Velaglucerase alfa and imiglucerase, both biotinylated and non-biotinylated (analytes) were serially diluted in 1× HBS-EP to obtain concentrations learn more of 0.31, 0.625, 1.25, 2.5, 5, and 10 nM, and injected at a flow rate of 50 μL/min with a contact time of 300 s and a dissociation time of 500–1000 s. After each cycle, the CM5 sensor chip was regenerated with 100 mM phosphoric acid, pH 2.0 at a flow rate of 60 μL/min with a contact time of 120 s. The sensorgrams were evaluated using Biacore™ T100 Evaluation Software with local Rmax fitting to a 1:1 binding model. Following the highly sensitive screening stage, a specific confirmatory assay was required to eliminate false-positives
from the screening results. The assay used was isotype-specific for IgG anti-drug antibody. The method described was identical for imiglucerase
antibodies, substituting imiglucerase for velaglucerase alfa wherever written. The assay was performed in solution phase in microdilution tubes positioned in an 8 × 12 tube rack, placed within a shielded box consisting of either leaded Plexiglas or lead foil. 100 μL of samples and controls was added to each tube, followed by 20 μL of 125I-velaglucerase alfa working solution. The working solution of 125I-velaglucerase Natural Product Library mw alfa was adjusted to 250,000 ± 8000 counts per minute (CPM) per 20 μL using dilution with RIP binding buffer (20 mM NaPO4 pH 7.0, 100 mM NaCl, 0.05% Acyl CoA dehydrogenase polyoxyethylene 20-sorbitan monolaurate). Each tube was mixed briefly, and incubated at room temperature for 2 h to allow IgG antibodies present to form antigen/antibody complexes. After 2 h, 120 μL of each sample was loaded into a separate Protein G column, assembled in a VersaPlate manifold connected to a vacuum pump, and incubated at room temperature for 20 min. The columns were washed five times with 1 mL of RIP binding buffer per wash. After the last wash, vacuum strength was increased to the maximum level for 2 min to remove all RIP binding buffer from the columns. To quantify the immune complex, each individual column was placed in
a separate gamma counter tube and counted using the appropriate settings for 125I for 1 min, and the mean, standard deviation, and percent relative standard deviation (% RSD) of the replicates for all samples, calibration curve points, controls and blank were calculated. The radioactive counts that retained in the mini-column were proportional to the concentration of anti-velaglucerase alfa IgG antibodies in the test sample. The concentration of anti-velaglucerase alfa IgG antibodies in test samples was estimated from a calibration curve using the same mouse anti-glucocerebrosidase monoclonal antibody calibrator discussed above. Serum samples for testing were diluted in RIP binding buffer, to a minimum dilution of 1/20.
times the thermal equilibrium signal at 9.4 T and 300 K Afatinib corresponds to 100% polarization. For comparison, the thermal polarization for 83Kr is P83Kr9.4T,300K=4.53×10-6 ( fmax9.4T,300K=2.21×105), and for 129Xe is P129Xe9.4T,300K=8.92×10-6 ( fmax9.4T,300K=1.12×105). Using the stopped-flow optical pumping method, 131Xe signal enhancements on the order of 5000 times greater than thermal signal at B0 = 9.4 T, 150 kPa, and 297 K were achieved (i.e. approximately 2.2% spin polarization) when mixture I was used. The 131Xe polarization build-up reached a steady-state relatively quickly compared to other noble gas isotopes (3He, 129Xe and, 83Kr – at similar SEOP conditions). The time dependence for the hp 131Xe polarization build-up is shown in Fig. 4 for the three different mixtures (5%, 20% and 93% Xe) under selleck chemicals 40 W of σ− circularly polarized 794.7 nm laser light.
To monitor the 131Xe polarization build-up, the magnetic field at the SEOP cell was initially switched off, while the cell was maintained under constant laser illumination at a constant temperature (453 K) and pressure (150 kPa) for 5–10 min. This procedure produced a ‘starting point’ at stable SEOP conditions but with no hyperpolarized 131Xe present and allowed for regeneration of the rubidium vapor after the shuttling procedure. The magnetic field of a pair of Helmholtz coils was then turned on for incremented time period, tp, after which the hp 131Xe was transferred to the sample cell where it was detected. The polarization value was obtained from the hp 131Xe signal intensities through comparison to the thermal signal
of 131Xe described in the experimental section. The time dependent build-up of hyperpolarization is described as : equation(3) P131XeSEOP=γseγse+Γ·γopγop+∑iκsdi[Mi](1-e-(γse+Γ)tp),where Nintedanib (BIBF 1120) γse is the Rb–Xe spin exchange rate and Γ = 1/T 1 is the quadrupolar driven fast self-relaxation rate of 131Xe. The destruction of Rb spin polarization by collisions with inert gas atoms is described by the sum of the products of the rate constants, κsdi, with their corresponding gas atom number densities [Mi]. The optical pumping rate per Rb atom, γop, depends on experimental parameters such as laser power, SEOP cell design, and SEOP temperature that were kept constant for all build-up experiments reported here. However only a reduced form of Eq. (3) was used for fitting of the experimental data since γse and Γ were unknown under the SEOP conditions used in this work: equation(4) P131XeSEOP(t)=A(1-e-Btp). The lower the xenon concentration used in the gas mixture, the larger was the resulting pre-exponential parameter A . The steady-state polarization P131XeSEOP(max) (i.e. at infinite long SEOP times) determined through A was 2.24 ± 0.03 for mixture I (5% xenon), 0.438 ± 0.007 for mixture II (20% xenon), and 0.0256 ± 0.0005 for mixture III (93% xenon). The ratios between the values obtained for A were 1:0.20:0.
Shapiro–Wilk test. Qualitative variables are presented in terms of absolute value and percentage. Differences between quantitative variables were verified using Student t-test or χ2 test for categorical RG 7204 variables. Accepted criteria for statistical significance is P < 0.05. Campylobacter
infections were diagnosed in 71 children (29 girls and 42 boys), which represented 5.28% of children among 1343 patients hospitalized because of vomiting or diarrhea in 2008–2010. In 2008, it accounted 2.99% of hospitalization, in 2009 – 6.84%, in 2010 – 6.25%. C. jejuni infection was diagnosed in 64 children (90.1%), C. coli in 4 children (5.6%) and Campylobacter species in 3 children (4.2%). In 22 children Campylobacter infection was accompanied by other gastrointestinal infections (enteropathogenic
strains of E. coli (EPEC) Enzalutamide in 10 children – 14.1%, Rotavirus in 11 children – 15.5%, Salmonella type C in 1 child – 1.4%). According to the age, none of co-existing infections differed in frequency ( Table I). Duration of hospitalization was from 2 to 26 days (mean 7.24 days). Main period of incidence occurred in the period between May and October. Among infants, Campylobacter infection was diagnosed in 29 cases (14 girls and 15 boys), which accounted for almost 41% of all Campylobacter bacterial infections. In the age group between 1 and 3 years of age Campylobacter infection was diagnosed in 45.1% of children (13 girls and 19 boys). In total, in the age group up to 3 years of age Campylobacter infection was diagnosed in 61 children (86% of all Campylobacter infections). In the group above 3-year-old Campylobacter bacterial infection was diagnosed in 14.1% of children. According to the age, at the initial stage of infection various clinical symptoms were observed, shown in Table II. In the group under 1 year of age (29 children), diarrhea developed in 82.7% of patients, including those 15 children
(51.7%) had diarrhea with blood. Among this group, in 5 children (17%) vomiting was the only symptom of Campylobacter infection. Fever occurred in 37.9% of patients (11 children). Additionally, in one child the upper respiratory tract infection was found. In the age group between 1- and 3-year-old (32 Orotidine 5′-phosphate decarboxylase children), diarrhea developed in all children (in 34.3% of cases it was diarrhea with blood). Vomiting was observed in 37.5% of children. Fever was the symptom which occurred in less than a half of the patients (43.7%). Upper respiratory tract infection was diagnosed in 37.5% of children. In this age group, abdominal pain was relatively rare (in 9.4% of children). Among children over 3-year-old (10 patients) diarrhea occurred in 90% of cases and only one child had stools with blood. Vomiting was observed in 50% of children, fever and abdominal pain occurred in 30% of cases. Respiratory tract infection occurred in 2 children.
In 2004 he was evaluated for the first time in our institution. At the initial observation, he complained of intermittent diarrhea and weigh loss. He had a body mass index (BMI) of 19.53 kg/m2 and was
medicated with steroids for a long time (steroid‐dependent). After further evaluation with blood tests, endoscopic and imaging studies he began treatment with azathioprine. The following year, the disease maintained a high level of activity (abdominal pain, diarrhea and weigh loss), and anti‐tumor necrosis factor (TNF) α therapy was initiated (infliximab 5 mg/kg). ATM/ATR phosphorylation In 2007, during clinical remission, he was diagnosed with esophageal candidiasis. At that time azathioprine was discontinued. In 2009, he had a clinical relapse and infliximab dosage was adjusted to 10 mg/kg every 8 weeks. In February 2010, disease was still active, the patient continued to lose weight (BMI 13.47) and a biological switch to adalimumab was attempted. In October 2010 the patient complained for the first time of progressive paraesthesias in both feet and hands and muscular weakness in upper and lower limbs. He could not specify the time of onset of the symptoms (several years) RO4929097 datasheet but mentioned an aggravation in the previous month. He was evaluated in the Neurology department and an acquired demyelinating polyneurophathy was diagnosed. Chronic inflammatory demyelinating polyneurophathy related to anti‐TNFα therapy was suspected but, because
those symptoms had been present for several years, a causal relationship was difficult to establish. We decided to stop anti‐TNFα therapy and steroids were started, without clinical improvement. Short afterwards, in November 2010, he presented with dysphagia.
Endoscopic evaluation revealed lesions suggestive of severe esophageal candidiasis. Chest radiography also revealed an infiltrate in the left lung suggesting pneumonia. He began antibiotics, anti‐fungic and enteral nutrition (nasogastric feeding tube). After two weeks, upper endoscopy was repeated and no esophageal lesions were observed. The nasogastric feeding tube was removed; however, the patient maintained complaints of dysphagia and began vomiting. In December parenteral nutrition was prescribed, adjusted to caloric requirements Bay 11-7085 with multivitamin infusion and trace elements supplementation. Concomitantly, enteral nutrition (nasoenteric feeding tube) was also initiated to stimulate gut protection and function. Three weeks later, he presented dyspnea and chest radiography revealed pneumonia in the right lung with pleural effusion. Empirical antibiotic therapy was restarted and a right thoracocentesis was performed. The following day, chest radiography revealed a right pneumothorax and a thoracic drain was placed. One week later, respiratory complications were resolved but esophageal and gastric dysfunctions were still present. The patient was severely malnourished (BMI: 10.93 kg/m2) with muscular atrophy and complained of visual impairment.
Our study on NSP (and
similar “anchor media”, Kuhn, 2010, Kuhn and Müller, 2005a, Kuhn and Müller, 2005b and Müller et al., 2010) was inspired by AI and an attempt to overcome the difficulties of the original approach described above. While preserving authenticity, www.selleckchem.com/products/PD-0332991.html ‘story’-character (narrative contexts) and student centered activity as design principles, it aims at an improved applicability to and implementation in a wider range of realistic educational settings, as text-based anchors are much easier and less expensive to develop and to modify than multimedia based anchors. The advantage of combining the general theoretical framework of narrative contexts, explained above, with design principles inspired by AI is that the latter already is based on a considerable body of evidence (see above) and has specific design principles to offer. Beyond those Osimertinib in vivo already mentioned, AI (and to a large extent also the
present work) is also based on the following ones (CTGV, 1991)5: Embedded data: the data necessary to solve a problem are “embedded” in the story of the learning anchor, and not given explicitly (as in conventional textbook problems). The rationale behind this design principle is as follows: (i) it is true for problems encountered in the real world (daily life, workplace, genuine research; cf. problem authenticity); (ii) the “translation” feature (OECD, 2006) is extended by a feature of “selection” of what is relevant from what is not (for a given problem), both contributing to cognitive activation.
For these reasons, “embedded data” are considered as an especially important characteristic of AI. Related problems (multiple contexts): learning should provide repeated opportunity and multiple contexts to acquire new concepts, not merely for the sake of repetition, but in order to avoid inert knowledge (cf. above); for single contexts, there is the danger of having the involved Cytidine deaminase concepts “welded” to them (CTGV, 1991). The number of related problem stories (anchors) for the acquisition of new conceptual (and procedural) knowledge thus should be at least two (for the AI anchors) or more (for the shorter NSP anchors). Collaborative learning: small group work, complemented by whole-class phases, ensures communication and social embedding considered necessary for active learning (social context or situatedness); this is also natural and easy to realize for the NSP approach (and actually a common element of contemporary science teaching in the authors׳ country). Horizontal (cross-disciplinary) and vertical (cross-grade, cumulative learning) connections, which again help to strengthen the perception of relevant contexts and to overcome inert knowledge: these features also hold for newspaper story problems: horizontal links are included by construction, NSP involving links to many other issues, such as societal, technological, biological, etc.
5% to record steady-state hemodynamic data. Hemodynamic parameters such as the mean blood pressure (MBP), peak LV pressure (LVP), LV end-diastolic
pressure (LVEDP), and the rate of intraventricular pressure were recorded as previously described . The study was performed in a blinded manner. Slices from ventricles of each heart were fixed in a 10% neutral formalin solution, then embedded in paraffin, sectioned at a thickness of 5 μm and stained with haematoxylin and eosin (H/E), and examined by light microscopy. The ventricle specimens were evaluated for typical histopathological features associated with clozapine-induced cardiotoxicity (including inflammation, myocyte vacuolar degradation, necrosis of myofibers, and interstitial fibrosis). Heart tissue was homogenised (Biohom homogeniser) in 20-mM phosphate buffer HDAC inhibitor (pH 7.4) containing 0.5 mM butylated hydroxytoluene to prevent sample oxidation. The homogenates were centrifuged at 3000 rpm at 4 °C for 15 min. Serum and the supernatant of the homogenate were used for biochemical assays. Creatinine kinase (CK-MB) activity was estimated E7080 molecular weight in serum according to the method of Bishop et al.  using diagnostic kit (Stanbio Laboratory, TX, USA). The increase in absorbance at 340 nm is measured spectrophotometrically to calculate CK-MB level as (U/L). LDH activity was determined using diagnostic kit provided from Biogamma (Rome-Italy). The increase in absorbance is
measured spectrophotometrically at 340 nm at 1 min intervals for 3 min. Serum total LDH activity was calculated as (U/L) according to the method of Whitaker . TNF-α in the cardiac homogenate was assayed using enzyme-linked immunosorbent assay Decitabine order (ELISA) using a microplate reader (Spectra III Classic, Tecan, Salzburg, Austria) as previously described . Lipid peroxidation was determined in the cardiac homogenates because thiobarbituric acid reactive species (TBARS; referred to as malondialdehyde, MDA) are considered markers of oxidative stress. The colour intensity is measured spectrophotometrically at 532 nm. Concentration of TBARS was calculated
for each sample after reference to the standard curve. Nitrate and nitrite are assayed calorimetrically as indicators of NO in the tissue because the half-life of NO is too short and it is proportionately converted into nitrite and nitrate. Then the total nitrite is then measured by Griess reaction, according to the method described by Green et al. . Reduced glutathione (GSH) was determined according to the method described before by Beutler et al. . The procedure is based on the reduction of 2-nitrobenzoic acid by glutathione to produce a yellow compound which was measured spectrophotometrically at 405 nm. Glutathione peroxidase (GSH-Px) activity was determined spectrophotometrically by the method of . Myeloperoxidase (MPO) activity was measured as an index of neutrophil accumulation.
Aparna Dixit and her research group for their help in flow cytometry data analysis. We are also thankful to Advance Instrumentation Facility (AIRF), JNU, New Delhi for various analytical
instruments used in this work. “
“Kerosene is a distillate of crude petroleum that contains aliphatic, aromatic and a variety of other branched saturated and unsaturated hydrocarbons . The use of crude kerosene has been a common practice in east Africa and other countries for many years, with the belief of it reducing the sex drive (libido) at the pubertal stage. In the course of daily meals consumption students are exposed to doses of kerosene as a dietary supplement, usually without Selleck C59 wnt their consent. The process of puberty results in the release of some specific hormones which are primarily responsible for the development of secondary sex characteristics and for the emergence of reproductive capabilities in boys . During this stage an increase in testosterone causes an increase in the sex drive (libido), enlargement of the reproductive organs such as the penis and testes, the production of sperm, increase of muscle mass and lowering of the voice, increased frequency of erection, and the growth of facial, chest, nipple and pubic hair among boys. The link between Testosterone
(T) levels and the sexual drive was demonstrated in a study done using adolescent boys with the findings indicating that the adolescent boys who had higher levels T levels AZD8055 supplier also reported higher levels of sexual activity (i.e., coitus) , ,  and . From the studies by Brooks-Gun and Halpern  and  it can be inferred that hormones may enhance feelings of sexual Tenoxicam arousal in adolescents but how they act on those feelings is very much determined by multiple internal and external variables. From the
study conducted by Olweus et al.  and  it was noted that adolescent boys with higher T levels were more likely to engage in aggressive behavior. Under conditions of threat or unfair treatment,  they were shown to be aggressive. They further showed a link between higher T level and a lower tolerance for frustration. Further to these, they also observed that when no provoking situation occurred, T levels did not predict aggression. Various animal studies conducted on mice demonstrated the link between aggressive behavior and increased T levels  and . In a study on mice exposed to jet kerosene continuously for 90 days, there was an observed increased incidence in the fighting of the test group mice . There is increasing trend regarding the percentage of teenagers reporting sexual initiation at younger ages . This early sexual initiation (before age 16) is likely to involve sexual risk-taking and expose young people to unwanted sex, sexually transmitted infections, and teenage pregnancy. This may be attributed to exposure to a highly sexualized media environment that may represent a primary source of sexual socialization and .
They are composed of a pore-forming α-subunit associated with up to four known different β-subunits. The tetrodotoxin
(TTX)-sensitive Na+ channels are classified according to sequence homology as Nav1.1 to Nav1.7 and they are differentially distributed in the central and peripheral nervous Epigenetics Compound Library chemical structure system, in skeletal muscle, and in cardiac muscle. VGSC and K+ channels dysfunction (channelopathies) can result in neuromuscular diseases and heart or brain disorders such as arrhythmias and epilepsy ,  and . Mutations in the genes encoding for Nav1.1 and Nav1.2 isoforms have been linked to various forms of epilepsy and febrile seizures . Thus, the key role of VGSCs in many tissues makes them important targets for pharmacological and biophysical studies, especially by dissecting the specific toxin–channel interactions. The investigation on the pharmacology of sodium channel toxins from sea anemones started more than Alectinib supplier 30 years ago  and , and further studies on site-directed mutagenesis took place later in the 1990s , ,  and .
Nevertheless, very few information on electrophysiological and selectivity effects in a broader range of channels was reported  and . Sea anemone type 1 toxins are peptides whose binding sites in VGSCs partially overlap with those of α-scorpion toxins. Their actions involve almost completely and selectively to induce a particular delay in ion channel conformational change called inactivation (transition from the open to the shut state) as opposed to the early process of activation (opening of the Na+-selective pore). This inactivated state is distinct from the closed state and there are many different methods to manipulate it from the intracellular side, either by using enzymes , drugs, point mutations (for a review see Ulbricht ) and specific toxins
from venomous animals. In the present paper, we studied three sea anemone type 1 toxins (CGTX-II, δ-AITX-Bcg1a and δ-AITX-Bcg1b) purified from the venom of the sea anemone Bunodosoma cangicum. Two Loperamide of those toxins (δ-AITX-Bcg1a and δ-AITX-Bcg1b) differ in only one amino acid (N16D), but their potencies are markedly different. Also, in contrast to CGTX-II, both δ-AITX-Bcg1a and δ-AITX-Bcg1b have substitutions at positions 36–38. These positions were reported, in other sea anemone toxins, to be involved in the toxin–channel interaction, then inducing a robust increase in the slow component of the inactivation , ,  and , which is the origin of the physiological prolongation of the action potential.
We have described how knowledge of protein termini will facilitate this by setting boundaries to the search space and acting as biomarkers defining the functional state of a protein. In the near future this will lead to exiting new biological insights into cellular and disease processes at a systems level and help close the gap between genotypes and phenotypes. Papers of particular interest, published within the period of review, have been highlighted as: • of special interest This work was supported by grants of the Canadian Institutes of Health Research; the Canadian Breast Cancer Research Alliance; the Canadian Breast Cancer Foundation; the Cancer Research
Society; a Canada Research Chair to C.M.O., the Michael Smith Foundation for Health Research,
Z-VAD-FMK solubility dmso the Breast Cancer Society of Canada, Alexander von Humboldt Foundation and the German Federal Ministry of Education and Research to P.F.L. “
“Current Opinion in Chemical Biology 2014, 23:23–30 This review comes from a themed issue on Molecular immunology Edited by Marcus Groettrup and Huib Ovaa For a complete overview see the Issue and the Editorial Available online 15th September 2014 http://dx.doi.org/10.1016/j.cbpa.2014.08.013 1367-5931/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). The incidence of autoimmune and autoinflammatory disorders is rapidly increasing in developed countries
. Addressing this clinical need will require continued innovation in immunomodulatory drug learn more development. Data from many sources, including analysis of how human genetic variation affects disease susceptibility, implicate aberrant cytokine production O-methylated flavonoid and signaling in the pathophysiology of these disorders (see Box 1 for background on the application of disease genetics to drug discovery). For example, mutations in the cellular machinery that processes the inflammatory cytokine interleukin-1β (IL-1β) to its mature form cause hereditary autoinflammatory diseases known as cryopyrin disorders (Figure 1a) . Protein therapies inhibiting IL-1β (canakinumab; rilonacept) or its receptor (anakinra) are used to treat cryopyrin disorders, as well as immune disorders with more complex etiologies, including gout, type-2 diabetes, rheumatoid arthritis (RA) and chronic granulomatous disease [3 and 4]. The clinical success of biopharmaceuticals targeting IL-1β or other cytokines (TNF-α, IL-6, IL-12/23) derives from their ability to disrupt protein–protein interactions with exquisite selectivity and predictable, long-lasting pharmacology [5•]. The study of human genetics can uncover factors that contribute to the initiation and maintenance of disease, and suggest new strategies for therapeutic intervention.
Summary statistics using FAS were selleck also calculated for mean percent change from baseline in (L2–L4) BMD at 6 and 12 months. Secondary endpoints were analyzed using FAS. Mean percent change from baseline was calculated for biochemical markers
of bone metabolism at 1, 3, 6, 9, 12 months, and at the end of the study (M12, LOCF). Vertebral fractures were also examined at 12 months and at the end of the study (M12, LOCF) by calculating the frequency, as well as the difference between the treatment groups and the 95% confidence intervals (CI). Subgroup analysis on the primary endpoint was performed using the baseline values of the biochemical markers. A total of 1251 individuals provided written informed consent and, of these, 852 subjects (429 subjects in the 2.5 mg once-daily group and 423 subjects in the 75 mg once-monthly group) were enrolled into the study and randomized (Fig. 1). A subject who had registered twice was excluded from all analyses, and the FAS comprised 850 subjects (428 subjects in the 2.5 mg once-daily group and 422 subjects in the 75 mg once-monthly group). The PPS group included 711 subjects (368 subjects in the 2.5 mg once-daily group, and 343 subjects in the 75 mg once-monthly group). Study discontinuation or withdrawal occurred in 48 and 58 subjects, respectively, in the 2.5 mg once-daily and 75 mg once-monthly groups. Pretreatment events, Caspase inhibitor which were defined as any untoward medical occurrence in a subject who had signed
informed consent to participate in the current study but prior to administration of any study medication, and adverse events were the most common reasons for discontinuation or withdrawal in both groups through the treatment period. A summary of baseline demographics
and characteristics of randomized subjects is presented in Table 1. With the exception of CTX/CRN levels, which were slightly higher in the 2.5 mg once-daily group compared with the 75 mg once-monthly group, all key baseline demographics and primary disease characteristics were similar in the two treatment groups. Patient characteristics at cAMP baseline in the PPS were similar to those of the randomized set. Mean percent change (SD) from baseline in (L2–L4) BMD at the end of the study (M12, LOCF) in the FAS was 5.69 (4.00)% in the 2.5 mg once-daily group and 5.98 (4.54)% in the 75 mg once-monthly group. In the non-inferiority t-test, the 75 mg once-monthly group proved to be non-inferior to the 2.5 mg once-daily group (p < 0.0001). The difference between treatment groups was 0.28% (95% CI, − 0.31% to 0.88%). Mean percent change from baseline in (L2–L4) BMD at the end of the study (M12, LOCF) in the PPS was similar to that in the FAS. Mean percent change (SD) from baseline in (L2–L4) BMD in the FAS at 6 months in the 2.5 mg once-daily and 75 mg once-monthly treatment groups was 5.01 (3.62)% and 4.67 (4.16)%, respectively, and at 12 months it was 5.81 (4.02)% and 6.11 (4.50)%, respectively (Fig. 2).