, fast atom-bombardment mass spectrometry, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. N-Octanol/water partition coefficients were determined at pH 6.4. Solubilities in water and a series of n-alkanols were obtained. Best-fit solubility parameters were determined from the solubilities of the respective compounds in London solvents and were also calculated from respective hexane solubilities, melting points and heats of fusion. Results. Methylation of the thalidomide molecule at its acidic nitrogen led to an aqueous solubility about 6-fold higher than thalidomide but, because the alkyl chain length was further extended from methyl to pentyl, aqueous solubilities decreased essentially exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increased solubility in nonpolar media. The log partition coefficient increased linearly with increasing alkyl chain length and the solubility parameters declined systematically through this series. By adding a methyl group to the thalidomide structure, the melting point dropped by more than 100°C. Adding to the alkyl chain length led to further, more modest decreases. Heats of fusion decreased dramatically upon thalidomides alkylation as well. Conclusion. Alkylation of the thalidomide molecule resulted in compounds with physicochemical properties that appear to be markedly better suited for percutaneous delivery.

Percutaneous delivery of thalidomide and its N-alkyl analogs.

AbstractPurpose. The purpose of this study was to determine the permeation parameters of thalidomide and three of its N-alkyl analogs and to establish a correlation between the physicochemical properties of these compounds and their percutaneous rates of absorption. Methods. In vitro permeation studies were performed from buffer, n-alkanols and various mixed components using vertical Franz diffusion cells fitted with human epidermal membranes. Results. Measured steady-state fluxes indicate that N-methyl thalidomide is a far better penetrant of human skin than the “parent molecule”. However, fluxes through skin drop off markedly from that of the methylated compound when the chain length is extended to propyl and pentyl. However, they remain well above the flux of thalidomide, which is less than 0.025 μg/cm2/h. Conclusions. The best skin permeant of this series was the N-methyl analog, which also exhibited the highest water (buffer) solubility compared to thalidomide, and the N-propyl and N-pentyl analogs. The N-propyl and N-pentyl analogs were more lipid soluble and exhibited higher partition coefficient values than the N-methyl analog. From all the permeability data using buffer, a series of n-alkanols and various combinations of solvents and enhancers as vehicles, the more water-soluble compound and not the more lipid soluble one was the best skin permeant.

The design of a population-based case-control study of systemic sclerosis (Scleroderma): Commentary on the University of Michigan study

‘Department of Epidemiology, School of Public Health, 2Department of Biostatistics, School of Public Health, ‘Division of Rheumatology, Department of Internal Medicine, School of Medicine, 4Division of Rheumatology, Department of Internal Medicine, Wayne State University School of Medicine and %n-vey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI 48109, U.S.A.

Establishing clinical severity for PROMIS® measures in adult patients with rheumatic diseases

PurposeDifferent patient-reported outcome (PRO) measures are used for rheumatic diseases (RD). The aims of this study are—(1) Identify PROMIS® domains most relevant to care of patients with RD, (2) Collect T-Score metrics in patients with RD, and (3) Identify clinically meaningful cut-points for these domains.MethodsA convenience sample of RD patients was recruited consecutively during clinic visits, and asked to complete computer-adaptive tests on thirteen Patient-Reported Outcomes Measurement Information System (PROMIS®) instruments. Based on discussion with clinical providers, four measures were chosen to be relevant and actionable (from rheumatologists’ perspective) in RD patients. Data from RD patients were used to develop clinical vignettes across a range of symptom severity. Vignettes were created based on most likely item responses at different levels on the T-score metric (mean = 50; SD = 10) and anchored at 5-point intervals (0.5 SDs). Patients with RD (N = 9) and clinical providers (N = 10) participated as expert panelists in separate one-day meetings using a modified educational standard setting method.ResultsFour domains (physical function, pain interferences, sleep disturbance, depression) that are actionable at the point-of-care were selected. For all domains, patients endorsed cut-points at lower levels of impairment than providers by 0.5 to 1 SD (e.g., severe impairment in physical function was defined as a T-score of 35 by patients and 25 by providers).ConclusionsWe used a modified educational method to estimate clinically relevant cut-points to classify severity for PROMIS measures This allows for meaningful interpretation of PROMIS® measures in a clinical setting of RD population.