Human osteoclast cathepsin K is processed intracellularly prior to attachment and bone resorption.

Cathepsin K is a member of the papain superfamily of cysteine proteases and has been proposed to play a pivotal role in osteoclast-mediated bone resorption. We have developed a sensitive cytochemical assay to localize and quantify osteoclast cathepsin K activity in sections of osteoclastoma and human bone. In tissue sections, osteoclasts that are distant from bone express high levels of cathepsin K messenger RNA (mRNA) and protein. However, the majority of the cathepsin K in these cells is in an inactive zymogen form, as assessed using both the cytochemical assay and specific immunostaining. In contrast, osteoclasts that are closer to bone contain high levels of immunoreactive mature cathepsin K that codistributes with enzyme activity in a polarized fashion toward the bone surface. Polarization of active enzyme was clearly evident in osteoclasts in the vicinity of bone. The osteoclasts apposed to the bone surface were almost exclusively expressing the mature form of cathepsin K. These cells showed intense enzyme activity, which was polarized at the ruffled border. These results suggest that the in vivo activation of cathepsin K occurs intracellularly, before secretion into the resorption lacunae and the onset of bone resorption. The processing of procathepsin K to mature cathepsin K occurs as the osteoclast approaches bone, suggesting that local factors may regulate this process.

The Role of Distal Variables in Behavior Change: Effects of Adolescents' Risk for Marijuana Use on Intention to Use Marijuana.

This study uses an integrative model of behavioral prediction as an account of adolescents' intention to use marijuana regularly. Adolescents' risk for using marijuana regularly is examined to test the theoretical assumption that distal variables affect intention indirectly. Risk affects intention indirectly if low-risk and high-risk adolescents differ on the strength with which beliefs about marijuana are held, or if they differ on the relative importance of predictors of intention. A model test confirmed that the effect of risk on intention is primarily indirect. Adolescents at low and high risk particularly differed in beliefs concerning social costs and costs to self-esteem. Not surprisingly, at-risk adolescents took a far more positive stand toward using marijuana regularly than did low-risk adolescents. On a practical level, the integrative model proved to be an effective tool for predicting intention to use marijuana, identifying key variables for interventions, and discriminating between target populations in terms of determinants of marijuana use.

DNA barcodes to identify species and explore diversity in the Adelgidae (Insecta: Hemiptera: Aphidoidea).

The Adelgidae are relatively small, cryptic insects, exhibiting complex life cycles with parthenogenetic reproduction. Due to these characteristics, the taxonomy of the group is problematic. Here, we test the effectiveness of the standard 658-bp barcode fragment from the 5'-end of the mitochondrial cytochrome c oxidase 1 gene (COI) in differentiating among 17 species of Adelgidae, in associating life-cycle stages, and in assessing patterns of geographical variation in selected species. Species of Adelgidae are well-differentiated by DNA barcodes, enabling the identification of different morphological forms, immature stages and individuals on different hosts and at different periods of the life cycle. DNA barcodes have uncovered cryptic diversity within taxa and, in other cases, a lack of sequence divergence in species pairs previously separated by life-cycle characteristics, indicating a need for further taxonomic analysis.

Targeting norm-related beliefs about marijuana use in an adolescent population.

The integrative model of behavior prediction and priming theory were used to evaluate the effects of anti-marijuana advertisements in an experimental context. In 1 original study and 2 replications, 435 adolescents were randomly assigned to condition, and those in the experimental condition viewed 3 ads that challenged undesirable normative beliefs about marijuana use. The results showed that ad exposure had small but positive (anti-drug) effects on adolescents' considerations of the outcomes of using marijuana and their perceptions of the social normative climate surrounding marijuana use. Priming effects also were observed but generally ran counter to predictions. Implications of the findings for anti-drug campaigns are discussed. Potential explanations for the unexpected priming effects also are offered.

Meaning and the family life cycle.

In this article, the authors integrate Viktor Frankl's concept of the "Will to Meaning" with a family-life-cycle model. This integration offers an overview of the opportunities for spiritual growth and the development of a sense of purpose for both the family and its individual members. Clinical illustrations highlight applications of the approach in actual practice.

The effectiveness of gateway communications in anti-marijuana campaigns.

Successful anti-marijuana messages can be hypothesized to have two types of effects, namely persuasion effects, that is, a change in people's beliefs about using marijuana, and priming effects, that is, a strengthened correlation between beliefs and associated variables such as attitude and intention. This study examined different sets of anti-drug advertisements for persuasion and priming effects. The ads targeted the belief that marijuana is a gateway to stronger drugs, a belief that is often endorsed by campaign planning officials and health educators. A sample of 418 middle and high school students was randomly assigned to a control video or one of three series of ads, two of which included the gateway message in either an explicit or implicit way. Results did not support the use of the gateway belief in anti-marijuana interventions. Whereas no clear persuasion or priming effects were found for any of the ad sequences, there is some possibility that an explicit gateway argument may actually boomerang. In comparison to the control condition, adolescents in the explicit gateway condition tended to agree less with the gateway message and displayed weaker correlations between anti-marijuana beliefs and their attitude toward marijuana use. The results suggest that the gateway message should not be used in anti-drug interventions.

Hospice access and use by African Americans: addressing cultural and institutional barriers through participatory action research.

This article describes a participatory action research project addressing the problem of African American access to and use of hospice. Qualitative interviews conducted with six African American pastors resulted in the identification of major themes used for development of a scale to measure barriers to hospice. A subsequent quantitative study documenting these barriers was conducted with 127 African American and European Americans. Results of both studies, which were used to further social action efforts in the community, indicated the cultural barriers of differences in values regarding medical care and differences in spiritual beliefs between African Americans and European Americans. Results also indicated institutional barriers, including lack of knowledge of services, economic factors, lack of trust by African Americans in the health care system, and lack of diversity among health care staff. Implications for social work practice and policy are discussed.

The treatment of advanced renal cell cancer with high-dose oral thalidomide.

Thalidomide is reported to suppress levels of several cytokines, angiogenic and growth factors including TNF-alpha, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The resulting anti-angiogenic, immunomodulatory and growth suppressive effects form the rationale for investigating thalidomide in the treatment of malignancies. We have evaluated the use of high-dose oral thalidomide (600 mg daily) in patients with renal carcinoma. 25 patients (all men; median age, 51 years; range 34-76 years) with advanced measurable renal carcinoma, who had either progressed on or were not suitable for immunotherapy, received thalidomide in an escalating schedule up to a maximum dose of 600 mg daily. Treatment continued until disease progression or unacceptable toxicity were encountered. 22 patients were assessable for response. 2 patients showed partial responses (9%; 95% CI: 1-29), 7 (32%; 95% CI: 14-55) had stable disease for more than 6 months and a further 5 (23%; 95% CI: 8-45) had stable disease for between 3 and 6 months. We also measured levels of TNF-alpha, bFGF, VEGF, IL-6 and IL-12 before and during treatment. In patients with SD > or = 3 months or an objective response, a statistically significant decrease in serum TNF-alpha levels was demonstrated (P = 0.05). The commonest toxicities were lethargy (> or = grade II, 10 patients), constipation (> or = grade II, 11 patients) and neuropathy (> or = grade II, 5 patients). Toxicities were of sufficient clinical significance for use of a lower and well tolerated dose of 400 mg in currently accruing studies.

Protracted venous infusion 5-fluorouracil in combination with subcutaneous interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer: a phase II study.

Our purpose was to assess the activity of alpha-interferon (IFN-alpha), interleukin-2 (IL-2) and 5 fluorouracil (5FU) administered by protracted venous infusion (PVI) as opposed to bolus injection. 55 patients with advanced renal cell cancer were treated as follows: IL-2 and IFN-alpha according to the schedule originally described by Atzpodien, with PVI 5FU 200 mg m(-2)day(-1)during weeks 5-9. 42 patients (76%) were of moderate or poor prognosis as defined by previous studies. The response rate by intention to treat was 31% (17 of 55, three complete response, 14 partial response; 95% CI = 19-45%) and in evaluable patients (completed one cycle, n = 42), it was 40% (95% CI = 26-57%). In addition, 24% (13 of 55) patients achieved disease stabilization. The overall median survival was 11 months with a 1-year survival of 45%. The median survival for evaluable patients was 18 months with 1- and 2-year survivals of 60% and 40% respectively. The median survival of responding patients was 31 months and the three patients achieving complete response remain progression-free at 14+, 18+ and 23+ months. Evaluable patients with poor prognostic features achieved a response rate of 54% and median survival of 18 months. Toxicity was significant yet manageable with 12 patients unable to complete one cycle due to side-effects and 36% experiencing grade 3-4 toxicities. The three on-treatment deaths were considered unlikely to be due to toxicity. The schedule of IFN-alpha, IL-2 and PVI 5FU has significant activity in advanced renal cell cancer with manageable toxicity. It is of particular interest that this regimen appears to have high activity in fit patients with poor prognostic features.

Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer.

To grow and metastasize, solid tumours must develop their own blood supply by neo-angiogenesis. Thalidomide inhibits the processing of mRNA encoding peptide molecules including tumour necrosis factor-alpha (TNF-alpha) and the angiogenic factor vascular endothelial growth factor (VEGF). This study investigated the use of continuous low dose Thalidomide in patients with a variety of advanced malignancies. Sixty-six patients (37 women and 29 men; median age, 48 years; range 33-62 years) with advanced measurable cancer (19 ovarian, 18 renal, 17 melanoma, 12 breast cancer) received Thalidomide 100 mg orally every night until disease progression or unacceptable toxicity was encountered. Three of 18 patients with renal cancer showed partial responses and a further three patients experienced stabilization of their disease for up to 6 months. Although no objective responses were seen in the other tumour types, there were significant improvements in patients' sleeping (P < 0.05) and maintained appetite (P < 0.05). Serum and urine concentrations of basic fibroblast growth factor (bFGF), TNF-alpha and VEGF were measured during treatment and higher levels were associated with progressive disease. Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy. No patients developed WHO grade 3 or 4 toxicity. Further studies evaluating the use of Thalidomide at higher doses as a single agent for advanced renal cancer and in combination with biochemotherapy regimens are warranted.