An essential role for ectodomain shedding in mammalian development.

The ectodomains of numerous proteins are released from cells by proteolysis to yield soluble intercellular regulators. The responsible protease, tumor necrosis factor-alpha converting enzyme (TACE), has been identified only in the case when tumor necrosis factor-alpha (TNFalpha) is released. Analyses of cells lacking this metalloproteinase-disintegrin revealed an expanded role for TACE in the processing of other cell surface proteins, including a TNF receptor, the L-selectin adhesion molecule, and transforming growth factor-alpha (TGFalpha). The phenotype of mice lacking TACE suggests an essential role for soluble TGFalpha in normal development and emphasizes the importance of protein ectodomain shedding in vivo.

Three dimensional reconstruction of a human breast carcinoma using routine laboratory equipment and immunohistochemistry.

AIMS: To establish a three dimensional reconstruction of an invasive breast carcinoma using basic laboratory equipment to evaluate and characterise the spatial arrangement of the parenchymal cells of the breast. METHODS: One hundred and twenty eight sequential 4 microm sections (20 microm apart) of the tumour were stained immunohistochemically with an epithelial specific marker (AE1/AE3) or tumour specific marker (c-erbB-2) to reconstruct two different three dimensional images of the normal and malignant parenchymal cells. Sections were digitally imaged using a microscope, scanner, and digital camera linked to a conventional personal computer. Accurate alignment of the digitalised images was carried out using a semiautomatic graphical method of manual interaction, using the cross correlation coefficient as a goodness of fit measure, and an automatic search algorithm using the Fibonacci search algorithm for automatic alignment. The volume was reconstructed using maximum, minimum point projection and "back to front" opacity blending. RESULTS: The quality of the reconstructed images was distinct and perfect, providing a comprehensive and explicit view of the normal and malignant parenchymal tissues of the breast that is not possible by viewing two dimensional histological sections. Specifically, this approach showed the spatial arrangement of the tumour cells and their relation to the surrounding tissues at a high resolution. CONCLUSION: This simple and reproducible approach enables the spread and infiltration of invasive carcinoma to be understood and could also be used to analyse the spatial relation between atypical hyperplastic and malignant in situ lesions of the breast.

The effects of risedronate on canine cancellous bone remodeling: three-dimensional kinetic reconstruction of the remodeling site.

To investigate the dose-dependent effects of risedronate on cancellous bone remodeling, adult female beagle dogs were treated with either placebo, 0.1, 0.5, or 2.5 mg/kg/day of risedronate orally in an intermittent cyclic regimen (7 days on 21 days off), repeated three times. Iliac cancellous bone samples were subjected to histomorphometric analysis and three-dimensional (3-D) kinetic reconstruction of the remodeling site was performed. In the 0.1 mg/kg dose group, resorption and activation indices were no different from the placebo group. However, wall thickness was increased resulting in a positive bone balance at the level of the remodeling unit. In the 0.5 and 2.5 mg/kg dose groups, a dose-dependent reduction in activation frequency and tissue level bone formation was observed. Resorption rates were also significantly decreased, 60% and 80% for the 0.5- and 2.5-mg/kg groups, respectively. An approximate 25% reduction in final erosion depth was noted in both these groups. Analyses of the growth curves of the bone packet confirmed that the kinetics of the growth of a completed packet were different in the 0.5- and 2.5-mg/kg dose groups compared with placebo. These changes were associated with a significant increase in the final wall thickness in both groups indicating no net impairment of osteoblast function. These increases in wall thickness in combination with the reductions in final erosion depth in the 0.5 and 2.5 mg/kg groups resulted in a significant dose-dependent positive bone balance. This pharmacological profile suggests that risedronate may be of therapeutic utility in the treatment of metabolic bone diseases where reductions in activation frequency and resorptive cell activity at the level of the remodeling unit are a therapeutic goal.

Effects of intermittent hPTH(1-34) alone and in combination with 1,25(OH)(2)D(3) or risedronate on endosteal bone remodeling in canine cancellous and cortical bone.

Therapies utilizing intermittent human parathyroid hormone(1-34) (hPTH[1-34]) in combination with other agents have recently been proposed as possible anabolic regimens for the treatment of osteoporosis. We conducted a 24 week study in aged beagle dogs to determine the effects of intermittent hPTH(1-34) administered alone or in combination with 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) on the endosteal remodeling in cancellous and cortical bone. Additionally, we tested the interaction between hPTH(1-34) and a new potent bisphosphonate, risedronate. The three treatment groups were compared with a vehicle control group. Kinetic reconstruction of the remodeling unit revealed substantial differences between the groups in resorption and formation at the basic multicellular unit level. Although the estimates of final erosion depth were unaffected by treatment, tunneling resorption was noted in six of the eight dogs administered hPTH(1-34) alone. These qualitative morphological changes in the resorption lacunae were attenuated or absent in dogs administered hPTH(1-34) in combination with either 1,25(OH)(2)D(3) or risedronate. Functional periods for resorption were significantly increased, and the resorption rates were significantly decreased in the hPTH(1-34) + risedronate group. Analyses of the formative site demonstrated that the wall thickness was significantly increased and the bone balance significantly more positive in all three hPTH(1-34) treatment groups. The most positive bone balance was achieved in the combined hPTH(1-34) + risedronate group (+ 15.6 + or - 14.2 mm, p <0.05). Increases in the mineral apposition rate in the early phases of the formative period suggest that an increase in osteoblastic activity (number or function) may contribute to the increase in wall thickness. Treatment with hPTH(1-34) alone or in combination with 1,25(OH)(2)D(3) caused an approximately 2-fold increase in the activation frequency in cancellous bone, which was essentially normalized to control values by the coadministration of risedronate. The impact of these changes on the cancellous bone microstructure was significant only in the combined hPTH(1-34) + risedronate group where normalized bone turnover in the face of a positive bone balance effected a significant increase in the trabecular thickness. Analyses of sequential fluorochrome labels, administered to reconstruct the temporal changes in intracortical activation, demonstrated the presence of an apparent cyclic pattern of activation in the cortex of placebo-treated dogs. Generally, activation was increased throughout the study in dogs administered hPTH(1-34) alone or in combination. However, in the hPTH(1-34) + risedronate group, activation was significantly blunted toward the end of the study, and the cyclic pattern of activation was modulated. These data suggest that intermittent hPTH(1-34) in combination with risedronate may be superior to hPTH(1-34) in combination with 1,25(OH)(2)D(3) as a therapeutic regimen for osteoporosis due to the protective effect of this bisphosphonate on the cortical and endocortical envelope.

Sequential histomorphometric changes in cancellous bone from ovariohysterectomized dogs.

To evaluate potential pharmacologic agents for the prevention or treatment of the bone loss associated with ovarian insufficiency, a predictable animal model is needed. To assess the potential utility of the ovariohysterectomized dog as a model of this condition, we characterized the sequential histomorphometric changes in canine cancellous bone in response to the loss of ovarian function. A group of 25 adult beagle dogs were ovariohysterectomized and terminated at 1, 3, 6, and 10 months following surgery. Iliac biopsies were performed following double-fluorochrome labeling at the time of surgery and at termination. Static and dynamic histomorphometry was performed on undecalcified sections. By 3 months postovariohysterectomy, there was activation of cancellous bone remodeling as indicated by significant increases in mineralizing surface and bone formation rate. Increases in osteoid surface, mineralizing surface, and bone formation rate were also apparent at 1 month postovariohysterectomy, and although not statistically significant, these trends suggest the skeletal response to acute loss of ovarian function was rapid. This increase in bone remodeling was transient. By 6 months, mineralizing surface and bone formation rate were depressed below presurgical levels. In addition to a reduction in bone formation, a reduction in osteoblast function characterized by reduced labeling of osteoid and a disproportionate increase in eroded surface also occurred. By 10 months postovariohysterectomy, cancellous bone remodeling was not significantly different from presurgical levels. At no time was a significant reduction in bone volume detected. These data suggest that the changes in cancellous bone remodeling in the ovariohysterectomized dog are a series of transient phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)

Contrasting effects of parathyroid hormone and insulin-like growth factor I in an aged ovariectomized rat model of postmenopausal osteoporosis.

Agents that exert anabolic effects on bone have generally been tested in young or estrogen-replete animals. It is unclear whether these agents exert similar effects in older ovariectomized (Ovx) animals. In this single study we examined the effects of intermittent (daily) human PTH-(1-34) and continuous infusion of human recombinant IGF-I alone and in combination on bone resorption and formation over a 14 day period in an aged Ovx rat model of postmenopausal osteoporosis (2-year-old rats, Ovx at 1 year). Compared to Ovx controls, PTH treatment increased bone mineral content (BMC) and bone volume and stimulated bone formation but had no effect on bone resorption. In contrast, IGF-I treatment reduced BMC and stimulated resorptive activity as assessed by increases in marrow volume, cortical porosity, osteoclast-positive eroded surfaces, and urinary hydroxyproline excretion. IGF-I had no effect on bone formation, but when combined with PTH, IGF-I blunted the response to PTH on the periosteal and endocortical surfaces. In summary, PTH stimulated bone formation in a manner similar to that observed in younger animals and IGF-I stimulated bone resorption rather than formation and blunted the bone-forming response to PTH. The effects of IGF-I in older Ovx rats may differ from those observed in younger estrogen-replete animals.

Prediction of body density and lean body weight in females 25 to 37 years old.

Sixty-one physically inactive females (ages 25 to 37 years) underwent hydrostatic weighing to determine body density (Db). A series of anthropometric measures were also obtained and were used to develop multiple regression equations for the prediction of (Db) and lean body weight (LBW). The anthropometric variables were also used to determine the prediction accuracy of several previously published regression equations. Mean Db was 1.0405 +/- 0.0131 g/ml, relative fat, 25.1 +/- 5.55%, and LBW, 42.14 +/- 4.64 KG. Percentage of body fat was calculated from Db using the formula of Brozek er al. (Am. N.Y. Acad. Med. 110: 113, 1963). Higher correlations were obtained between actual and predicted LBW (R = 0.66 to 0.82). The best regression equation was found to be one using a combination of body weight, one skinfold, and four circumferences. When selected multiple regression equations developed by other authors were used to predict the Db and LBW of the present subjects, the actual values were both over- and underestimated, and correlations between measured and predicted values were lower. It was concluded that even though the body composition of these women was similar to that of college-age women, different regression equations are needed for accurately predicting their Db and LBW.

Histogenesis of hyperosteoidosis in 1,25(OH)2D3-treated rats fed high levels of dietary calcium.

The purpose of this investigation was to determine by sequential quantitative morphometry the histogenesis of metaphyseal changes induced in rats fed high levels of dietary calcium and treated with pharmacologic doses of 1,25(OH)2D3. Young adult female rats were placed on a diet containing 2.5% calcium and 0.3% phosphorus and administered either ethanol or 135 ng (5 units) 1,25(OH)2D3 in ethanol IP daily for 10 days. Rats were terminated at Days 1, 2, 3, 4, 6, 8, and 10. At Day 1 the proximal tibias from rats treated with 1,25(OH)2D3 had a dramatic increase in osteoclasts/mm total trabecular surface perimeter compared with placebo-treated rats. Osteoclast numbers decreased in 1,25(OH)2D3-treated rats to the levels in placebo-treated rats by Days 3 and 4 and decreased significantly below placebo-treated levels at Days 6, 8, and 10. Active resorbing surface was significantly increased at Days 1 and 2 and decreased at Days 8 and 10 in 1,25(OH)2D3-treated rats compared with placebo-treated rats. From Day 4 through Day 10 in 1,25(OH)2D3-treated rats, there was a progressive increase in osteoblasts/mm total trabecular surface perimeter, osteoid surface, active osteoid surface, and metaphyseal osteoid. Metaphyseal osteoid increased markedly at Days 8 and 10 in 1,25(OH)2D3-treated rats and caused a significant increase in the amount of osseous tissue in the metaphysis. Metaphyseal mineralized bone, however, was not consistently affected by 1,25(OH)2D3 treatment. Serum calcium and phosphorus were elevated in 1,25(OH)2D3-treated rats at more time periods. In rats fed high levels of dietary calcium, repeated supraphysiologic doses of 1,25(OH)2D3 result in a net increase in metaphyseal osseous tissue, predominantly osteoid.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrastructural development of hyperosteoidosis in 1,25(OH)2D3-treated rats fed high levels of dietary calcium.

To evaluate the sequential ultrastructural pathogenesis of the increase in osseous tissue and hyperosteoidosis previously demonstrated in rats administered supraphysiologic doses of 1,25(OH)2D3 and fed high levels of dietary calcium, young adult female rats were placed on a 2.5% calcium and 0.3% phosphorus diet, administered ethanol or 135 ng (5 units) 1,25(OH)2D3 IP daily, and killed after 2, 4, 6, 8, and 10 days. Metaphyseal trabeculae from 1,25(OH)2D3 and placebo-treated rats were examined. Osteoblast hypertrophy characterized by increased cytoplasmic area, abundant rough endoplasmic reticulum, and prominent Golgi apparatus was evident in 1,25(OH)2D3-treated rats at Day 4. These osteoblasts were interpreted to be active in matrix synthesis. Widened osteoid seams were present at Day 6. Osteoblast hypertrophy and widened osteoid seams persisted through Day 10 in 1,25(OH)2D3-treated rats. The unmineralized bone matrix in 1,25(OH)2D3-treated rats contained more numerous cytoplasmic processes from adjacent osteoblasts than did control animals and loosely arranged collagen fibrils, which failed to aggregate in regions adjacent to the osteoid-mineralized bone interface as in placebo-treated rats. Osteoid seams in 1,25(OH)2D3-treated rats contained irregular electron-dense foci, which were often concentrated around embedded cytoplasmic processes. Osteocytic hypertrophy characterized by increased cytoplasmic area, developed rough endoplasmic reticulum, and increased numbers of mitochondria was evident at Day 2 and was sustained through Day 10 in 1,25(OH)2D3-treated rats. Variable-sized aggregates of electron-dense deposits similar to those concentrated around osteoblast cytoplasmic processes were observed in the pericellular space and on and immediately adjacent to the plasma membranes of osteocytes and embedding osteoblasts in 1,25(OH)2D3-treated rats as early as Day 4.(ABSTRACT TRUNCATED AT 250 WORDS)

The Conneulor: unbiased estimation of connectivity using physical disectors under projection.

The Euler number and the connectivity of an arbitrary object is defined, and it is illustrated why the connectivity of an n-dimensional object cannot be estimated in an (n-1)-dimensional section. The disector--principle for 3-D counting of the Euler--events is illustrated in cancellous bone. The correct handling for unbiased counting of events at artificial edges is outlined. A nomogram for predicting the precision of an estimate is provided.

Stochastic simulation of vertebral trabecular bone remodeling.

Bone remodeling changes bone mass, architecture, and thereby bone strength, during normal aging. These changes seem to be accelerated during the menopause. Several therapeutic agents have been used in order to delay the onset of the menopause-related changes. The effects of these agents on the remodeling process have been determined histomorphometrically in several short-term clinical studies, but data from long-term clinical studies are difficult to achieve, as are data on the influence on bone strength. The aim of this study was to develop a computer stimulation model that could assist in predicting the long-term effects of changes in the remodeling process on bone mass, trabecular thickness, and perforations. The paper presents such a stochastic model of the remodeling process in human vertebral trabecular bone. The computer model is based on histomorphometric and structural data from human studies. It is presented in terms of flow charts, and simulations performed with the model are discussed in relation to measurements on human vertebral bone samples. The results show that a menopause-related doubling of the activation frequency causes a transient, mainly reversible bone loss. If the menopause is accompanied by an increase in both activation frequency and resorption depth, then the resulting bone loss will be more pronounced and with a larger part being irreversible bone loss (perforations). The two antiresorptive agents. Etidronate and estrogen both cause a slight increase in bone mass (reducing remodeling space), and Etidronate also seems capable of preventing perforations. During fluoride therapy, an initial increase in remodeling space followed by a reduction is seen. Very few perforations are found to take place during fluoride therapy. The present model has been validated by assessing the effects of the menopause and treatment with antiresorptive or anabolic agents. It was found that the results mirrored or anabolic agents. It was found that the results mirrored very closely the results (bone mass measurements) from short-term clinical studies. It is therefore concluded that the model provides a tool for evaluating existing and new therapeutic regimens.

Unbiased estimation of vertebral trabecular connectivity in calcium-restricted ovariectomized minipigs.

The topological changes in vertebral cancellous bone were estimated in vertebrae from calcium-restricted ovariectomized Sinclair S-1 minipigs, a recently described animal model of cancellous osteopenia. Connectivity was estimated using unbiased stereological principles in disector pairs of sections from the first lumbar vertebrae. Connectivity density was increased approximately twofold when compared with sham-operated minipigs fed a standard diet. These alterations in topology occurred coincident with a 25% increase in final resorption depth and a 150% increase in vertebral marrow star volume. Taken together, these changes suggest that in calcium-restricted ovariectomized minipigs, trabecular plates are transformed into rods by perforation. These changes in topology appear to be due, at least in part, to excessive resorptive cell function at the level of the bone remodeling unit. Conventional two-dimensional estimators of structural parameters of cancellous bone were not only less sensitive to these changes in topology but, in some cases, the estimates were directionally reversed.

Direct stereological estimation of three-dimensional connectivity in rat vertebrae: effect of estrogen, etidronate and risedronate following ovariectomy.

Newly developed unbiased stereological methods were employed to investigate the effects of estrogen deficiency on the three-dimensional connectivity of vertebral cancellous bone from ovariectomized (OVX) rats. The effects of two classes of antiresorptive agents, estrogen and bisphosphonates, on changes in connectivity in this animal model were also evaluated. Female rats were either sham-operated (sham-op) or surgically OVX at 90 days of age. OVX rats were administered either vehicle, estrogen (10 micrograms/kg 17-beta estradiol, 5 days/week subcutaneously [SC], etidronate disodium (5 mg/kg SC) or risedronate (5 micrograms/kg SC). The bisphosphonates were administered daily for 1 week followed by 3 weeks with no treatment. Treatment duration was 360 days. Systematic random sections, 30-microns thick, were prepared from methylmethacrylate-embedded decalcified second lumbar vertebrae. Total trabecular number and connectivity density were estimated using the ConnEulor principle. Vertebral cancellous bone volume was estimated on undecalcified sections from the first lumbar vertebrae. Connectivity density and cancellous bone volume were significantly reduced (approximately 25% and 40%, respectively) in the OVX group compared with the sham-op group. Estrogen treatment essentially maintained connectivity and cancellous bone volume at the level of the sham-op rats. Connectivity density and total trabecular number were significantly increased in the etidronate- and risedronate-treated rats compared with both the sham-op and OVX rats. These data demonstrate that reduction in the three-dimensional connectivity of vertebral cancellous bone is a long-term consequence of ovariectomy in the rat. This reduction in connectivity can be effectively prevented by the administration of antiresorptive agents such as estrogen, etidronate and risedronate.(ABSTRACT TRUNCATED AT 250 WORDS)

Metaphyseal bone lesions in young dogs with systemic canine distemper virus infection.

Bone lesions, restricted to the metaphyses of long bones, were observed in young dogs with systemic distemper following experimental and spontaneous infection. Canine distemper virus (CDV) antigen was found immunocytochemically in hematopoietic marrow cells, osteoclasts, osteoblasts and rarely in osteocytes. In experimentally infected dogs, viral antigen was demonstrated in the metaphysis between 5 and 36 days after infection. Associated lesions, characterized by necrosis of osteoclasts, persistence of primary spongiosa and atrophy and necrosis of osteoblasts and marrow cells, were mild and most prominent between 8 and 32 days postinfection. Metaphyseal osteosclerosis (MO) of the long bones, varying from mild to severe, was observed macroscopically in 8 (19%) out of 42 dogs with spontaneous distemper. Affected animals were between 3 and 6 months of age and belonged mainly to the large breeds. In these animals, MO was characterized histologically by persistence of primary spongiosa, loss of bone marrow cells and necrosis of osteoclasts and bone marrow cells varying from mild to severe. Summarized, CDV-associated bone lesions were only transient and there were no indications of viral persistence in bones of dogs experimentally infected with CDV. Although no clinical signs related to the bones were observed, the present study reveals that infection of metaphyseal bone cells is common in young dogs with systemic distemper and occurrence of viral antigen in these cells results in defects in bone modelling.

Teratocarcinoma of the ovary in a mare.

A 5-year-old Appaloosa mare had a history of mild intermittent abdominal discomfort and clinical signs that were suggestive of intestinal obstruction. Palpation per rectum revealed a large mass attached to the left uterine horn, with smaller masses extending dorsally and cranially and causing constriction of the rectum. At necropsy, numerous multilobulated masses were observed in the abdominal cavity and several nodules were seen in the lungs. The left ovary was large and contained both cartilage and hairlike material. Sections from all masses had similar histologic features and confirmed the tentative diagnosis of teratocarcinoma.

NE-58095: a diphosphonate which prevents bone erosion and preserves joint architecture in experimental arthritis.

The rat adjuvant arthritis model, like human rheumatoid arthritis, is characterized by fulminating intra- and periarticular inflammation and bone lysis. This model was used to determine the effectiveness of a potent antiresorptive diphosphonate (NE-58095: monosodium [2-(3-pyridinyl) ethylidene] hydroxy diphosphonate) prophylactically in Lewis rats and therapeutically in Sprague-Dawley rats. Modified Freund's adjuvant (MFA) was injected into the tail of Lewis and Sprague-Dawley rats. Prophylactic treatment in Lewis rats [oral (PO): 14.8 mg/kg/day); subcutaneous (SC): 0.148 mg/kg/day] was begun on the day of MFA injection. A significant reduction in paw swelling was seen as early as day 12 after MFA injection with both oral and parenteral treatment. NE-58095 produced a reduction in paw swelling of 28, 39 and 61% on days 12, 17 and 24 respectively, as compared to the saline-treated MFA control. Bone lysis in the saline-treated MFA group was 85% of total possible incidence for 6 joint regions in the hind paws and 4 regions in the front paws at day 24. This resorption was reduced by 70% in the rats administered NE-58095 PO and SC at 24 days after MFA. In the therapeutic experiments with Sprague-Dawley rats, treatment with NE-58095 (SC: 0.148 mg/kg/day) was begun on day 14 after MFA injection, at which time significant paw swelling (greater than 0.5cc) had occurred. On day 25 (12 days of treatment), paw swelling was reduced 70% by NE-58095 treatment as compared to the saline-treated MFA controls. Histologically, the architecture of the tibio-tarsal joints in the saline-treated MFA rats was affected, in contrast to the NE-58095-treated MFA rats where the architecture of the joint was preserved. This new potent diphosphonate is not an anti-inflammatory compound by any of the classical tests and is effective both orally and parenterally. The mechanism by which this diphosphonate protects joint integrity is not clear but appears to be related to its ability to block bone resorption and the consequent inhibition of the diffusion into the joint space of calcium, chemotactic factors and cytokinas released from bone matrix, resulting in a quenching of the arthritic process.

Effect of dietary calcium on the response of bone to 1,25 (OH)2D3.

The purpose of this investigation was to evaluate, by static and dynamic histomorphometry, the comparative influence of dietary calcium on the effect of 1,25(OH)2D3 on bone. Young adult female rats were fed a diet containing 0.3% phosphorus and 0.05%, 0.5%, or 1.0% calcium. Rats in each group received placebo, or 27 ng or 135 ng of 1,25(OH)2D3, intraperitoneally, for 10 days. A dramatic osteosclerosis and hyperosteoidosis characterized by an increase in metaphyseal hard tissue percentage and percentage metaphyseal osteoid, a decrease in osteoclasts per millimeter of trabecular surface perimeter and longitudinal growth, and hypertrophy of osteoblasts developed in the proximal tibial metaphysis of rats fed 1.0% calcium diet and given 135 ng of 1,25(OH)2D3 compared with placebo-treated rats fed the same diets. Similar histomorphometric changes, with the exception of increased metaphyseal hard tissue percentage, occurred in rats fed 0.5% dietary calcium and treated with 135 ng of 1,25(OH)2D3. Metaphyseal hard tissue percentage, percentage metaphyseal osteoid, and osteoclasts per millimeter of trabecular surface perimeter were not affected by treatment with 135 ng of 1,25(OH)2D3 in rats fed a 0.05% calcium diet. Serum calcium was significantly elevated in all 1,25(OH)2D3-treated rats. Dietary calcium appears to modulate the effects of 1,25(OH)2D3 on bone. Only diets containing adequate dietary calcium permit exogenous pharmacologic levels of 1,25(OH)2D3 to produce a positive skeletal balance either by decreasing osteoclasis and/or increasing bone matrix synthesis.

Establishing an active patient partnership.

Pharmacists face many changes in the coming decade, some of which threaten their professional survival. Although uncertainty may currently prevail, one of these changes, the shift in the patient-health care professional relationship from the patient taking a passive role to an active partnering role, provides pharmacists with many opportunities to realize the vision of patient-centered care that has been advocated by pharmacy innovators and leaders for almost three decades. To take advantage of these changes, pharmacists must modify their practice paradigms and use their existing strengths, such as easy patient access and high levels of patient trust, to help develop a new model of pharmaceutical care. The concern that the magnitude of these changes will prevent successful practice transformations may be exaggerated. In reality, these proposed "new" roles have been in existence for much of this century. Most pharmacists can expand and enhance their traditional roles as self-care advisors and patient educators simply by incremental improvements in interpersonal and clinical skills. Rather than a Star Trek approach to "go where no man has gone before," the profession needs only a pharmaceutical sequel to Back to the Future.

Pharmacist-managed patient-care services and prescriptive authority in the U.S. Public Health Service.

The Indian Health Service (IHS), an agency of the US Public Health Service, instituted a broad range of clinical pharmacy services for ambulatory patients in the 1960s and early 1970s. One outgrowth of these services was that pharmacists were authorized to provide certain prescription legend drugs directly to patients without physician preauthorization. Also, pharmacists monitored patients' progress and were authorized to make therapeutic substitutions of drugs. Pharmacist prescribing privileges in these programs were defined by P & T Committee-approved protocols. Success with these programs led to expanding the pharmacist's role to include physical assessment and differential diagnosis of patients with specific diseases and to manage their care when that care consisted primarily of medications. The development and implementation of these programs and the results of a study of pharmacist prescribing within the IHS are described in this article, as is the IHS clinical pharmacy training program.

Physical fitness capacity and absenteeism of police officers.

Police officers (n = 514) were studied to determine the relationship between physical fitness capacity and annual absenteeism rate. Hierarchical regression analyses revealed that for officers aged 34 years and younger, only 5% of the variability in absenteeism could be accounted for by age, sex, and physical fitness variables. For officers 35 years old and older, 7% of the variability was explained by these variables, and a bicycle ergometer score was a significant predictor of absenteeism. Each individual test and an overall physical fitness score were classified into five levels. ANOVAs revealed no significant differences between overall fitness levels and absenteeism. However, men 35 and over who were most fit on the bicycle ergometer test had fewer absences, and women 34 and under who were thinnest had more absences. In conclusion, at least among police officers, the extent to which physical fitness capacity can predict absenteeism is low.