The complementary and confirmatory insights offered by MDS were evaluated. Results from MDS of the relationship between indicators confirmed the closer relationship within sickness and within depression-like indicators (Fig. 6 left). Dimension 2 differentiated between Selleckchem Torin 1 sickness indicators (receiving positive coefficients) and depression-like indicators (receiving negative coefficients). Dimension 1 differentiated among the sickness indicators weight change (receiving positive coefficients) and activity (receiving negative coefficients). The overall consistency of results between the PCA and MDS analyses speaks to the strength of the relationships

among the behavioral indicators measured in this study. The slight differences between the relative coefficients in the PCA and MDS implementations is related to the PCA identification of the linear combination

of indicators that maximize the explained variance adjusted for all higher order combinations, meanwhile MDS preserved the distances between items while representing the items in a lower dimensional space. The results from MDS confirmed the distribution of mice within and between BCG-treatment groups observed in the PCA (Fig. 6 right). Mice from the BCG0 and BCG10 groups were located on either side of the two-dimensional Trichostatin A datasheet plot, meanwhile mice in the BCG5 group were located in-between. Multidimensional scaling analysis offered insights into the relative behavior of BCG10 mouse number 22 that clustered closer to the BCG0 group. Fig. 6 (right) demonstrates that this mouse was approximately half-way in between

group BCG10 and BCG0. Closer inspection of the indicators revealed that despite exhibiting levels of horizontal locomotor activity, rearing, forced swim immobility, and sucrose preference consistent with other mice in the BCG10 group, this mouse maintained weight during the trial. The unique combination of levels displayed by this mouse suggests the need to consider multiple sickness and depression-like Non-specific serine/threonine protein kinase indicators simultaneously and the need to measure additional mice. Linear discriminant analysis enabled a perfect discrimination of the mice among the corresponding BCG-treatment groups without miss-assignments. Leave-one-out cross validation confirmed these BCG-treatment class assignments. The coefficients of the behavioral indicators in the indices that discriminate between BCG10, BCG5 and BCG0 offered insights into the impact of indicators in the discrimination between BCG-treated and BCG0 but also within BCG-treated groups (Table 1). A linear trend was observed between the coefficient of the indicator and the BCG-treatment level in all except two behavior indicators. The linear trend consists on an increase (or decrease) in the coefficient with BCG-treatment level. This trend slightly departed for the forced swim immobility; however, the difference in coefficients between BCG-treatment levels was only 10%.

Recently, it was reported that chronic exposure to organophosphate pesticides can potentiate the risk of coronary artery disease presumably through diminished paraoxonase activity (Zamzila et al., 2011). Higher incidence of the late-onset nephropathies like chronic kidney disease and chronic renal failure has been reported in middle-aged Tanespimycin in vivo people (40–60 years) living in the agricultural areas with more prevalence in men. The results of a survey in North Central Province of Sri Lanka have presented

a significant relationship between chronic renal failure and environmental factors in farming areas (Wanigasuriya et al., 2007). Exposure to acetylcholinesterase inhibiting pesticides was associated with chronic renal failure (Peiris-John et al., 2006). Furthermore, higher

level of organochlorine pesticides buy H 89 was detected in chronic kidney disease patients along with a reduced glomerular filtration and increased oxidative stress (Siddharth et al., 2012). Asthma is considered as the most common disorder among chronic respiratory dysfunctions affecting both children and adults. Its close relationship with work-related exposures has been known from 18 centuries so that occupational asthma is characterized as a disease in medicine. There have been several reports on increased rate of asthma in people occupationally exposed to pesticides (Hernandez et al., 2011). Moreover, the result of an agricultural health study indicated that exposure to some pesticides may increase the risk of chronic obstructive pulmonary disease

(COPD) in farmers (Hoppin et al., 2007). However, there are sporadic reports on the association of exposure to pesticides with different types of human chronic diseases, including chronic fatigue syndrome (Behan and Haniffah, 1994), autoimmune diseases like systemic lupus erythematous and rheumatoid arthritis (Cooper et al., 2004, Gold et al., 2007 and Parks et al., Lonafarnib datasheet 2011) which need further investigations for more proof (Table 2). Genetic damages are caused by direct interaction with genetic material resulting in DNA damage or chromosomal aberrations and considered as a primary mechanism for chronic diseases within the context of carcinogenesis and teratogenesis. They are studied in the field of genetic toxicology and can be detected by distinctive kinds of genotoxicity tests. Growing body of data concerning genetic toxicity of pesticides have been collected from epidemiological and experimental studies using different types of examinations, including chromosomal aberrations, micronucleus, sister chromatid exchanges and comet assay (Bolognesi, 2003 and Bull et al., 2006). Indeed, genetic damages are classified into three groups as follows: 1. Premutagenic damages like DNA strand breaks, DNA adducts or unscheduled DNA synthesis; 2. Gene’s mutation which means insertion or deletion of a couple of base pairs; 3.

There is high foreign and local demand to join the co-management plans; all plans have a waiting list to issue new licenses. In the interviews, stakeholders stated global and local measures had to be taken to control fishing effort. This concurs with the measures adopted Akt inhibitor by the DGPM; fishers must have completed 20 days at sea in the previous campaign and be active members of an Asturian cofradía to renew their

license. The cofradías have also established their own criteria in accepting new fishers, the Cabo Peñas plan members unanimously decided to only allow one new member for every three that leave the plan and others set a moratorium on issuing new licenses until they reach their target size. According to the focus groups, the fishers perceive their opinion on management guidelines is valued

and enforced. The joint approach to control fishing effort in Asturias can only be possible through a co-management system. Moreover, this approach also aids in including the fishers in the management process and generates a sense of empowerment. One of the main concerns expressed by fishers during the focus groups was the presence of poachers who exploit their TURFs, particularly during the closed season or in banned areas. The DGPM finances one surveillance officer per management plan who works a daily shift. Due to the surveillance effort several poaching cases have been documented and sanctioned by local authorities. However, according to the resource users many cases go unpunished or receive relatively small Epacadostat cell line fines. Fishers expressed a sense of entitlement, characteristic to exclusive rights systems, and saw an imminent need to protect their resource. Thus, in Cudillero-Oviñana, Luarca and Puerto de Vega all members have agreed to personally carry out a few days of surveillance in special interest areas. In the interviews and focus groups multiple resource users expressed concern to the constraints in compatibility between target species. The gooseneck barnacle fishery is legally compatible Sinomenine with shellfish pot, eel fishing

sieve and hook and line fishing. However, compatible gears can vary among plans. Nonetheless, to exploit incompatible resources, those that require passive-fishing gears such as gillnets and trammelnets, the fishers must resign their license for the rest of the fishing campaign. During the focus groups fishers that belong to a professional fishing vessel conveyed the most apprehension towards these measures, they generally only work for the first half of the campaign (October–December) and then depart to other fisheries. This generates a partition of gooseneck barnacle fishers into two groups, professional fishers and autonomous fishers who do not belong to a professional vessel and only have an individual license, with different exploitation seasonality.

Our reported

post-operative transfusion rate of 43% is very similar to those reported elsewhere [28] and [29]. The reason Selleckchem ZVADFMK for the higher rate of peri-operative transfusion in patients with DSA compared with Non-DSA is therefore uncertain. It may be due to the greater medical and surgical complexities of this patient group and their greater waiting time on dialysis for example. However, it is notable that there was no difference in gender, re-transplantation, deceased donors or Pre-RBCT between the DSA and Non-DSA groups at time of surgery, or between the haemoglobin at surgery or at 1 month post-surgery. Although residual confounding by indication remains possible, it is not possible to either entirely adjust or explain and this difference requires further testing. The immunological interaction of blood transfusion and transplantation is complex. Pre-RBCT is associated with better graft outcomes and less acute rejection, and this is suggested to be due to immunomodulation with down-regulation of an immune response and the induction of regulatory T-cells [11] and [30]. Indeed

our study confirms the continued benefit of Pre-RBCT alone with this group having the lowest rate of Non-AMR. We also confirm that Pre-RBCT is still associated with an increased risk of HLA-antibody sensitisation. Several recent reports [28] and [29] raise some concern that post-operative transfusion is associated with poor graft outcome. However these studies did not consider sensitisation or prior transfusion Staurosporine in vitro as potential modifiers and these factors may account for their conflicting conclusions. Here we report that peri-operative blood transfusion is associated with an increased risk of AMR, but only in recipients with pre-transplant DSA detected using solid phase assays, all of whom had been previously

exposed to RBCT and other sensitising events. This effect of peri-operative transfusion was not found in recipients without DSA, suggesting that the combination of DSA and peri-operative blood transfusion may be particularly detrimental to the transplanted Rapamycin price graft. Importantly, adverse events after peri-operative blood transfusion included not only antibody mediated rejection, but also poorer long term graft outcome and recipient death, independent of the risk of AMR and Non-AMR, consistent with the findings of O’Brien et al. [28]. In light of our findings it is worth considering the immunological mechanisms whereby blood transfusion could increase the pathogenicity of pre-existing DSA. This might be through direct quantitative or qualitative alterations in antibody or indirectly via specific transfusion factors. Scornik et al. [16] have previously identified that re-exposure to blood in those with prior sensitising events such as transplant or pregnancy elicits a broad antibody response; findings that are consistent with our study.

A detailed description of the model construction and its modeling strategy for a long-term scale is introduced in Zhang et al. (2010). In this paper we introduce mainly the concepts of representative climate input conditions for the morphodynamic model and the methodology for generating representative climate input conditions.

The coastline changes of this area in the next 300 years, based on four different climate scenarios derived from different studies, are then projected by the model, through which the impacts of accelerated sea level rise and storm frequency on long-term coastline change are quantified. Simulation of the PI3 kinase pathway decadal-to-centennial morphological evolution of the Darss-Zingst peninsula is based on a multi-scale morphodynamic model consisting of 8 modules to calculate different physical processes that drive the evolution of the specific

coastal environment. The two-dimensional vertically integrated circulation module, the wave module, the bottom boundary layer module, the sediment transport module, the cliff erosion module and the nearshore storm module are real-time calculation modules that aim to solve short-term NU7441 cost processes. A bathymetry update module and a long-term control function set, in which the ‘reduction’ concepts and technique for morphological update acceleration are implemented, are integrated to up-scale the effects of short-term processes to a decadal-to-centennial scale. Boundary input conditions for a long-term (decadal-to-centennial) morphodynamic model such as time series of tides, winds, waves and mass flux cannot be specified at a centennial time span owing to the lack of measurements. On the other hand, even if detailed, measured Tau-protein kinase time series of boundary conditions were provided, it would be an extremely time-consuming job for a high-resolution process-based model to calculate the centennial-scale coastal evolution with the measured time series. This is because the time step of calculation in high-resolution process-based models is determined by the shortest time scale process, which usually

has to be solved on a time scale of seconds or minutes. Representative input conditions, which are generated by the statistical analysis of the measured time series, provide an effective way of solving the input problem for the long-term model. The generation of representative input conditions is based on the concept of ‘input reduction’ for long-term modelling (de Vriend et al. 1993a,b). The criterion for judging the validity of the representative input conditions is whether the simulation results based on the representative input conditions are the same as the reference data. As the effects of tides can be neglected in the southern Baltic Sea, only the time series of winds are needed for generating the representative input conditions.

, Beijing 100193, CHINA Fax/voice: 86-10-628-15937 E-mail: [email protected] Web: www.iwss.info/coming_events.asp 2013 INTERNATIONAL HERBICIDE RESISTANCE CONFERENCE 18–22 February RG 7204 Perth, AUSTRALIA S. Powles, AHRI, School of Plant Biol., Univ. of Western Australia, 35 Stirling Hwy., Crawley, Perth 6009, WA, AUSTRALIA Fax: 61-8-6488-7834 Voice: 61-8-6488-7870 E-mail: [email protected] AMERICAN PHYTOPATHOLOGICAL SOCIETY ANNUAL MEETING 10–14 August Providence, RI, USA Info: APS, 3340 Pilot Knob Rd., St. Paul, MN 55121, USAFax: 1-651-454-0755 Voice: 1-651-454-3848 E-mail: [email protected] Web: www.apsnet.org Full-size table Table options View in

workspace Download as CSV “
“Paulson AS, Cao HST, Tempero AZD9291 supplier MA, et al. Therapeutic advances in pancreatic cancer. Gastroenterology 2013;144:1316–1326. In the above article, in Table 1, the R0 resection rate data from Daouadi et al was transposed. Table 1 should reflect that in the Daouadi et al study, the R0 resection rate in laparoscopic distal pancreatectomy was 64% vs 100%

when robotic-assisted pancreatectomy was performed. “
“Lee WL, Hynan LS, Rossaro L, et al. Intravenous N-Acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009;137:856–864.e1 The study medication in the above paper was described as follows: “After randomization, infusion of either 5% dextrose (placebo) or 5% dextrose with N-acetylcysteine (Acetadote; Cumberland Pharmaceuticals, Nashville, TN) was begun, with an initial loading dose of 150 mg/kg/h of NAC over 1 hour, followed by 12.5 mg/kg/h for 4 hours, then continuous infusions of 6.25 mg/kg NAC for the remaining 67 hours. The published dosage of “continuous infusions of 6.25 mg/kg NAC for the remaining Sclareol 67 hours” was incorrect. The correct dosage is 6.25 mg/kg/hr for the remaining 67 hours. “
“Event Date and Venue Details from 2012 FUMIGANTS & PHEROMONES INTERNATIONAL CONFERENCE 16–18 May, 10th “Pest Management Around the World,” Indianapolis, IN, USA Info: http://tinyurl.com/86eprkw 64th INTERNATIONAL SYMPOSIUM ON CROP PROTECTION 22 May Ghent, BELGIUM

Info: B. Vandekerkhove, Fac. of Biosci., Ghent Univ., Coupure Links 653, BE-9000 Gent, BELGIUM Fax: 32-09-264-6223 Voice: 32-09-264-6145 E-mail: [email protected] Web: www.iscp.ugent.be ANNUAL ARTHROPOD GENOMICS SYMPOSIUM 31 May–02 June 6th Kansas City, MO, USA Info: D. Merrill E-mail: [email protected] Web: www.k-state.edu/agc INTERNATIONAL FUSARIUM LAB WORKSHOP 03–08 June Bari, ITALY Info: www.mycotox-society.org/fusarium-2012 VI INTERNATIONAL WEED SCIENCE CONGRESS 17–22 JuneDynamic Weeds, Diverse Solutions, Hangzhou CHINA H.J. Huang, IPP, CAAS, No. 2 West Yuanmingyuan Rd., Beijing 100193, CHINA Fax/voice: 86-10-628-15937 E-mail: [email protected] Web: www.iwss.info/coming_events.asp * 5th SUDDEN OAK DEATH SCIENCE SYMPOSIUM 19–21 June Petaluma, CA, USA K. Palmieri Voice: 1-510-847-5482Info: KPalmieri@berkeley.

0%, p = 0.02), the incidence of a high-grade restenosis ≥70% showed no significant buy Sotrastaurin difference between the two groups (3.3% vs. 2.8%). A clinical impact of an ISR on ipsilateral stroke or death during follow-up could not be observed. Advanced age was a clinical risk factor, which could be identified to be predictive for developing carotid restenosis [17]. To date, to the best of our knowledge, no data about rates of restenosis have yet been published by the other commonly known large randomized controlled studies

comparing CEA and CAS especially the International Carotid Stenting Study (ICSS) [31], the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) [4], and the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy study (SAPPHIRE) [11] and [32]. Within the analysed non-randomised trials, there was a wide range concerning the amount of treated patients. The smallest study included 100 patients [33]; the largest number of CAS patients was enrolled in the study of Setacci et al. (n = 814) [25]. In the vast majority, patients aged 60 years or over with roughly two-thirds male sex were included in the reviewed studies. The relevant data which were extracted are delineated in Table 1. The diagnostic tool used to detect an ISR was serial duplex ultrasound in all studies (n = 13).

A confirmatory diagnostic procedure such Selleckchem SP600125 as CTA or conventional angiography had been carried out after ultrasound in ten studies [19], [21], [22], [23], [24], [25], [26], [27], [29] and [30]. Notably, there was a wide variation concerning the ultrasound criteria applied for the detection of an ISR between the studies. As one of the main key features for the detection of a restenosis, a cut-off peak systolic

velocity is mentioned [19], [22], [24], [26], [28], [29] and [30] sometimes in addition to other criteria such as end-diastolic velocity or the ICA/CCA index [18], [20], [21], [23], [25] and [27]. Although the minority of the studies reported concise details about the exact time point of ISR occurrence, most ISR were found Progesterone to occur within the first year (median: 8 months, IQR: 7–9) after CAS [16], [18], [20], [21], [26], [29] and [30]. There was a broad range concerning the clinical complications for patients with ISR between 0% [21], [22], [24], [26] and [29] and 25% [30] for stroke and from 0% [19], [21], [22], [23], [25], [26] and [29] to 11.1% [18] for death, respectively. Common baseline characteristics like advanced age [19], female gender [19], prior revascularization treatment, [23], [25], [27], [34] and [35] the treatment of a radiogenic stenosis [23] or prior neck cancer [21] could be found to be predictive for ISR development. Furthermore, some cardiovascular risk factors such as smoking [17], lowered HDL cholesterol, [26] diabetes mellitus [22] or elevated HbA1c [18] and [36] could be identified as predictors for ISR, too.

Section 4 provides discussion, while Section 5 presents concluding remarks and policy recommendations. The model used is developed by Flaaten and Mjølhus [14] and [15], based on the logistic growth model. This section presents the parts necessary for the current analysis. Important characteristics

of this model are that it ensures the same growth and yield potential pre- and post-MPA (denoted model A in Flaaten and Mjølhus [14] and [15]). The pre-MPA population is assumed to grow logistically and growth is given by equation(1) Ṡ=rS(1−S)−Y,where S is population size normalized by setting the carrying capacity equal to unity. Patchiness and ecosystem issues are disregarded and the habitat of the resource is a homogenous area, also equal to unity.

The intrinsic growth rate is r and Y is the harvest, PARP inhibitor assuming that harvest can be described by the SGI-1776 solubility dmso Schaefer catch function, Y=rES, where E is fishing effort, scaled such that the catchability coefficient equals the intrinsic growth rate. 1 This harvest function will be used later (see the last expression in Eq. (3)), but using stock density in the fishing zone rather than the total stock density. Pre-MPA S represents both the population size and density in a population distribution area of unit size. With the introduction of a reserve and a harvest area below, the population density in the harvest zone enters the harvest function instead of the total population. The carrying capacity as well as the habitat area is, as noted above, equal to unity in this modeling approach. When an

MPA is established it means that a fraction of the carrying capacity and the habitat is set aside for protection from fishing and other activities that could harm natural growth. This fraction is denoted m and is the size of the MPA relative to the habitat area. Introduction of an MPA of size m, a harvest zone (HZ) of size 1−m and assuming density dependent migration between the two areas alters the dynamics to equation(2) Ṡ1=r[S1(1−S1−S2)−γ(S1m−S21−m)] equation(3) Ṡ2=r[S2(1−S1−S2)+γ(S1m−S21−m)−ES21−m].S1 denotes population in area 1, the MPA, S2 the population in area 2, the HZ, E fishing effort and γ=σ/r, where σ >0 is the migration coefficient. Thus Dehydratase γ, the relative migration rate is the ratio of the migration coefficient to the intrinsic growth rate. Note that the population density in the HZ, and not the total population density, now enters the harvest function as shown in the last term in Eq. (3). The sustainable yield in the case of an MPA is equation(4) Y(S1,S2)=r(S1+S2)(1−(S1+S2)).Y(S1,S2)=r(S1+S2)(1−(S1+S2)).Thus sustainable yield is determined by the total stock, benefiting from the spillover to the harvest zone from the MPA. Unit price of harvest and cost of effort is assumed2 to be constant and the profit can thus be described by equation(5) π=pY–C,where p is the price per unit harvest and C is the total cost. Two different price and cost functions are used.

, 2004, Grant et al., 2001 and Rippy et al., in press). Details of the HB06 FIB experiment are reported in Rippy et al. (in press). Briefly, FIB concentrations at Huntington Beach (which runs approximately north–south) were measured for 5 h on October

16th, 2006, at eight stations. Four of these stations spanned a 1000 m alongshore transect from the Santa Ana River, north. The remaining four stations were on a 300 m cross-shore transect starting at the northernmost alongshore station and terminating at an offshore mooring (Rippy BMN 673 concentration et al., in press, their Fig. 1). Water samples (100 ml) were collected at all stations, every 20 min, from 0650 to 1150 PDT. All samples were analyzed for Escherichia coli (IDEXX selleck inhibitor Colilert)

and Enterococcus (USEPA method 1600) concentrations by Orange County Sanitation District personnel. Acoustic Doppler Velocimeters (ADV’s) mounted on fixed tripod frames were used to measure currents along the shoreward-most 150 m of the cross-shore transect (Rippy et al., in press, their Fig. 1). These data were used to force alongshore currents in the 2D FIB models discussed below. Enterococcus species identification was performed to detect spatial patterns that could indicate the presence of multiple Enterococcus sources (potentially exhibiting differing mortality rates) in the nearshore. Species were identified at the Orange County Public Health Laboratory using presumptive Enterococcus colonies grown up from water samples on mEI agar plates. Three presumptive Enterococcus colonies were examined per plate when colony counts allowed, corresponding to three colonies per water sample. Initial colony

identification was performed using a Microscan Walk-Away 96 system containing Microscan Pos Combo Type 12 panels (Dade Bhering Inc., West Sacramento, CA). The type 12 panel contains 27 dried biochemical tests for the identification Phosphatidylinositol diacylglycerol-lyase of gram-positive bacteria. The software database for this system contains 42 gram-positive cocci, including seven species of Enterococcus. Additional biochemical tests were also used for identification purposes including carbohydrate fermentation in brain heart infusion broth with 1% sucrose (35 °C), a motility test using motility medium with Triphenyl Tetrazolium Chloride (30 °C), and a pigment production assay using Trypticase soy agar with 5% sheep’s blood (35 °C). Final identification was determined utilizing published standard biochemical identification charts ( Moore et al., 2008). Due to the retentive nature of the surfzone (Reniers et al., 2009), special attention was paid to cross-shore variability of Enterococcus species distributions. All identified Enterococcus isolates were classified based on their collection location as either “onshore” (SAR, TM, FHM, and F1) or “offshore” (stations ⩾ 50 m seaward of the surfzone: F5 and F7). Species composition onshore vs. offshore was compared using a Pearson chi-squared test.

Therefore, it was considered that the amount of accumulation of bisphosphonate within bone after each single intermittent dose was more than that obtained with continuous administration. It was considerable that the amount of risedronate accumulation is higher in the 75 mg once-monthly group than in the 2.5 mg once-daily group after each single 75 mg once-monthly group treatment. Therefore, each administration of risedronate 75 mg once-monthly, which has a larger accumulation Cabozantinib in bone, is possibly associated with more diffusion in bone than 2.5 mg once-daily administration. Therefore,

it may be possible that this difference of distribution in bone between daily and monthly risedronate administration causes the difference in the prevention of bone fracture, but further research is required to obtain more data. With regard to safety, the frequency of overall AEs, gastrointestinal AEs (which are typical AEs during bisphosphonate therapy), serious AEs, and the number of subjects for whom treatment was discontinued due to AEs, were comparable

in the two treatment groups. The frequency of AEs associated with gastrointestinal symptoms was similar between treatment groups. There was no notable difference in baseline demographics, complications, and medical history between subjects who GKT137831 had developed AEs associated with gastrointestinal symptoms and those who had not. AEs associated with gastrointestinal symptoms developed most frequently during the period from the

initial administration to Day 30; the frequency of new onset of gastrointestinal symptoms tended to decrease thereafter in each of the treatment groups (data not presented). One of the AEs, diarrhea, was remarkable as its frequency was higher in the 75 mg once-monthly group than in the 2.5 mg once-daily group. However, the number of subjects who discontinued due to diarrhea did not differ significantly between the two treatment groups (4 and 5 subjects in the 2.5 mg once-daily and 75 mg once-monthly groups, respectively) and its severity was mild or moderate. Influenza-like illness associated with Org 27569 both IV and oral bisphosphonates is transitory and self-limiting and usually does not recur after subsequent drug administration. This influenza-like illness is referred to as APR [28]. In the current study, AEs potentially associated with APRs only occurred in the 75 mg once-monthly group; the incidence was low, severity was mild or moderate, and these events were not considered to be clinically important. In the multinational (ex-Japan) phase III study, AEs potentially associated with APRs occurred at a similarly low rate as in our study; 1.4% (9/650) of subjects treated with risedronate 150 mg once-monthly and 0.2% (1/642) of subjects treated with 5 mg once-daily [7].