A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys.

Cathepsin K is an osteoclast-derived cysteine protease that has been implicated as playing a major role in bone resorption. A substantial body of evidence indicates that cathepsin K is critical in osteoclast-mediated bone resorption and suggests that its pharmacological inhibition should result in inhibition of bone resorption in vivo. Here we report the pharmacological characterization of SB-462795 (relacatib) as a potent and orally bioavailable small molecule inhibitor of cathepsin K that inhibits bone resorption both in vitro in human tissue and in vivo in cynomolgus monkeys. SB-462795 is a potent inhibitor of human cathepsins K, L, and V (K(i, app)=41, 68, and 53 pM, respectively) that exhibits 39-300-fold selectivity over other cathepsins. SB-462795 inhibited endogenous cathepsin K in situ in human osteoclasts and human osteoclast-mediated bone resorption with IC50 values of approximately 45 nM and approximately 70 nM, respectively. The anti-resorptive potential of SB-462795 was evaluated in normal as well as medically ovariectomized (Ovx) female cynomolgus monkeys. Serum levels of the C- and N-terminal telopeptides of Type I collagen (CTx and NTx, respectively) and urinary levels of NTx were monitored as biomarkers of bone resorption. Administration of SB-462795 to medically ovariectomized or normal monkeys resulted in an acute reduction in both serum and urinary markers of bone resorption within 1.5 h after dosing, and this effect lasted up to 48 h depending on the dose administered. Our data indicate that SB-462795 potently inhibits human cathepsin K in osteoclasts, resulting in a rapid inhibition of bone resorption both in vitro and in vivo in the monkey. These studies also demonstrate the therapeutic potential of relacatib in the treatment of postmenopausal osteoporosis and serves to model the planned clinical trials in human subjects.

Proximal scaphoid rib graft arthroplasty.

We prospectively reviewed 14 patients with deficiency of the proximal pole of the scaphoid who were treated by rib osteochondral replacement arthroplasty. Improvement in wrist function occurred in all except one patient with enhanced grip strength, less pain and maintenance of wrist movement. In 13 patients wrist function was rated as good or excellent according to the modified wrist function score of Green and O'Brien. The mean pre-operative score of 54 (35 to 80) rose to 79 (50 to 90) at review at a mean of 64 months (27 to 103). Carpal alignment did not deteriorate in any patient and there were no cases of nonunion or significant complications. This procedure can restore the mechanical integrity of the proximal pole of the scaphoid satisfactorily and maintain wrist movement while avoiding the potential complications of alternative replacement arthroplasty techniques and problems associated with vascularised grafts and salvage techniques.

Constrained total hip arthroplasty in a paediatric patient with cerebral palsy and painful dislocation of the hip. A case report.

We describe a patient with cerebral palsy, of normal intelligence, who could not walk but who by the age of 16 had been successfully managed with a staged bilateral total hip arthroplasty using a constrained liner.

The reactivity of various free radicals with hyaluronic acid: steady-state and pulse radiolysis studies.

The reactions of the primary water radicals with the biopolymer hyaluronic acid have been studied by pulse radiolysis. Bimolecular rate constants, expressed in terms of the disaccharide repeating sub-unit of hyaluronic acid, for OH., H. and eaq- were found to be 7 X 10(8) M-1 X s-1, 5 X 10(7) M-1 X s-1 and less than 5 X 10(6) M-1 X s-1, respectively. By comparing the viscosities of samples, gamma-irradiated in the steady state under a variety of conditions, with unirradiated controls, the efficiencies with which selected radicals cause chain breakage have been determined. Efficiencies of 30%, 15%, 0%, 0.2% and 5% were estimated for OH., H., eaq-, methanol radicals and tert-butanol radicals, respectively. The presence of oxygen during irradiation increased the extent of chain breakage by a factor of 1.75.

Increased osteoblastogenesis and decreased bone resorption protect against ovariectomy-induced bone loss in thrombospondin-2-null mice.

Although bone is composed primarily of extracellular matrix (ECM), the dynamic role that the ECM plays in regulating bone remodeling secondary to estrogen loss is relatively unexplored. Previous studies have shown that mice deficient in the matricellular protein thrombospondin-2 (TSP2-null) form excess endocortical bone; thus, we postulated that enhanced bone formation in TSP2-null mice could protect against ovariectomy (OVX)-induced bone loss. Wild-type (WT) OVX mice showed a significant loss of both midfemoral endocortical and proximal tibial trabecular bone, but OVX did not significantly alter TSP2-null bone. TSP2-null mice showed an increase in bone formation, as indicated by a 70% increase in serum osteocalcin two weeks post OVX and a two-fold increase in bone formation rate (BFR) five weeks post OVX as measured by dynamic histomorphometry. WT animals showed only a 20% increase in serum osteocalcin at two weeks and no change in BFR at five weeks. This increase in bone formation in TSP2-null OVX mice was accompanied by a three-fold increase in osteoprogenitor number. Although these results provide a partial explanation for the maintenance of bone geometry post-OVX, TSP2-null mice five weeks post-OVX also showed a significantly lower level of bone resorption than OVX WT mice, as determined by serum levels of the amino-terminal telopeptide of type I collagen (NTx). We conclude that the absence of TSP2 protects against OVX-induced bone loss by two complementary processes: increased formation and decreased resorption.

Intracellular signaling pathways as a target for the treatment of rheumatoid arthritis.

Recent advances in our understanding of cellular and molecular mechanisms of rheumatoid arthritis have highlighted a critical role for interleukin-1 and tumor necrosis factor alpha. The quest for chemically amenable targets has recently led to the identification and characterization of the intracellular signaling pathways associated with these inflammatory cytokines. In particular the mitogen-activated protein kinase pathway, the nuclear factor kappaB pathway and the cross-talk between these offer several potential therapeutic opportunities for rheumatoid arthritis.

Popliteus tendon tenosynovitis.

This case report highlights an unusual cause of anterolateral knee pain. The popliteus muscle arises from three origins--that is, the lateral femoral condyle, the fibula head, and the lateral meniscus--and inserts into the proximal tibia above the soleal line. It may be subjected to a number of pathologies including tenosynovitis, acute calcific tendonitis, rupture, and even avulsion. In this case, the diagnosis of popliteus tendon tenosynovitis was not made from magnetic resonance imaging findings, but was confirmed and successfully treated during arthroscopic examination.

A potent small molecule, nonpeptide inhibitor of cathepsin K (SB 331750) prevents bone matrix resorption in the ovariectomized rat.

Inhibition of the cyteine proteinase, cathepsin K (E.C. 3.4.22.38) has been postulated as a means to control osteoclast-mediated bone resorption. The preferred animal models for evaluation of antiresorptive activity are in the rat. However, the development of compounds that inhibit rat cathepsin K has proven difficult because the human and rat enzymes differ in key residues in the active site. In this study, a potent, nonpeptide inhibitor of rat cathepsin K (K(i) = 4.7 nmol/L), 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-1-(3-oxo-1-[2-(3-pyridin-2-yl-phenyl)-ethenoyl]-azepan-4-ylcarbanoyl)-butyl)-amide (SB 331750), is described, which is efficacious in rat models of bone resorption. SB 331750 potently inhibited human cathepsin K activity in vitro (K(i) = 0.0048 nmol/L) and was selective for human cathepsin K vs. cathepsins B (K(i) = 100 nmol/L), L (0.48 nmol/L), or S (K(i) = 14.3 nmol/L). In an in situ enzyme assay, SB 331750 inhibited osteoclast-associated cathepsin activity in tissue sections containing human osteoclasts (IC(50) approximately 60 nmol/L) and this translated into potent inhibition of human osteoclast-mediated bone resorption in vitro (IC(50) approximately 30 nmol/L). In vitro, SB 331750 partially, but dose-dependently, prevented the parathyroid hormone-induced hypercalcemia in an acute rat model of bone resorption. To evaluate the ability of SB 331750 to inhibit bone matrix degradation in vivo, it was administered for 4 weeks at 3, 10, or 30 mg/kg, intraperitoneally (i.p.), u.i.d. in the ovariectomized (ovx) rat. Both 10 and 30 mg/kg doses of compound prevented the ovx-induced elevation in urinary deoxypyridinoline and prevented the ovx-induced increase in percent eroded perimeter. Histological evaluation of the bones from compound-treated animals indicated that SB 331750 retarded bone matrix degradation in vivo at all three doses. The inhibition of bone resorption at the 10 and 30 mg/kg doses resulted in prevention of the ovx-induced reduction in percent trabecular area, trabecular number, and increase in trabecular spacing. These effects on bone resorption were also reflected in inhibition of the ovx-induced loss in trabecular bone volume as assessed using microcomputerized tomography (microCT; approximately 60% at 30 mg/kg). Together, these data indicate that the cathepsin K inhibitor, SB 331750, prevented bone resorption in vivo and this inhibition resulted in prevention of ovariectomy-induced loss in trabecular structure.

Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen-induced airway responses in neonatally immunised rabbits.

1. The effects of the inhaled corticosteroid budesonide and a novel PDE 4 inhibitor CDP840 given systematically, were evaluated in a model of antigen-induced airway inflammation in the rabbit. 2. Adult litter-matched NZW rabbits (2.4-3.5 kg) immunised within 24 h of birth with Alternaria tenuis antigen were pretreated with budesonide (total dose 100 micrograms, inhaled over 2 days) or CDP840 (total dose 7 mg kg-1, i.p. over 3 days), before antigen challenge. For each drug-treated group a parallel group of rabbits was pretreated with the appropriate vehicle. In all groups airway responsiveness to inhaled histamine was assessed and bronchoalveolar lavage (BAL) performed 24 h before and after antigen challenge. 3. Basal lung function in terms of total lung resistance (RL; cmH2O l 1s-1) and dynamic compliance (Cdyn; ml cmH2O-1) were unaltered by pretreatment with budesonide or CDP840 compared to their respective vehicles 24 h before or after antigen challenge. 4. The RL component of the acute bronchoconstriction induced by inhaled Alternaria tenuis aerosol was unaffected by pretreatment with budesonide. However, budesonide prevented the fall in Cdyn due to antigen. Treatment with CDP840 significantly reduced antigen-induced acute bronchoconstriction in terms of both RL and Cdyn. 5. Airway hyperresponsiveness (AHR) to inhaled histamine was indicated by reduced RL PC50 (2.4-4.5 fold) and Cdyn PC35 (2.1-3.9 fold) values 24 h after antigen challenge. Treatment with either budesonide or CDP840 abolished the antigen-induced increase in responsiveness to inhaled histamine. 6. Total cells recovered per ml of BAL fluid increased 24 h after antigen challenge. Antigen-induced pulmonary eosinophilia was reduced (93%) in budesonide and (85%) in CDP840 treated rabbits. Antigen-induced increases in neutrophil numbers were reduced (76%) with budesonide but not CDP840 pretreatment. 7. Inhalation of Alternaria tenuis aerosol elicited an acute bronchoconstriction, followed 24 hours later by an increased responsiveness to inhaled histamine and pulmonary neutrophil and eosinophil recruitment. CDP840 was more effective than budesonide in preventing the antigen-induced increase in total lung resistance (RL); however, both drugs prevented the antigen-induced reduction in dynamic compliance (Cdyn). CDP840 and budesonide also prevented antigen-induced AHR and eosinophilia in the immunised rabbit.

Effects of theophylline and rolipram on antigen-induced airway responses in neonatally immunized rabbits.

1. The effects of the xanthine, theophylline, a non-selective phosphodiesterase (PDE) inhibitor, and the phosphodiesterase type 4 (PDE 4) inhibitor, rolipram, were evaluated in a model of antigen-induced airway responses in the allergic rabbit. 2. Adult litter-matched NZW rabbits (2.5-3.9 kg), immunized within 24 h of birth with Alternaria tenuis antigen, were pretreated twice daily for 3 days with theophylline (3 mg kg-1, i.p) or rolipram (1 mg kg-1, i.p) prior to antigen challenge (Alternaria tenuis). For each drug-treated group, a parallel group of rabbits were pretreated with the appropriate vehicle. In all groups airway responsiveness to inhaled histamine and bronchoalveolar lavage (BAL) was performed 24 h before and after antigen-challenge. 3. Basal lung function in terms of resistance (RL, cmH2O 1(-1)s-1) and dynamic compliance (Cdyn, ml cmH2O-1) were unaltered by pretreatment with theophylline or rolipram compared to their respective vehicles 24 h prior to or post antigen challenge. 4. The acute bronchoconstriction induced by inhaled Alternaria tenuis aerosol was unaffected by pretreatment with theophylline or rolipram. 5. Airway hyperresponsiveness to inhaled histamine was indicated by reduced RL PC50 (2.4-3.5 fold) and Cdyn PC35 (2.5-2.6 fold) values 24 h after antigen challenge. Treatment with rolipram, but not theophylline, prevented the increase in responsiveness to inhaled histamine 24 h after antigen challenge. 6. Total cells per ml of BAL fluid increased 24 h after antigen challenge due to the recruitment of neutrophils and eosinophils. Antigen-induced increases in pulmonary neutrophils were unaffected; however, eosinophils were reduced 57.5% in theophylline and 82% in rolipram-treated rabbits. 7. Inhalation of Alternaria tenuis aerosol elicits an acute bronchoconstriction, followed 24 h later by an increased responsiveness to inhaled histamine and pulmonary neutrophil and eosinophil recruitment in the immunized rabbit. With the dosing regimes used, both rolipram and theophylline inhibited eosinophil recruitment, whilst only rolipram prevented the development of airway hyperresponsiveness. Neither agent inhibited the acute bronchoconstriction due to inhaled antigen.

Type A behavior in children: demographic, behavioral, and physiological correlates.

This article provides descriptive data on the Type A behavior pattern from an urban, biracial sample of 8 to 10-year-old children from Minneapolis. Type A behavior was assessed using the Matthews Youth Test for Health (MYTH). High MYTH scores were more prevalent in males relative to females and in black males relative to white males. Parent self-reports suggested that Type A children were more outgoing, talkative, and physically active than Type B children; they were more aggressive in their interactions with others and were more likely to experience a greater number of aversive significant life events than Type B children. No differences in resting heart rate, diastolic or systolic blood pressures were found between Type A and Type B children; there were no differences on measures of the family environment. These results provide additional evidence for the construct validity of the MYTH and offer new information on the correlates of Type A behavior in children.

The shape up challenge: a community-based worksite exercise competition.

PURPOSE: To assess organizational and employee participation during three community-wide worksite exercise competitions in two communities. DESIGN: A one-group, posttest-only design was used. Lack of controls, exercise baseline, and the short-term nature of the interventions were limitations. SETTING: The Minnesota Heart Health Program conducted annual exercise campaigns between 1982 and 1989 within three intervention communities to reduce behavioral risk for cardiovascular disease. The Shape Up Challenge was a worksite exercise competition designed, in conjunction with other campaign activities, to increase levels of physical activity. SUBJECTS: A total of 119 participating companies in two Minnesota communities, and 17,626 employees within these worksites, composed the subjects in this study. INTERVENTION: Eligible worksites were invited to participate in a month-long competition during which employees recorded minutes spent daily in aerobic activities. Incentives were established to promote intragroup cooperation and intergroup competition. Companies competed for awards that were based on average minutes of exercise per employee versus per participant. MEASURES: Numbers of companies recruited and participating, campaign activities, minutes of exercise, and costs were recorded on implementation logs. Companies completed surveys describing business type, number and sex of employees, existing health promotion programs, and perceived benefits of participation. RESULTS: Of the 365 companies invited to participate, 33% participated (range 15% to 50%). Participating companies were more likely than nonparticipating companies to offer other health promotion programs and perceived greater benefits from participation. Women and smaller companies had significantly greater participation rates than men and larger companies. Average employee participation rates ranged from as high as 84% in smaller organizations to as low as 16% as organization size increased. CONCLUSIONS: Community-based worksite exercise competitions appear to be a viable strategy for promoting employee exercise, particularly in smaller companies. Group-based contingencies applied in natural work units may facilitate employee participation. Further research is needed to assess the relative efficacy of this approach, compare alternative incentives, and identify strategies to enhance exercise maintenance after the intervention has ceased.

Factors associated with occupational exposure and compliance with universal precautions in an urban school district.

Factors associated with occupational exposure and universal precautions (UP) compliance were assessed among employees in one urban school district. Half of the employees surveyed reported responding to bleeding injuries and cleaning blood or other body fluids (e.g., vomit, urine) during the previous school year. Also, 1 in 4 custodians and 1 in 10 teachers/teacher's aides had direct contact with blood or body fluids without protection. In multivariate logistic regression analyses, direct contact was most likely among secondary school employees in unpredictable situations who did not have protective equipment or comply with UP. UP compliance was greater among those who had protective equipment available and felt self-confident. Self-confidence was associated with having received training or protective equipment. Routine communications between administrators and employees, staff training, provision of protective equipment, and exposure incident monitoring are essential to effective implementation of UP policies in schools and work settings where occupational exposure could occur.

Differences in smoking cessation strategies between men and women.

This descriptive research was designed to identify differences in smoking cessation strategies between men and women in a cross-sectional population sample of current smokers in the upper Midwest. Data on the number of previous quit attempts, the success and persistence in quit attempts, future intentions to change smoking habits, and strategies planned for cessation were obtained from 1669 smokers. Log-linear analyses controlling for age and the number of cigarettes smoked revealed significant gender differences. Men and women appear to approach smoking cessation differently. Women were more tentative and less committed to quitting smoking entirely. Women were also less successful in sustaining smoking cessation attempts for longer than one week. Efficacy expectations and differential attributions for failure were suggested as possible explanations for the results, however further research will be necessary to confirm or disconfirm these hypotheses.

A randomised trial of knife versus diathermy in pilonidal disease.

BACKGROUND: Pilonidal disease is a common debilitating condition. This prospective randomised study compared excision of pilonidal disease with a scalpel or diathermy with respect to operation time, postoperative pain, functional recovery and wound healing. PATIENTS AND METHODS: Patients undergoing surgery for pilonidal disease were randomised to excision by scalpel (group 1) or diathermy (group 2). Patients received regular peri-operative oral analgesia and a standardised general anaesthetic technique. Duration of operation was recorded. Following surgery, pain, analgesic requirements, sedation, nausea and vomiting scores and time to mobilise and time to complete healing were compared. RESULTS: Statistical significance between groups was obtained for five outcomes after 32 patients had been recruited; of these, 81% were admitted as emergencies with an abscess. The duration of surgery in group 2 was significantly less, postoperative pain scores and morphine requirements were lower and mobility was regained sooner. CONCLUSIONS: We advocate the use of diathermy needle rather than scalpel blade when undertaking excision of pilonidal disease in both acute and chronic patients.

Localized wear of compomer restorative materials.

PURPOSE: To determine and compare the localized wear of six compomer restorative materials. MATERIALS AND METHODS: Ten specimens of Dyract, Dyract AP, F2000, Compoglass F, Elan and Hytac were prepared in a custom fixture and polished. A pretest surface profile was generated using an MTS 3-D surface profilometer and the specimens were subjected to 400,000 cycles in a Leinfelder wear machine equipped with a conical stylus tip to simulate localized wear. A post-test profile was generated and the before and after profiles were fitted and analyzed using AnSur 3-D software. The total volume loss and depth of the wear facet on each specimen was calculated and statistical analysis was accomplished (ANOVA and Tukey's test). RESULTS: Volume loss (mm3) was as follows: F2000, 0.027 +/- 0.002; Hytac, 0.007 +/- 0.023; Elan, 0.054 +/- 0.013; Compoglass F, 0.135 +/- 0.006; Dyract AP, 0.135 +/- 0.023; Dyract, 0.185 +/- 0.032. Maximum depth of the wear facets (microm) was as follows: F2000, 112.2 +/- 10.2; Hytac, 132.8 +/- 9.3; Elan, 144.3 +/- 23. 1; Compoglass F, 168.3 +/- 13.0; Dyract AP, 194.0 +/- 19.7; Dyract, 220.6 +/- 15.8. There was not a difference (P > 0.05) in volumetric loss between F2000 and Hytac or between Hytac and Elan. The volume loss and maximum depth of the wear facets of F2000, Hytac and Elan was significantly less (P< 0.05) than Compoglass F, Dyract AP and Dyract The results of this study indicate that there are significant differences in the in vitro wear rates of compomer materials.

Receipt of school health education and school health service among adolescent immigrants in Massachusetts.

This study assessed whether immigrant adolescents receive health education and services in schools at levels comparable to native-born peers. Surveys from 2,635 8th and 10th graders allowed comparisons between students living in the United States "always" (n = 2,080), "more than six years" (n = 299), and "six years or less" (n = 191). Immigrant students were equally likely to receive health education, more likely to use peer counseling or support groups (p < .001), and less likely to use health services (p < .05). They communicated more often with staff (p < .05), were more concerned about mental health issues (p < .01), and were likely to have these topics addressed in school (p < .05). They were more positive about health education (p < .05), learned something new (p < .01), and communicated with parents when offered (p < .001). Schools provide a critical gateway and opportunity for reaching immigrant students and families with programs designed to meet their unique health and mental health needs. Questions remain, however, about health education and services being provided to non-mainstreamed, Limited English Proficient students who recently immigrated. Implications for program and service delivery and future research are discussed.

Aortic valvuloplasty: potential nursing diagnoses.

The use of transluminal balloon angioplasty has become widespread in the treatment of cardiovascular diseases. Since critical care nurses are responsible for the assessment and management after the procedure in the critical care unit, the authors provide information on the pathophysiology and potential nursing diagnoses for these patients. In this way, the critical care nurse can support the patient before, during, and after the procedure.

An unusual cause for a painful Birmingham hip resurfacing.

The painful total hip arthroplasty requires careful evaluation and investigation. This is usually focused on the prosthesis and adjacent anatomical structures. We present a case report of a 64-year-old man who had a Birmingham hip resurfacing procedure for primary osteoarthritis. His hip pain worsened following the procedure and was under systematic investigation for this. Subsequent investigation for vascular disease revealed a total infrarenal aortic occlusion. An aortobifemoral bypass improved the hip pain and function dramatically, and the patient now has an excellent quality of life.

Preservation of the original femoral cement mantle during the management of infected cemented total hip replacement by two-stage revision.

The removal of all prosthetic material and a two-stage revision procedure is the established standard management of an infected total hip replacement (THR). However, the removal of well-fixed femoral cement is time-consuming and can result in significant loss of bone stock and femoral shaft perforation or fracture. We report our results of two-stage revision THR for treating infection, with retention of the original well-fixed femoral cement mantle in 15 patients, who were treated between 1989 and 2002. Following partial excision arthroplasty, patients received local and systemic antibiotics and underwent reconstruction and re-implantation at a second-stage procedure, when the infection had resolved. The mean follow-up of these 15 patients was 82 months (60 to 192). Two patients had positive microbiology at the second stage and were treated with six weeks of appropriate antibiotics; one of these developed recurrent infection requiring further revision. Successful eradication of infection was achieved in the remaining 14 patients. We conclude that when two-stage revision is used for the treatment of peri-prosthetic infection involving a THR, a well-fixed femoral cement mantle can be safely left in situ, without compromising the treatment of infection. Advantages of this technique include a shorter operating time, reduced loss of bone stock and a technically more straightforward second-stage procedure.