Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy.

Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as "responders", experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease.

Detection of first gammaherpesvirus sequences in Central African bats.

Herpesviruses have been identified in many species; however, relatively few bat herpesvirus are known, considering the enormous diversity of bats. We used consensus PCR to test bats from the Republic of the Congo and found DNA of two different novel bat herpesviruses. One was detected in a Pipistrellus nanulus, the other in a Triaenops persicus bat and both resemble gammaherpesviruses. On the amino acid level, the amplified sequences differ by 55% from each other, and by 27% and 25% from the next closest known viruses. The findings point towards the diversity of herpesviruses in Central African bats.

Viral emergence in marine mammals in the North Pacific may be linked to Arctic sea ice reduction.

Climate change-driven alterations in Arctic environments can influence habitat availability, species distributions and interactions, and the breeding, foraging, and health of marine mammals. Phocine distemper virus (PDV), which has caused extensive mortality in Atlantic seals, was confirmed in sea otters in the North Pacific Ocean in 2004, raising the question of whether reductions in sea ice could increase contact between Arctic and sub-Arctic marine mammals and lead to viral transmission across the Arctic Ocean. Using data on PDV exposure and infection and animal movement in sympatric seal, sea lion, and sea otter species sampled in the North Pacific Ocean from 2001-2016, we investigated the timing of PDV introduction, risk factors associated with PDV emergence, and patterns of transmission following introduction. We identified widespread exposure to and infection with PDV across the North Pacific Ocean beginning in 2003 with a second peak of PDV exposure and infection in 2009; viral transmission across sympatric marine mammal species; and association of PDV exposure and infection with reductions in Arctic sea ice extent. Peaks of PDV exposure and infection following 2003 may reflect additional viral introductions among the diverse marine mammals in the North Pacific Ocean linked to change in Arctic sea ice extent.

A Health Services Research Agenda for Bariatric Surgery Within the Veterans Health Administration.

In 2016, the Veterans Health Administration (VHA) held a Weight Management State of the Art conference to identify evidence gaps and develop a research agenda for population-based weight management for veterans. Included were behavioral, pharmacologic, and bariatric surgery workgroups. This article summarizes the bariatric surgery workgroup (BSWG) findings and recommendations for future research. The BSWG agreed that there is evidence from randomized trials and large observational studies suggesting that bariatric surgery is superior to medical therapy for short- and intermediate-term remission of type 2 diabetes, long-term weight loss, and long-term survival. Priority evidence gaps include long-term comorbidity remission, mental health, substance abuse, and health care costs. Evidence of the role of endoscopic weight loss options is also lacking. The BSWG also noted the limited evidence regarding optimal timing for bariatric surgery referral, barriers to bariatric surgery itself, and management of high-risk bariatric surgery patients. Clinical trials of pre- and post-surgery interventions may help to optimize patient outcomes. A registry of overweight and obese veterans and a workforce assessment to determine the VHA's capacity to increase bariatric surgery access were recommended. These will help inform policy modifications and focus the research agenda to improve the ability of the VHA to deliver population-based weight management.

Genetic dissection of intraspecific variation in a male-specific sexual trait in Drosophila melanogaster.

An open question in evolutionary biology is the relationship between standing variation for a trait and the variation that leads to interspecific divergence. By identifying loci underlying phenotypic variation in intra- and interspecific crosses we can determine the extent to which polymorphism and divergence are controlled by the same genomic regions. Sexual traits provide abundant examples of morphological and behavioral diversity within and among species, and here we leverage variation in the Drosophila sex comb to address this question. The sex comb is an array of modified bristles or 'teeth' present on the male forelegs of several Drosophilid species. Males use the comb to grasp females during copulation, and ablation experiments have shown that males lacking comb teeth typically fail to mate. We measured tooth number in >700 genotypes derived from a multiparental advanced-intercross population, mapping three moderate-effect loci contributing to trait heritability. Two quantitative trait loci (QTLs) coincide with previously identified intra- and interspecific sex comb QTL, but such overlap can be explained by chance alone, in part because of the broad swathes of the genome implicated by earlier, low-resolution QTL scans. Our mapped QTL regions encompass 70-124 genes, but do not include those genes known to be involved in developmental specification of the comb. Nonetheless, we identified plausible candidates within all QTL intervals, and used RNA interference to validate effects at four loci. Notably, TweedleS expression knockdown substantially reduces tooth number. The genes we highlight are strong candidates to harbor segregating, functional variants contributing to sex comb tooth number.

Outcomes of intravenous tissue plasminogen activator for acute ischaemic stroke in HIV-infected adults.

BACKGROUND AND PURPOSE: To our knowledge there are no studies reporting the use and short-term outcomes of intravenous tissue plasminogen activator (IV-TPA) for the treatment of acute ischaemic stroke (AIS) in people living with HIV. METHODS: The US Nationwide Inpatient Sample (NIS) (2006-2010) was searched for HIV-infected AIS patients treated with IV-TPA. RESULTS: In the NIS, 2.2% (62/2877) of HIV-infected AIS cases were thrombolyzed with IV-TPA (median age 52 years, range 27-78, 32% female, 22% Caucasian) vs. 2.1% (19 335/937 896) of HIV-uninfected cases (median age 72 years, range 17-102 years, 50% female, 74% Caucasian; P = 0.77). There were more deaths in HIV-infected versus uninfected patients with stroke (220/2877, 7.6% vs. 49 089/937 547, 5.2%, P < 0.001) but no difference in the proportion of deaths amongst IV-TPA-treated patients. The age- and sex-adjusted odds ratio for death following IV-TPA administration in HIV-infected versus uninfected patients was 2.26 (95% CI 1.12, 4.58), but the interaction on mortality between HIV and IV-TPA use was not statistically significant, indicating no difference in risk of in-hospital death by HIV serostatus with IV-TPA use. A higher number of HIV-infected patients remained in hospital versus died or were discharged at both 10 and 30 days (P < 0.01 at 10 and 30 days). No difference in the proportion of intracerebral hemorrhage in the two groups was found (P = 0.362). CONCLUSIONS: The in-hospital mortality is higher amongst HIV-infected AIS patients than HIV-uninfected patients. However, the risk of death amongst HIV-infected patients treated with IV-TPA is similar to HIV-uninfected groups.

Older individuals with HIV infection have greater memory deficits than younger individuals.

The prevalence of HIV-associated neurocognitive disorder (HAND) remains persistently high in the era of combination antiretroviral therapy. We aimed to characterize the pattern of neurocognitive dysfunction in older subjects with HAND in particular amnestic versus non-amnestic impairment. One hundred six subjects from the Johns Hopkins University NIMH Clinical Outcomes cohort underwent standardized neuropsychological (NP) testing between November 2006 and June 2010. We examined performance in seven cognitive domains (memory, attention, speed of processing,visuospatial, language, motor, and executive). Older subjects were defined as age >50 years at the time of NP testing.Subjects were diagnosed with HAND according to established criteria and dichotomized into amnestic cognitive impairment or non-amnestic cognitive impairment with deficit defined as z scores <−1.5 for the verbal and nonverbal memory domains.There were 32 older subjects with a mean age (SD) of 54.2 (2.8) years and 74 younger subjects, 43.7 (4.3) years. Older age was associated with a 4.8-fold higher odds of memory deficits adjusted for potential confounders (p =0.035) identified a priori. With age modeled as a continuous covariate,every 1 year increase in age was associated with a 1.11-fold higher odds of memory deficit (p =0.05). There was a higher proportion of amnestic cognitive impairment among older subjects than younger subjects with HIV infection. Neurodegenerative processes other than those directly due to HIV maybe increasingly important as individuals with chronic HIV infection and HAND survive into older age.

A comparison of radiological and computer navigation measurements of lower limb coronal alignment before and after total knee replacement.

We compared lower limb coronal alignment measurements obtained pre- and post-operatively with long-leg radiographs and computer navigation in patients undergoing primary total knee replacement (TKR). A series of 185 patients had their pre- and post-implant radiological and computer-navigation system measurements of coronal alignment compared using the Bland-Altman method. The study included 81 men and 104 women with a mean age of 68.5 years (32 to 87) and a mean body mass index of 31.7 kg/m(2) (19 to 49). Pre-implant Bland-Altman limits of agreement were -9.4° to 8.6° with a repeatability coefficient of 9.0°. The Bland-Altman plot showed a tendency for the radiological measurement to indicate a higher level of pre-operative deformity than the corresponding navigation measurement. Post-implant limits of agreement were -5.0° to 5.4° with a repeatability coefficient of 5.2°. The tendency for valgus knees to have greater deformity on the radiograph was still seen, but was weaker for varus knees. The alignment seen or measured intra-operatively during TKR is not necessarily the same as the deformity seen on a standing long-leg radiograph either pre- or post-operatively. Further investigation into the effect of weight-bearing and surgical exposure of the joint on the mechanical femorotibial angle is required to enable the most appropriate intra-operative alignment to be selected.

An indigenous plant food used by lactating mothers in west Africa: the nutrient composition of the leaves of Kigelia africana in Ghana.

Although the leaves of Kigelia africana are used to make a palm-nut soup which is consumed mainly by lactating women in many parts of sub-Saharan Africa, little is known about the nutrient qualities of this underutilized and underappreciated plant food. Leaves of Kigelia africana, called "sausage tree" in English and "nufuten" in the Twi language of Ghana, were collected in Kumasi and analyzed for their content of nutritionally important fatty acids, amino acids, minerals, and trace elements. The dried leaves contained 1.62% fatty acids, of which α-linolenic acid and linolenic acid accounted for 44% and 20%, respectively, of the total. Protein accounted for 12.6% of the dry weight and, except for lysine, its overall essential amino acid profile compared favorably to a World Health Organization protein standard for school children. Kigelia leaf contained considerable amounts of many essential elements, including calcium (7,620 µg/g), iron (161 µg/g), magnesium (2,310 µg/g), manganese (14.6 µg/g), zinc (39.9 µg/g), and chromium (0.83 µg/g); selenium, however, was not detected. These data indicate that Kigelia africana leaf compares favorably with many other commonly-consumed green leafy vegetables such as spinach and provides a rational basis for promoting the conservation and propagation of the plant and encouraging its wider use in the diets of populations in sub-Saharan Africa.

Re-thinking wastewater landscapes: combining innovative strategies to address tomorrow's urban wastewater treatment challenges.

Most major cities worldwide face urban water management challenges relating to drinking supply, stormwater and wastewater treatment, and ecological preservation. In light of climate change and finite natural resources, addressing these challenges in sustainable ways will require innovative solutions arising from interdisciplinary collaboration. This article summarizes five major urban water management strategies that bridge the fields of engineering, ecology, landscape architecture, and urban planning. A conceptual implementation of these strategies is demonstrated through a design for a small constructed wetland treatment system in San Francisco, California. The proposed decentralized system described in this article consists of a detention basin, vegetated and open free water surface wetlands, and ultraviolet disinfection. In wet weather, the system would detain and treat combined sewer discharges (CSD), and in dry weather it would treat residential greywater for toilet flushing and irrigation in a nearby neighborhood. It is designed to adapt over time to changing climatic conditions and treatment demands. Importantly, this proposal demonstrates how constructed wetland engineers can incorporate multiple benefits into their systems, offering a vision of how wastewater infrastructure can be an attractive community, educational, recreational, and habitat amenity through the integration of engineering, ecology, and landscape design.

A mechanism of injury to the forefoot in car crashes.

OBJECTIVE: The purpose of this study was to determine a mechanism of injury of the forefoot due to impact loads and accelerations as noted in some frontal offset car crashes. METHODS: The impact tests conducted simulated knee-leg-foot entrapment, floor pan intrusions, whole-body deceleration, muscle tension, and foot/pedal interaction. Specimens were impacted at speeds of up to 16 m/s. To verify this injury mechanism research was conducted in an effort to produce Lisfranc type injuries and metatarsal fractures. A total of 54 lower legs of post-mortem human subjects were tested. Two possible mechanisms of injury were investigated. For the first mechanism the driver was assumed to be braking hard with the foot on the brake pedal and at 0 deg plantar flexion (Plantar Nominal Configuration) and the brake pedal was in contact with the foot behind the ball of the foot. The second mechanism was studied by having the ball of the foot either on the brake pedal or on the floorboard with the foot plantar-flexed 35 to 50 deg (Plantar Flexed Configuration). RESULTS: The Plantar Nominal injury mechanism yielded few injuries of the type the study set out to produce. Out of 13 specimens tested at speeds of 16 m/s, three had injuries of the metatarsal (MT) and tarsometatarsal joints. The Plantar Flexed Configuration injury mechanism yielded 65% injuries at high (12.5-16 m/s) and moderate (6-12 m/s) speeds. CONCLUSION: It is concluded that Lisfranc type foot injuries are the result of impacting the forefoot in the Plantar Flexed Configuration. The injuries were consistent with those reported by physicians treating accident victims and were verified by an orthopedic surgeon during post impact x-ray and autopsy. They included Lisfranc fractures, ligamentous disruptions, and metatarsal fractures.

CDtool-an integrated software package for circular dichroism spectroscopic data processing, analysis, and archiving.

CDtool is a software package written to facilitate circular dichroism (CD) spectroscopic studies on both conventional lab-based instruments and synchrotron beamlines. It takes format-independent input data from any type of CD instrument, enables a wide range of standard and advanced processing methods, and, in a single user-friendly graphics-based package, takes raw data through the entire processing procedure and, importantly, uses data-mining techniques to retain in the final output all the information associated with the processing. It permits the facile comparison of data obtained from different instruments without the need for reformatting and displays it in graphical formats suitable for publication. It also includes the ability to automatically archive the processed data. This latter feature may be especially useful in light of recent funding institution directives with regard to data sharing and archiving and requirements for "good practice" and "traceability" within the pharmaceutical industry. In addition, CDtool includes a means of interfacing with protein data bank coordinate files and calculating secondary structures from them using alternate definitions and algorithms. This feature, along with a function that permits the facile production of new reference databases, enables the creation of specialized databases for secondary structural analyses of specific types of proteins. Thus the CDtool software not only enables rapid data processing and analyses but also includes many enhanced features not available in other CD data processing/analysis packages.

Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. I. Investigation of potential experimental and mechanistic explanations.

1. SB-265123 is a novel alphavbeta3 (the vitronectin receptor) antagonist. Previous rat studies with it revealed an apparent absolute oral bioavailability (Fapp) of greater than 100%. The present studies were conducted to investigate the potential causes for this observation. 2. Of 49 SB-265123 analogues evaluated in rat using an identical experimental design, Fapp > 100% was observed for 22 of them, suggesting that the observed Fapp >100% with SB-265123 was not anomalous. All 22 compounds had clearances < 15 ml min(-1) kg(-1). However, Fapp>100% were not recorded for all low-clearance analogues. 3. Using SB-265123 as a model to investigate potential artefacts, it was demonstrated that using a chiral assay did not decrease Fapp. Additionally, qualitative sample analysis demonstrated that no metabolites were present in the plasma that could interfere with the liquid chromatography coupled with tandem mass spectrometry detection assay. The high Fapp was also dose-order-, delivery system- and vehicle-independent, and was not affected by the feeding status of the animals. Furthermore, a linearity experiment and an absorption study indicated that oral administration of SB-265123 does not result in hepatic portal vein concentrations that exceed the pharmacokinetic linearity of SB-265123. 4. These observations suggest that the observed Fapp > 100% for SB-265123 is not due to an experimental artefact or an obvious pharmacokinetic non-linearity. The mechanism(s) for this phenomenon is explored further in the second part of the present paper.

Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. II. Studies implicating transporter-mediated intestinal secretion.

1. Transporters have been increasingly identified as a factor in limiting the oral bioavailability of certain drugs. Previously, the present authors investigated a compound (SB-265123) with an apparent absolute oral bioavailability (Fapp) consistently > 100%, and excluded likely artefactual causes for this observation, as well as standard considerations of non-stationary or non-linear pharmacokinetics. The data led the authors to believe that SB-265123 might be a transporter substrate in the rat, and it was hypothesized that transporter interactions might be responsible for the observed Fapp > 100%. 2. In the present study, a model was proposed incorporating rapid and complete absorption and elimination by a saturable intestinal secretory pathway. Intestinal secretion was demonstrated for SB-265123 using a rat single-pass intestinal perfusion technique. In addition, in a study employing both independent and simultaneous intravenous and oral administration of SB-265123, exposure to SB-265123 was greater than additive on joint intravenous and oral administration, lending further support to the hypothesis of a saturable transporter. Furthermore, in a study with co-administration of GF120918A, a transporter inhibitor, the observed Fapp for SB-265123 was only 84 +/- 17%, providing additional evidence for transporter involvement in the >100% Fapp phenomenon. 3. Experience with SB-265123 illustrates a counterintuitive impact of transporters on oral bioavailability and highlights the importance of considering transporter interactions in the systemic disposition of xenobiotics, even those not demonstrating low oral bioavailability.

NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

NOD2/caspase recruitment domain (CARD)15 variants are identified in up to 50% of Crohn's disease (CD) patients. Functional variants of toll-like receptor-4 (TLR4) and CD14 genes may also be relevant to disease pathophysiology. We aimed to assess the contribution of NOD2/CARD15, TLR4 and CD14 variants in Scottish and Irish CD patients. In all, 612 patients with well-characterised inflammatory bowel disease (252 Scottish CD, 247 Scottish UC, 113 Irish CD) and 304 controls were genotyped for variants of NOD2/CARD15 (1007fsinsC, G908R, R702W, P268S), TLR4 (A299G) and CD14 (T-159C). Genotype-phenotype analyses were performed. Variant 1007fsinsC (P=0.003) and G908R (P=0.008) but not R702W (P=0.269) alleles were more prevalent in Scottish CD (4.7, 1.8 and 7.1%, respectively) than Scottish control (2.3, 0.3 and 5.4%). CD allelic frequencies were lower than the series from Europe (P<0.00001) and North America (P<0.00001) but not Scandinavia (P<0.7). Associations were identified with age at diagnosis (P=0.002), ileal disease (P<0.02), penetrating disease (P=0.04) and inflammatory joint disease (P<0.02). TLR4 and CD14 variants did not differ between CD and controls. In conclusion, we present compelling evidence for genetic heterogeneity within Europe. These NOD2/CARD15 variants have a minor contribution in Scottish and Irish CD patients, consistent with an emerging pattern from Northern Europe.

Accuracy, efficiency and robustness of four algorithms allowing full sibship reconstruction from DNA marker data.

In the problem of reconstructing full sib pedigrees from DNA marker data, three existing algorithms and one new algorithm are compared in terms of accuracy, efficiency and robustness using real and simulated data sets. An algorithm based on the exclusion principle and another based on a maximization of the Simpson index were very accurate at reconstructing data sets comprising a few large families but had problems with data sets with limited family structure, while a Markov Chain Monte Carlo (MCMC) algorithm based on the maximization of a partition score had the opposite behaviour. An MCMC algorithm based on maximizing the full joint likelihood performed best in small data sets comprising several medium-sized families but did not work well under most other conditions. It appears that the likelihood surface may be rough and presents challenges for the MCMC algorithm to find the global maximum. This likelihood algorithm also exhibited problems in reconstructing large family groups, due possibly to limits in computational precision. The accuracy of each algorithm improved with an increasing amount of information in the data set, and was very high with eight loci with eight alleles each. All four algorithms were quite robust to deviation from an idealized uniform allelic distribution, to departures from idealized Mendelian inheritance in simulated data sets and to the presence of null alleles. In contrast, none of the algorithms were very robust to the probable presence of error/mutation in the data. Depending upon the type of mutation or errors and the algorithm used, between 70 and 98% of the affected individuals were classified improperly on average.

Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease are associated with disease severity but not NOD2/CARD15 mutations.

Anti-Saccharomyces cerevisiae antibodies (ASCAs) have been proposed as serological markers, which may differentiate Crohn's disease (CD) from ulcerative colitis (UC) and predict disease phenotype. Their importance in pathogenesis is unproven. We investigated the relationship between ASCAs, disease phenotype and NOD2/CARD15 genotype in CD and whether ASCAs were related to antibodies to other fungal proteins. Serum from 228 patients [143 CD, 75 UC, 10 with indeterminate colitis (IC)] and 78 healthy controls (HC) were assayed for ASCA. Antibodies (IgA, IgG) to other fungal proteins (Fusarium species ATC20334, Mycoprotein) were measured in the same samples using an in-house enzyme-linked immunosorbent assay (ELISA) assay. ASCAs were present in 57% of CD, 19% of UC, 30% of IC and 8% of HCs. ASCA-positive status was a predictor for CD with sensitivity of 57%, specificity of 87%, positive predictive value of 78% and negative predictive value of 68%. ASCA was associated with proximal (gastroduodenal and small bowel involvement) rather than purely colonic disease (P < 0.001) and with a more severe disease phenotype and requirement for surgery over a median follow-up time of 9 years (P < 0.0001). No associations with NOD2/CARD15 mutations were seen. There was no association between ASCA and antibodies to MP (IgA or IgG). These data implicate ASCA as a specific marker of disease location and progression in CD, emphasizing the heterogeneity within IBD.

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.