Effects of long term treatment with high doses of odanacatib on bone mass, bone strength, and remodeling/modeling in newly ovariectomized monkeys.

The objectives here were to evaluate the effects of odanacatib (ODN) at doses exceeding the clinical exposure on biomechanical properties of lumbar vertebrae (LV), hip and central femur (CF), and compare ODN to alendronate (ALN) on bone remodeling/modeling in ovariectomized (OVX) monkeys. Ten days post-surgery, animals were treated with vehicle (VEH), ODN-L (2mg/kg/day, p.o.), ODN-H (8/4mg/kg/day), or ALN (30µg/kg/week, s.c.) for 20months. An intact group was also included. ODN-L provided systemic exposures of 1.8-fold of clinical exposure. ODN-H started at 20-fold for 5.5months, and then reduced to 7.8-fold of clinical exposure, compared to ALN at approximated clinical exposure. From cross sectional analyses, LV density and peak load in ODN at both doses or ALN were not different from VEH or Intact. However, cortical thickness of femoral neck (FN) and CF in ODN were higher (21-34%, p<0.05) than VEH, due to smaller endocortical (Ec) perimeter of FN (10-11%; p<0.05) and CF (9-12%; ODN-L, p<0.05), and larger CF periosteal (Ps) perimeter (2-12%; ODN-H, p<0.001) versus VEH. ODN groups also showed slightly higher cortical porosity and Ps non-lamellar bone in CF. ODN-H treatment resulted in higher CF peak load (p<0.05) versus VEH. For all bone sites analyzed, a positive, linear relationship (r(2)=0.46-0.69, p<0.0001) of peak load to density or structural parameters was demonstrated. No treatment-related differences in the derived intrinsic strength properties were evidenced as compared between groups. ALN reduced all remodeling surfaces without affecting Ps modeling. Trabecular and intracortical remodeling were reduced in ODN groups, similar to ALN. Ec mineralizing surface in ODN-H trended to be lower than VEH by month 20, but Ec bone formation indices in ODN groups generally were not different from VEH. Ps modeling in ODN groups was significantly higher than other treatment groups. This study overall demonstrated the bone safety profile of ODN and its unique mechanism on cortical bone supporting the clinical application for osteoporosis treatment.

Bone loss in the oestrogen-depleted rat is not exacerbated by sitagliptin, either alone or in combination with a thiazolidinedione.

Antihyperglycaemic therapy on bone was evaluated in the ovariectomized (OVX), non-diabetic adult rat. Animals were treated daily for 12 weeks with various doses of sitagliptin, pioglitazone, rosiglitazone, combinations of sitagliptin with pioglitazone or vehicle alone. Sitagliptin target engagement was confirmed by assessing inhibition of plasma dipeptidyl peptidase-4 (DPP-4) and oral glucose tolerance. Parameters related to bone health were evaluated in femur and vertebrae by dual-energy X-ray absorptiometry and histomorphometry. Bone mineral density (BMD) generally did not differ significantly between OVX-sitagliptin-treated animals and OVX-vehicle controls. In lumbar vertebrae, however, there was significantly less BMD loss with increasing sitagliptin dose. Thiazolidinedione (TZD) treatment generally resulted in lower BMD; OVX-TZD-treated (but not OVX-sitagliptin-treated) animals also had lessened cortical thickness in central femur and profoundly greater bone marrow adiposity in lumbar vertebrae. These findings support prior findings with TZDs and suggest a neutral or beneficial impact of DPP-4 inhibition on bone health.

Bone density, strength, and formation in adult cathepsin K (-/-) mice.

Cathepsin K (CatK) is a cysteine protease expressed predominantly in osteoclasts, that plays a prominent role in degrading Type I collagen. Growing CatK null mice have osteopetrosis associated with a reduced ability to degrade bone matrix. Bone strength and histomorphometric endpoints in young adult CatK null mice aged more than 10 weeks have not been studied. The purpose of this paper is to describe bone mass, strength, resorption, and formation in young adult CatK null mice. In male and female wild-type (WT), heterozygous, and homozygous CatK null mice (total N=50) aged 19 weeks, in-life double fluorochrome labeling was performed. Right femurs and lumbar vertebral bodies 1-3 (LV) were evaluated by dual-energy X-ray absorptiometry (DXA) for bone mineral content (BMC) and bone mineral density (BMD). The trabecular region of the femur and the cortical region of the tibia were evaluated by histomorphometry. The left femur and sixth lumbar vertebral body were tested biomechanically. CatK (-/-) mice show higher BMD at the central and distal femur. Central femur ultimate load was positively influenced by genotype, and was positively correlated with both cortical area and BMC. Lumbar vertebral body ultimate load was also positively correlated to BMC. Genotype did not influence the relationship of ultimate load to BMC in either the central femur or vertebral body. CatK (-/-) mice had less lamellar cortical bone than WT mice. Higher bone volume, trabecular thickness, and trabecular number were observed at the distal femur in CatK (-/-) mice. Smaller marrow cavities were also present at the central femur of CatK (-/-) mice. CatK (-/-) mice exhibited greater trabecular mineralizing surface, associated with normal volume-based formation of trabecular bone. Adult CatK (-/-) mice have higher bone mass in both cortical and cancellous regions than WT mice. Though no direct measures of bone resorption rate were made, the higher cortical bone quantity is associated with a smaller marrow cavity and increased retention of non-lamellar bone, signs of decreased endocortical resorption. The relationship of bone strength to BMC does not differ with genotype, indicating the presence of bone tissue of normal quality in the absence of CatK.

Environmental Sensitivity of Soybean Cultivar Response to Sclerotinia sclerotiorum.

ABSTRACT The sporadic occurrence of Sclerotinia stem rot in soybeans often is attributed to the sensitivity of Sclerotinia sclerotiorum to environmental factors. Environmental sensitivity in soybean response to the pathogen also could contribute to the unpredictable nature of this disease. We used stability analysis to determine whether soybean cultivar response to S. sclerotiorum was sensitive to light and temperature. Five greenhouse experiments examined the response of seven cultivars to limited-term inoculation with S. sclerotiorum. The cultivars, selected at random from Pennsylvania variety trials, represented maturity groups grown in Pennsylvania and other states sharing that latitude. Photon flux density of photosynthetically active radiation (PAR) and temperature were recorded hourly and varied among experiments. Environmental sensitivity was detected in the response of five cultivars to S. sclerotiorum when individual cultivar disease ratings (assessed 6 days after inoculation) were regressed against the mean disease rating of each experiment. Stability analysis with temperature during the 48-h inoculation period as the environmental index found that all cultivars responded similarly to the number of hours that temperatures were <19 degrees C, 19 to 22 degrees C, or >22 degrees C. In contrast, cultivars separated into PAR-sensitive and PAR-insensitive groups when the environmental index was moles of PAR at a photon flux density >/=475 mumol m(-2) s(-1) during the inoculation period. The photon flux density of PAR on a cloudy day in the field is

First Report of Sudden Death Syndrome Caused by Fusarium solani f. sp. glycines on Soybean in Pennsylvania.

A small, circular patch of soybean (Glycine max) showing symptoms consistent with sudden death syndrome (SDS) (2) was noted on July 25, 1998, in a producer's field in Jersey Shore, PA. Foliar symptoms included interveinal chlorosis and necrosis, leaf cupping, and leaf abscission. The vascular cylinder of roots and stems had areas of reddish-brown discoloration. A slow-growing Fusarium sp., which produced a bluish-purple color on potato dextrose agar, was isolated from the roots of several symptomatic plants. The fungus was identified as Fusarium solani by The Fusarium Research Center, The Pennsylvania State University. Koch's postulates were tested on soybean cultivars A2506, Stine 3171, Pioneer 9305 and 9306, and Jack. Five plants per cultivar were inoculated at growth stage V1 by pouring 35 ml of a 4 × 107 spores per ml suspension on the growth mix in each pot. Five plants per cultivar were treated similarly with sterile water. Foliar symptoms of SDS began to appear 3 weeks after inoculation. Seven weeks after inoculation, symptoms of interveinal chlorosis and/or necrosis, leaf cupping, and occasional leaf abscission were apparent on the inoculated plants and on several noninoculated plants. The percentage of the plant showing symptoms was recorded and converted to the 0 to 5 scale (in which 0 = 0%, 1 = 1-10%, 2 = 11-30%, 3 = 31-40%, 4 = 41-90%, and 5= 91-100% of the leaf area affected) used by Rupe (3). Regardless of the rating method, there was a significant difference (P = 0.0001) between inoculated and noninoculated plants. There were no significant differences among cultivars. Roots of the inoculated plants were frequently discolored, in contrast to those of the noninoculated plants. F. solani was isolated from the roots of 97% of the inoculated plants and 23% of the noninoculated plants. Fungus gnats were suspected of spreading the pathogen to the noninoculated plants (1). F. solani f. sp. glycines causes SDS in soybean and its identity is confirmed by the symptoms produced on soybean (2). The symptoms produced when soybean plants were inoculated in the greenhouse were consistent with those of SDS (2) and indicate that the F. solani isolate recovered from symptomatic plants in the field was F. solani f. sp. glycines. This is the first documented occurrence of SDS on soybean in Pennsylvania. References: (1) D. W. Kalb and R. L. Millar. Plant Dis. 70:752, 1986. (2) K. W. Roy et al. Plant Dis. 81:1100, 1997. (3) J. C. Rupe. Plant Dis. 73:581, 1989.

Using a quality improvement team to reduce patient falls.

Preventing falls among hospitalized patients continues to be a major concern of nurses, as evidenced by the volume of literature on this subject during the past 10 years. Yet, preventing falls, like preventing medication errors, has been a difficult and chronic issue for most nursing departments. Carolyn Corbett and Barbara Pennypacker describe how the nursing staff at Robert Packer Hospital in Sayre, PA, finally has experienced success by applying the systematic methods and principles of continuous quality improvement and establishing a fall prevention process.