William W. Scott

Predicting femoral neck strength from bone mineral data. A structural approach.

An interactive computer program was developed to derive femoral neck geometry from raw bone mineral image data for an estimate of hip strength using single plane engineering stress analysis. The program, which we call Hip Strength Analysis (HSA), was developed as an attempt to improve the predictive value of hip bone mineral data for osteoporosis fracture risk assessment. We report a series of experiments with an aluminum phantom and with cadaver femora, designed to test the accuracy of derived geometric measurements and strength estimates. Using data acquired with both Lunar DP3 (DPA) and Hologic QDR-1000 (x-ray) scanners, HSA computed femoral neck cross-sectional areas (CSA) and cross-sectional moments of inertia (CSMI) on an aluminum phantom were in excellent agreement with actual values (r greater than .99). Using Lunar DP3 data, CSA and CSMI measurements at mid-femoral necks of 22 cadaver specimens were in good general agreement with literature values. HSA computed cross-sectional properties of three of these specimens were compared with measurements derived from sequential CT cross-sectional images. Discrepancy between the two methods averaged less than 10% along the length of the femoral neck. Finally, breaking strengths of 20 of the femora were measured with a materials testing system, showing better agreement with HSA predicted strength (r = .89, percent standard of the estimate (%SEE) = 21%) than femoral neck bone mineral density (r = .79, %SEE = 28%).

Comparison of spontaneous and experimentally induced canine prostatic hyperplasia.

Spontaneous prostatic hyperplasia in the beagle appears to progress with age from a glandular to a cystic histological appearance. Prostatic hyperplasia can be induced in young beagles with intact testes by treatment for 4 mo with either dihydrotestosterone or 5 alpha-androstane-3 alpha, 17 beta-diol, alone, or with either of these steroids in combination with 17 beta-estradiol. In contrast, the induction of prostatic hyperplasia in young castrated beagles, in which the gland had been allowed to involute for 1 mo, requires the administration of both 17 beta-estradiol and either 5 alpha-androstane-3 alpha, 17 beta-diol or dihydrotestosterone. Testosterone and 17 beta-estradiol, either singly or in combination, did not produce the hyperplastic condition in intact or castrated beagles. The experimentally induced prostatic hyperplasia is identical in pathology to the glandular hyperplasia that occurs naturally in the aging dog with intact testes. However, cystic hyperplasia was not produced by any of the treatments tested in young animals.

Hormonal therapy of prostatic cancer.

The principle goal of hormonal therapy in the treatment of prostatic cancer, as Huggins suggested in 1941, is the suppression of androgenic stimuli. Consequently, the treatment of advanced prostatic cancer has consisted of orchiectomy, estrogen administration, antiandrogen therapy, adrenalectomy or hypophysectomy, or a combination of some of these. Although the three VACURG studies are subject to several valid criticisms, they provide the best available information to date. In summary, these studies report 1) patients with low stage disease who are treated with estrogen (diethylstilbestrol 5 mg/day) have a higher death rate, mainly cardiovascular, than men not receiving estrogen and 2) in patients with high stage disease, delayed hormonal therapy is as effective as early hormonal therapy. Castration appears to be as effective as treatment with estrogens or a combination of the two and does not evoke the untoward side‐effects of estrogen administration. Although subjective improvement has been observed following adrenal or pituitary ablation, the duration of response is usually short, and consequently these procedures are used infrequently now. Experience with the use of antiandrogens is even more limited. Efforts must continue to develop means of predicting hormonal responsiveness. If receptor measurements prove to be an accurate means for predicting the hormonal responsiveness of prostatic cancer, as they have in breast cancer, then our current plan of treatment will need modification. In those men who are unlikely to respond to hormonal therapy, early chemotherapy should be instituted.

Treatment of newly diagnosed metastatic prostate cancer patients with chemotherapy agents in combination with hormones versus hormones alone

A prospective trial from July 1976 to September 1980 by the National Prostatic Cancer Project randomized newly diagnosed metastatic prostate cancer patients to DES 1 mg orally three times daily or orchiectomy; or DES, 1 mg, three times daily, plus cyclophosphamide at 1 mg/m2 iv every three weeks, or cyclophosphamide 1 g/m2 iv every three weeks plus estramustine phosphate (Estracyt) at 600 mg/m2 orally daily in three divided doses. There were 246 patients evaluated for response of 301 entered. These consisted of 83 on the DES/orchiectomy arm, 77 on DES plus cyclophosphamide, and 86 on Estracyt plus cyclophosphamide. Objective response rates, initially evaluated at 12 weeks, were similar among the treatments. However, chemotherapy as used in this study early in the diagnosis of metastatic disease appears to exhibit an improved effect on overall survival compared to hormone therapy alone. Analysis within groups having pain versus no pain at entry revealed a marked advantage after 80 weeks for chemotherapy when pain was initially present and a slight advantage during treatment (throughout follow‐up) when the pain was absent. Median survival times were 92, 91, and 94 weeks, respectively, for the three treatments. The progression‐free interval for responders showed no difference between initial treatments, although nearly one half of the patients are still in remission; hence, further follow‐up will be essential. Side effects were not excessive for the chemotherapy treatment arms and patient compliance was good. This national multicenter trial provides the basis for further testing of chemotherapy agents at an earlier phase for patients with newly diagnosed metastatic prostate cancer.

Fatty infiltration of the liver: ultrasonographic and computed tomographic correlation.

To evaluate the accuracy of ultrasonography in diagnosing fatty infiltration of the liver (FIL), the authors compared gray‐scale B‐mode ultrasonography and unenhanced computed tomographic (CT) liver images in a study of 47 patients. The CT scans, which served as the diagnostic standard, were classified as normal, Grade 1 (mild FIL), Grade 2 (moderate FIL), and Grade 3 (severe FIL). Applying predetermined sonographic textural criteria, two experienced radiologists independently graded each ultrasound study for the presence and severity of FIL. The overall accuracy of ultrasonography in detecting FIL was 85 per cent, with 100 per cent sensitivity and 56 per cent specificity. The sonographic/CT correlation in grading the severity of FIL was particularly good for Grade 2 and Grade 3 FIL. Ultrasound is a sensitive and reasonably accurate diagnostic tool in assessing fatty infiltration of the liver.

Chemotherapy of advanced prostatic cancer Evaluation of response parameters

A total of 125 patients with progressing advanced prostatic cancer were entered into a chemotherapy study comparing cyclophosphamide, 5-fluorouracil, and standard therapy. Parameters of response were studied in 110 patients who could be evaluated. Thirty-six patients (33 per cent) were considered to have an objective response, that is becoming stable (29 patients) or in partial regression (7 patients). Negative response parameters (predictors of a poor response to chemotherapy or standard theraphy leading to progress) included (1) bone marrow evidence of prostatic cancer, (2) abnormal liver scan, (3) prior radiation therapy (indirectly through increased toxicity to chemotherapy), and (4) lack of bilateral orchiectomy prior to randomization. Positive indicators (predictors of good responses) included (1) reduction of primary tumor mass, especially after administration of 5-fluorouracil or cyclophosphamide, and (2) hemoglobin values. There were more objective responders to cyclophosphamide than standard therapy whether the hemoglobin was initially normal or low. Indeterminate parameters of response included weight gain, presence of bony or soft tissue metastases, relief of pain, performance status, excretory urography, and biochemical determinations of liver and renal function.

Spontaneous benign prostatic hyperplasia in the beagle. Age-associated changes in serum hormone levels, and the morphology and secretory function of the canine prostate.

This paper is a cross-sectional study of spontaneous benign prostatic hyperplasia (BPH) in a single canine species. The effects of aging and hormonal changes on the growth, histology, and glandular secretory function of the canine prostate were studied in 42 male beagles ranging in age from 8 mo to 9 yr. The beagle prostate enlarges for at least 6 yr, whether normal or hyperplastic. In contrast, prostatic secretory function, determined by ejaculate volume and total ejaculate protein, declines markedly after 4 yr of age. These reciprocal growth and functional changes in the prostate are closely associated with a progressive increase in the incidence of BPH, which is already apparent in some dogs by age two. With age there is a modest decrease in serum androgen levels with no apparent change in serum 17 beta-estradiol levels. This suggests that the growth and functional changes that are associated with the development of BPH and are initiated very early in life reflect an altered sensitivity of the prostate to serum androgens or a response to the relative decrease in the serum androgen to estrogen ratio.

Familial aggregation of osteoarthritis: Data from the Baltimore longitudinal study on aging

OBJECTIVE To evaluate the familial aggregation of osteoarthritis (OA) in a cohort of healthy volunteers drawn from a community setting. METHODS Hand radiographs obtained between 1978 and 1991 and bilateral standing knee radiographs obtained between 1984 and 1991 were read for changes of OA, using Kellgren-Lawrence (K-L) scales. The hand sites were distal interphalangeal (DIP) joints, proximal interphalangeal (PIP) joints, and first carpometacarpal (CMC1) joints. For each joint group, the presence of OA in at least 1 joint in a joint group, the number of affected digits in each joint group, and the sum of the K-L grade across all joints were analyzed. Polyarticular OA was recorded if there were OA findings in 2 of 3 hand joint groups plus 1 or both knees. Data from 167 families with hand radiographs, 157 families with knee radiographs, and 148 families with both hand and knee radiographs were analyzed for sib-sib correlations. RESULTS After adjustment for age, sex, and body mass index, clinically relevant sib-sib common correlations were found for OA of the DIP, PIP, and CMC1 joints, for OA at 2 or 3 hand sites, and for polyarticular OA (r = 0.33-0.81) when OA was defined according to the number of affected joints or as the sum of the K-L grade across all joints. CONCLUSION These results from a cohort of volunteers drawn from a community setting and ascertained without regard to OA status demonstrate familial aggregation of OA and contribute to the evidence for heritability of OA.

Reliability of grading scales for individual radiographic features of osteoarthritis of the knee: The Baltimore longitudinal study of aging atlas of knee osteoarthritis

RATIONALE AND OBJECTIVES The authors present an atlas of individual radiographic features of osteoarthritis of the knee and evaluate the inter- and intra-reader reliability of trained readers using this atlas. METHODS Four trained readers graded 30 standing anterior-posterior knee radiographs for eight selected features of osteoarthritis (medial and lateral osteophytes, joint space narrowing, and sclerosis; osteophytes of the tibial spines and chondrocalcinosis) as well as the Kellgren-Lawrence global scale. Inter- and intra-reader reliability were calculated using intraclass correlation coefficients. RESULTS For all features except sclerosis and osteophytes of the tibial spines, inter-reader reliability ranged from 0.63 to 0.83, whereas intra-reader reliability ranged from 0.82 to 0.95. CONCLUSION Using this atlas, trained readers are reliable in measuring the presence and severity of individual radiographic features of osteoarthritis of the knee. This atlas should be useful in clinical and epidemiologic studies of osteoarthritis of the knee.

Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis

OBJECTIVE Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)-specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD-4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti-PAD-4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti-PAD-4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD-4 polymorphisms influence the anti-PAD-4 autoantibody response. METHODS Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti-PAD-4 autoantibodies by immunoprecipitation of in vitro-translated PAD-4. The epitope(s) recognized by PAD-4 autoantibodies were mapped using various PAD-4 truncations. PAD-4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method. RESULTS PAD-4 autoantibodies were found in 36-42% of RA patients, and were very infrequent in controls. Recognition by anti-PAD-4 autoantibodies required the 119 N-terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti-PAD-4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti-PAD-4 antibodies were associated with more severe joint destruction in RA. CONCLUSION Our findings indicate that anti-PAD-4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti-PAD-4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD-4 protein, potentially contributing to disease propagation.