Teriparatide (biosynthetic human parathyroid hormone 1-34): a new paradigm in the treatment of osteoporosis

The ideal treatment of osteoporosis should preferably prevent fractures through normalization of bone mass and bone micro-architecture. Biosynthetic human parathyroid hormone 1-34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2-3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 microg/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecules targeted at the parathyroid hormone receptor may be envisaged.     

Anthrone and oxanthrone C-glycosides from Picramnia latifolia collected in Peru

Cytotoxicity-based, bioassay-guided fractionation of the chloroform-soluble extracts of both the roots and leaves of Picramnia latifolia led to the isolation of two new anthrone C-glycosides, picramniosides G (1) and H (2), two new oxanthrone C-glycosides, mayosides D (3) and E (4), and a new benzanthrone natural product, 6,8-dihydroxy-10-methyl-7H-benz[de]anthracen-7-one (5), together with 10 known compounds, 6,8-dihydroxy-4-methyl-7H-benz[de]anthracen-7-one (6), nataloe-emodin (7), chrysophanein, chrysophanol, 1,5-dihydroxy-7-methoxy-3-methylanthraquinone, pulmatin, 7-hydroxycoumarin, 7-hydroxy-6-methoxycoumarin, beta-sitosterol, and beta-sitosterol glucoside. The structures of 1-5 were established by spectroscopic methods, including 1D and 2D NMR, HRMS, and CD data interpretation. The cytotoxic activity of all isolates was evaluated in a small panel of human cancer cell lines. Compound 7 exhibited significant in vitro cytotoxic activity in the tested cell lines, but no significant activity was observed with an in vivo hollow fiber model at doses of 6.25, 12.5, 25, and 50 mg/kg/injection.     

The selective estrogen receptor modulator arzoxifene and the rexinoid LG100268 cooperate to promote transforming growth factor beta-dependent apoptosis in breast cancer

We show that the selective estrogen receptor modulator arzoxifene (Arz) and the rexinoid LG100268 (268) synergize to promote apoptosis in a rat model of estrogen receptor-positive breast carcinoma and in estrogen receptor-positive human breast cancer cells in culture. We also show that it is not necessary to administer Arz and 268 continuously during tumor progression to prevent cancer in the rat model because dosing of these drugs in combination for relatively short periods, each followed by drug-free rests, is highly effective. This new approach to chemoprevention uses high doses of drugs that are too toxic for long-term administration. However, when given for short periods, the agents are nontoxic and still induce apoptosis in breast cancer cells. We also show that the ability of the two drugs to induce apoptosis is the combined result of induction of transforming growth factor beta by Arz, together with inhibition of the prosurvival nuclear factor kappaB and phosphatidylinositol 3' kinase signaling pathways by 268. The new protocol we have developed for chemoprevention allows the efficacious and safe administration of 268 and Arz, and these agents now should be considered for clinical use.     

Absence or low expression of fas-associated protein with death domain in acute myeloid leukemia cells predicts resistance to chemotherapy and poor outcome

In acute myeloid leukemia (AML), coexpression of death receptors and ligands of the tumor necrosis factor (TNF) receptor/TNF-alpha superfamily on leukemic cells after chemotherapy is not always accompanied by apoptosis, suggesting that the apoptotic death receptor signaling pathway is disrupted. Because Fas-associated protein with death domain (FADD) is the main adaptor for transmitting the Fas, TNF-related apoptosis-inducing ligand receptors, and TNF receptor 1 death signal, expression of FADD was analyzed by Western blot and immunocytochemistry in leukemic cells of 70 de novo AML patients treated with the European Organization of Research and Treatment of Cancer AML-10 randomized trial before initiation of induction chemotherapy. Thirty seven percent of patients (17 of 46) with FADD negative/low (FADD(-/low)) leukemic cells had a primary refractory disease compared with 12% of FADD(+) patients (3 of 24; P = 0.05). FADD(-/low) expression was significantly associated with a worse event-free survival [EFS (P = 0.04)] and overall survival (P = 0.04). In multivariate analysis, FADD(-/low) protein expression was independently associated with a poor EFS and overall survival (P = 0.002 and P = 0.026, respectively). Importantly, FADD(-/low) protein expression predicted poor EFS even in patients with standard- or good-risk AML (P = 0.009). Thus, we identified low or absent expression of the FADD protein in leukemic cells at diagnosis as a poor independent prognostic factor that can predict worse clinical outcome even for patients with standard- or good-risk AML.     

Dose-dependent effects of dietary alpha- and gamma-tocopherols on genetic instability in mouse Mutatect tumors

Vitamin E in foodstuffs is a mixture of tocopherols. In mouse Mutatect tumors, a model designed to detect DNA mutations, the hypoxanthine phosphoribosyltransferase (Hprt) gene mutation frequency is associated with the number of tumor-infiltrating neutrophils and both are markedly decreased in mice fed high levels of alpha-tocopherol. Dietary alpha-tocopherol is also associated with a decrease in neutrophil-associated loss of an interleukin 8 (IL-8)-expressing transgene in this tumor model. We examined Hprt gene mutation frequency (expressed as the number of 6-thioguanine-resistant colonies per 10(5) clonable tumor cells), IL-8 transgene loss, and myeloperoxidase activity (an indirect measure of neutrophil number) in tumors from Mutatect mice fed diets supplemented with various concentrations of D-alpha-tocopherol acetate and/or D-gamma-tocopherol acetate or neither tocopherol for 4 weeks. Hprt gene mutation frequency and myeloperoxidase activity were statistically significantly lower in tumor cells from mice fed alpha-tocopherol at 50 or 100 mg/kg body weight per day than in tumor cells from mice fed 0 mg/kg body weight per day alpha-tocopherol (P<.001 for each comparison). IL-8 transgene loss occurred in 28 of 28 tumors (100%; 95% confidence interval [CI] = 86% to 100%) from mice fed alpha-tocopherol at 50 mg or less/kg body weight per day and seven of 18 tumors (39%; 95% CI = 24% to 54%) from mice fed 100 mg/kg body weight per day (P<.001, Fisher's exact test, referent groups [pooled] 0, 25, and 50 mg/kg). gamma-Tocopherol had no detectable effect on any of the three endpoints. Thus, dietary alpha-tocopherol decreases two forms of genetic instability in a dose-dependent manner in this experimental tumor model.     

Navigating federalwide assurance requirements when conducting research in community-based care settings

There is an urgent need for research on quality of life and healthcare delivery for older adults living in community-based care settings, yet implementing current federalwide assurance (FWA) requirements can be a challenge in these settings. This paper discusses FWA requirements for engagement in federally funded research as the requirements pertain to community-based care settings. Factors that impede community facilities in achieving FWA approval include lack of organizational structure to provide oversight for the ethical conduct of research, administrator concerns regarding potential liability associated with obtaining the FWA, lack of resources to complete required paperwork, and lack of staff knowledge about human subjects protection and federal requirements for participating in research. Effects of the FWA process on investigators include the burden of extra time needed to support community-based facilities to acquire a FWA and concerns that studies may be limited to only those community facilities with the resources to complete the FWA process. Investigator-initiated strategies for conducting research in community-based settings include considering study designs that are exempt from the FWA process and proactively assisting community-based facilities to acquire FWA status. Investigators need to work with potential research sites and the office for human research protections to ensure that subjects are protected without shifting the burden of protection to ill-prepared community administrators.     

Resistance training in the early postoperative phase reduces hospitalization and leads to muscle hypertrophy in elderly hip surgery patients--a controlled, randomized study

OBJECTIVES: To better understand how immobilization and surgery affect muscle size and function in the elderly and to identify effective training regimes. DESIGN: A prospective randomized, controlled study. SETTING: Bispebjerg University Hospital, Copenhagen, Denmark. PARTICIPANTS: Thirty-six patients (aged 60-86) scheduled for unilateral hip replacement due to primary hip osteoarthrosis. INTERVENTION: Patients were randomized to standard home-based rehabilitation (1 h/d x 12 weeks), unilateral neuromuscular electrical stimulation of the operated side (1 h/d x 12 weeks), or unilateral resistance training of the operated side (3/wk x 12 weeks). MEASUREMENTS: Hospital length of stay (LOS), quadriceps muscle cross-sectional area (CSA), isokinetic muscle strength, and functional performance. Patients were tested presurgery and 5 and 12 weeks postsurgery. RESULTS: Mean+/-standard error LOS was shorter for the resistance training group (10.0+/-2.4 days, P<.05) than for the standard rehabilitation group (16.0+/-7.2 days). Resistance training, but not electrical stimulation or standard rehabilitation, resulted in increased CSA (12%, P<.05) and muscle strength (22-28%, P<.05). Functional muscle performance increased after resistance training (30%, P<.001) and electrical stimulation (15%, P<.05) but not after standard rehabilitation. CONCLUSION: Postoperative resistance training effectively increased maximal muscle strength, muscle mass, and muscle function more than a standard rehabilitation regime. Furthermore, it markedly reduced LOS in elderly postoperative patients.     

Pulmonary manifestations of systemic autoimmune disease

Patients with systemic autoimmune disease may present with a number of different pulmonary manifestations. In order to recognise, diagnose and manage these manifestations, it is necessary to have a working knowledge of the anatomy and physiology of the thorax. This chapter will describe the clinical symptoms and clinical examination findings in patients who may have underlying pulmonary disease. It will describe the investigations that can be used to confirm or refute a possible diagnosis and describe approaches to managing these complex clinical cases. The importance of multidisciplinary team working using the skills of clinicians, radiologists and pathologists will be highlighted. The use of high-resolution computed tomography scanning of the thorax to help to delineate the type of interstitial lung disease will be described and some of the newer modalities available for the treatment of pulmonary hypertension introduced. By the end of the chapter, the reader should understand that patients with a single underlying autoimmune disease may present with one or more pulmonary manifestations and that different autoimmune diseases may present with similar pulmonary manifestations. This heterogeneity poses both diagnostic and treatment challenges, and many questions still remain regarding optimal treatment.     

Studies relying on passive retrospective cohorts developed from health services data provide biased estimates of incidence of sexually transmitted infections

OBJECTIVE: Passive retrospective cohorts composed of persons who have tested 2 or more times for a sexually transmitted infection (STI) of interest during clinical visits have been used to estimate STI incidence. We hypothesized that the analytic period of a passive cohort might affect the estimate of STI incidence, with shorter periods yielding higher estimates of incidences of infection. STUDY: We analyzed data collected from women, 12 to 24 years of age, tested for chlamydia 2 or more times at 6 sites in San Francisco between January 1997 and December 2000. Incidence was calculated for 10 different analytic periods. RESULTS: The calculated incidence of chlamydial infection during 1997 was 16.8 (95% confidence interval [CI], 10.9-24.0) per 1000 person-months of follow up. The calculated incidence dropped markedly as the analytic period lengthened, with the incidence estimated to be 9.7 (95% CI, 8.6-10.9) using a study period of 4 years (1997-2000). Estimates of incidence were similar when using the same analytic period, regardless of calendar year, and there was a similar decline in estimated incidence using longer analytic periods. CONCLUSIONS: Estimates of STI incidence based on passive cohort data may have limited epidemiologic value because incidence measures may be highly dependent on the analytic period.