Herein, we investigated the plant-derived isoquinoline alkaloid b

Herein, we investigated the plant-derived isoquinoline alkaloid berberine, which has been reported to have anticancer activity, and synthetic 13-arylalkyl derivatives thereof for their effects

on Wnt/-catenin signaling. Berberine did not show major effects on viability of HEK-293 embryonic kidney and HCT116 colon carcinoma cells and was not toxic in concentrations up to 20 mu M. Berberine inhibited -catenin transcriptional activity and attenuated anchorage-independent growth. As a result of berberine treatment, cellular levels of active -catenin were reduced concomitant with an increase in the expression of E-cadherin. However, in unstimulated cells, the effects on -catenin levels were low. A screen of synthetic 13-arylalkyl berberine derivatives identified compounds exhibiting activities superior selleck products to those of the naturally occurring parent substance with more BAY 80-6946 chemical structure than 100-fold lower EC50 values for Wnt-repression. Thus, berberine and its synthetic derivatives represent potential therapeutic agents to inhibit Wnt/-catenin signaling in tumorigenesis. (c) 2013 BioFactors, 39(6):652-662, 2013″
“Here, we investigated the prevalence of headache among adults in Jordan. The study was conducted from January 2007 to November 2008. A sample of 4,836 participants were permitted to complete a self-conducted screening questionnaire. As much as 82.3% of participants complained from headache at least once per year. 36.1%

were tension-type headache and 59% of the participants had other family members who suffered from headache. Headaches affected everyday activities in 51.6% of the participants; 82.7% of participants did not seek medical attention for their headaches. Among those who used analgesics (75.6%), acetaminophen was the most common (91.43%). In conclusion, headache and overuse selleck chemicals llc of analgesics were prevalent in a significant part of the society. Thus, there is a need to educate the public to ensure safe practices and to make the use and selling of analgesics more stringent.”
“The aim of this study was to evaluate the quality of compounded capsules

of different drugs for chronic diseases. It were assessed two samples, from two different pharmacies, for each of the following drugs: ranitidine 150 mg, methyldopa 250 mg, enalapril maleate 20 mg, fluoxetine hydrochloride 20 mg, propranolol hydrochloride 40 mg, and furosemide 40 mg. The assays of mean weight, content determination, content uniformity and dissolution were performed according to Brazilian Pharmacopoeia. All samples were approved in the assay of mean weight, and the samples M1 and Flu1 had failed in the assay of content determination. In the test of uniformity of dosage units the samples M1, Flu1, E1, E2 and Flu2 had failed. Only the samples M2, P1, P2, F1 and F2 were accepted in all pharmacopoeial tests, evidencing that the others did not achieve the minimum requirements to ensure safety, quality and efficacy of the drugs.

Statistical analyses of release data performed by the


Statistical analyses of release data performed by the

analysis of variance (ANOVA) method indicated significant differences within experimental measurements. (C) 2010 Wiley Periodicals, Inc. J Appl Polym Sci 119: 1268-1274, 2011″
“Objective. Thalassemic patients present with multiple immune abnormalities that may predispose them to oral Candida, however this has not been investigated. The aim of this study was to assess oral candidal colonization in a group of patients with beta-thalassemia major both qualitatively and quantitatively.

Study design. The oral mycologic flora of Selleck Prexasertib 50 beta-thalassemia major patients and 50 age- and sex-matched control subjects was assessed using the concentrated oral rinse technique. Candida species Ulixertinib research buy were identified using the germ tube test and the Vitek yeast identification


Results. Oral Candida was isolated from 37 patients (74%) and 28 healthy subjects (56%; P = .04). The mean candidal count was significantly higher in thalassemic patients compared with the healthy group ( P < .05) and in patients who had surgical splenectomy compared with nonsplenectomized patients ( P = .04).

Conclusion. Oral Candida colonization and candidal counts are significantly higher in beta-thalseemia major patients than in healthy subjects. Surgical splenectomy may increase the quantity of colonizing oral candidal organisms in thalassemic patients. ( Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109: 252-256)”
“The enhancement of current density in inverted organic light emitting diodes is achieved by thermal annealing after device process. The current-voltage characteristics of annealed devices are improved as compared to that of nonannealed devices. The current improvement is attributed to the increase in electron injection efficiency from the inverted cathodes. X-ray and ultraviolet photoemission spectroscopy

were also carried out to investigate the origins of the enhancement. The result shows that the activation of doping effect of the inverted Alq(3) trilayers occurs after thermal annealing. However, the current density is still not compatible to that of normal devices with Alq3 trilayers as the cathode on the top. MCC950 purchase The reason is found to be related to the oxidation of aluminum cathodes, which are deposited first in the inverted devices. (C) 2010 American Institute of Physics. [doi: 10.1063/1.3512911]“
“In this study, a systematic investigation on the nonisothermal crystallization kinetics of conversional polypropylene (PP) containing various amounts of ultra-high molecular weight polyethylene (UHMWPE) was reported, and the effects of UHMWPE on crystallization behavior of these PP materials and their foaming properties were also presented. The kinetic studies revealed that the incorporation of UHMWPE into PP led to an increase in the crystallization temperature and temperature range during the crystallization process as well as the relative crystallinity.

“Clinical manifestations of flavivirus infection may be va

“Clinical manifestations of flavivirus infection may be various, from unapparent to severe meningoencephalitis. Our patient, 2 weeks after returning home from a holiday at Elba Island, developed biphasic fever, later associated with nausea and vomiting and followed by incoming seizures responsive to thiopental sodium only. Brain MRI showed bilateral hyperintensity (T2) in amygdale, hippocampus, left insular and temporal inferior cortex. Standard and microbiological CSF examination was normal, but microbiological serum analysis showed seroconversion for flavivirus. The patient came to our observation

6 months after disease onset and at that time he was affected by frequent seizures and severe cognitive impairment with behavioural disturbances; the patient also showed distal weakness with footstepping. EEG Selonsertib price showed bitemporal epileptic foci. During the following months, seizures greatly decreased and cognitive status improved in response to a complex antiepileptic therapy. Flavivirus encephalitis should selleckchem be taken into account in the differential diagnosis of encephalitis selectively involving temporal lobes.”
“Background: Humoral immune responses play a key role in the

development of immunity to malaria, but the host genetic factors that contribute to the naturally occurring immune responses to malarial antigens are not completely understood. The aim of the present investigation was to determine whether, in subjects exposed to malaria,

GM and KM allotypes-genetic markers of immunoglobulin gamma and kappa-type light chains, respectively-contribute to the magnitude of natural antibody responses to target antigens that are leading vaccine candidates for protection against Plasmodium vivax.

Methods: Sera from 210 adults, who had been exposed to malaria transmission in the Brazilian Amazon endemic area, were allotyped for several GM and KM determinants by a standard hemagglutination-inhibition method. IgG subclass antibodies to P. vivax apical membrane antigen 1 (PvAMA-1) and merozoite surface protein 1 (PvMSP1-19) were determined by an enzyme-linked GF120918 immunosorbent assay. Multiple linear regression models and the non-parametric Mann-Whitney test were used for data analyses.

Results: IgG1 antibody levels to both PvMSP1-19 and PvAMA-1 antigens were significantly higher (P = 0.004, P = 0.002, respectively) in subjects with the GM 3 23 5,13,14 phenotype than in those who lacked this phenotype.

Conclusions: Results presented here show that immunoglobulin GM allotypes contribute to the natural antibody responses to P. vivax malaria antigens. These findings have important implications for the effectiveness of vaccines containing PvAMA-1 or PvMSP1-19 antigens. They also shed light on the possible role of malaria as one of the evolutionary selective forces that may have contributed to the maintenance of the extensive polymorphism at the GM loci.

Following prochemerin secretion, protease-mediated generation of

Following prochemerin secretion, protease-mediated generation of chemerin isoforms with a range of biological

activities is a key regulatory mechanism controlling local, context-specific chemerin bioactivity. Together, experimental and clinical data indicate that localized and/or circulating chemerin expression and activation are elevated in numerous metabolic and inflammatory diseases including psoriasis, obesity, type 2 diabetes, metabolic syndrome and cardiovascular disease. These elevations are positively correlated with deleterious changes in glucose, lipid, and cytokine homeostasis, and may serve as a link between obesity, inflammation and other metabolic disorders. This review highlights the current state

of knowledge regarding chemerin expression, processing, PXD101 biological function and NCT-501 chemical structure relevance to human disease, particularly with respect to adipose tissue development, inflammation, glucose homeostasis and cardiovascular disease. Furthermore, it discusses study variability, deficiencies in current measurement, and questions concerning chemerin function in disease, with a special emphasis on techniques and tools used to properly assess chemerin biology. An integration of basic and clinical research is key to understanding how chemerin influences disease pathobiology, and whether modulation of chemerin levels and/or activity may serve as a potential method to prevent and treat metabolic diseases.”
“Background: Coagulopathy is present in 25% to 38% of trauma patients on arrival to the hospital, and these patients are four times more likely to die than trauma patients without coagulopathy. Recently, a high ratio of fresh frozen plasma (FFP) to packed red blood cells (PRBCs) has been shown to decrease mortality in massively transfused trauma patients. Therefore, we hypothesized that patients with elevated International Normalized Ratio (INR) on arrival to the hospital may benefit more from transfusion

with a high ratio of FFP:PRBC than those with a lower INR.

Methods: Retrospective multicenter cohort study of 437 massively transfused trauma patients was conducted to determine whether the effect of the ratio of FFP:PRBC on death at 24 hours is modified by a patient’s admission INR on arrival to the hospital. Contingency tables and logistic regression were used.

Results: Trauma patients who arrived to the hospital with an elevated INR had a greater risk of death than those with a lower INR. However, as the ratio of FFP:PRBC transfused increased, mortality decreased similarly between the INR quartiles.

Conclusions: The mortality benefit from a high FFP:PRBC ratio is similar for all massively transfused trauma patients. This is contrary to the current belief that only coagulopathic trauma patients benefit from a high FFP:PRBC ratio.

Participants completed three questionnaires (SF-12 (R) Health Sur

Participants completed three questionnaires (SF-12 (R) Health Survey, Brief Symptom Inventory and the Impact of Events Scale) before prophylactic surgery and again 1?year after surgery. Measures of health-related quality of life, of general psychological distress and of ovarian cancer worry before and after surgery were compared. Results Few women who underwent salpingo-oophorectomy experienced a worsening in physical or mental health functioning after salpingo-oophorectomy. On average, women experienced less ovarian cancer-specific worry after surgery; 34.3% experienced moderate to severe

ovarian cancer-specific distress before surgery, compared with 18.6% after surgery. Conclusions PHA-739358 solubility dmso For most women, physical and mental health-related quality of life did not deteriorate after prophylactic salpingo-oophorectomy, and they were less worried about ovarian cancer. A subset of women continued to experience moderate to severe cancer-specific distress. Identification of these women is important PF-04929113 clinical trial in order to provide continued counseling and support. Copyright (c) 2011 John Wiley & Sons, Ltd.”
“Study Design. Biomechanical study of vertebroplasty in cadaver motion segments.

Objectives. To determine how the volume of injected cement influences: (a) stress distributions on fractured and adjacent vertebral bodies, (b) load-sharing between the vertebral bodies and neural arch, and (c) cement leakage.


of Background Data. Vertebroplasty is increasingly used to treat vertebral fractures, but there are problems concerning adjacent level fracture and cement leakage, both of which may depend on the volume of injected cement.

Methods. Nineteen thoracolumbar motion segments from 13 cadavers (42-91 years) were loaded to induce fracture. Fractured vertebrae received 2 sequential injections (VP1 and

VP2) of selleck inhibitor 3.5 cm(3) of polymethylmethacrylate cement. Before and after each intervention, motion segment stiffness was measured in compression and in bending, and “”stress profilometry”" was used to quantify the distribution of compressive stress in the intervertebral disc (which presses equally on fractured and adjacent vertebrae). Stress profiles were obtained by pulling a pressure transducer through the disc while the motion segment was compressed in flexed and extended postures. Stress profiles yielded the intradiscal pressure (IDP), the magnitude of stress peaks in the anterior and posterior (SP(P)) anulus, and the percentage of the applied compressive force resisted by the neural arch (F(N)). Cement leakage and vertebral body volume were quantified using water-immersion, and the percentage cement fill was estimated.

Results. Bending and compressive stiffness fell by 37% and 50% respectively following fracture, and were restored only after VP2. Depending on posture, IDP fell by 59-85% after fracture whereas SP(P) increased by 107-362%.

001) and Childhood Trauma Questionnaire (P = 0 014) Only the dif

001) and Childhood Trauma Questionnaire (P = 0.014). Only the differences in scores on the Childhood Trauma Questionnaire subscales Emotional Neglect (P = 0.013) and Emotional Abuse (P = 0.014) reached statistical significance.

Dissociative phenomena and a reported history of childhood trauma are more common in patients with PNESD than in those with TLE. However, only emotional neglect and abuse were associated with PNESD in this study. (C) 2010 Elsevier Inc. All rights reserved.”
“Up Entrectinib mw to 50% of persons with HIV and a diagnosis of tuberculosis (TB) in Thailand die during TB treatment. In a prospective observational study, a team of physicians ascribed the cause of death after reviewing verbal autopsies (interviews of family members about events preceding death), laboratory data, and medical records. Of 849 HIV-infected TB patients enrolled, 142 (17%) died. The cause of death was TB for 38 (27%), including 6 with multidrug-resistant NSC-2260804 TB and 20 with disseminated TB; an HIV-associated condition other than TB for 50 (35%); and a condition unrelated to TB or HIV for 22 (15%). Twenty-three patients (16%) were judged not to have had TB at all. Death from all causes except those unrelated to TB or HIV

was less common in persons receiving antiretroviral therapy (ART). In addition to increasing the use of ART, death rates may be reduced through expanded use of modern TB diagnostic techniques.”
“Background: Real-time PCR is a sensitive and specific method for

the analysis of Plasmodium DNA. However, Omipalisib prior purification of genomic DNA from blood is necessary since PCR inhibitors and quenching of fluorophores from blood prevent efficient amplification and detection of PCR products.

Methods: Reagents designed to specifically overcome PCR inhibition and quenching of fluorescence were evaluated for real-time PCR amplification of Plasmodium DNA directly from blood. Whole blood from clinical samples and dried blood spots collected in the field in Colombia were tested.

Results: Amplification and fluorescence detection by real-time PCR were optimal with 40x SYBR (R) Green dye and 5% blood volume in the PCR reaction. Plasmodium DNA was detected directly from both whole blood and dried blood spots from clinical samples. The sensitivity and specificity ranged from 93-100% compared with PCR performed on purified Plasmodium DNA.

Conclusions: The methodology described facilitates high-throughput testing of blood samples collected in the field by fluorescence-based real-time PCR. This method can be applied to a broad range of clinical studies with the advantages of immediate sample testing, lower experimental costs and time-savings.”
“We describe 17 children with nocturnal or early-morning seizures who were switched to a proportionally higher evening dose of antiepileptic drugs and were retrospectively reviewed for seizure outcome and side effects.

g , superoxide radicals, singlet oxygen, hydroxyl radicals and pe

g., superoxide radicals, singlet oxygen, hydroxyl radicals and peroxynitrite] from the decomposition of hydrogen peroxide and their analytical applications. We discuss the advantages and the limitations of applying CL methods to routine analysis. (c) 2012 Elsevier Ltd. All rights reserved.”
“Two new insecticidal sesquiterpene esters with a -dihydroagarofuran sesquiterpene skeleton, ejaponine A (1) and ejaponine B (2), and two known compounds, 3 and 4, were 8-Bromo-cAMP price isolated from the EtOAc extract of the root bark of Euonymus japonicus Thunb. by bioassay-guided fractionation. Their chemical structures

were elucidated mainly by analysis of MS and NMR spectral data. The LD50 values of ejaponine A (1), ejaponine B (2), 3 and 4 showed against Mythimna separata were 89.2, 98.6, 181.4 and 109.2 mu g g-1, respectively.”
“To elucidate left ventricular function in pulmonary hypertension, we measured parameters of left ventricular as well as right ventricular function by echocardiography in 11 Fer-1 patients with pulmonary hypertension (idiopathic pulmonary artery hypertension in 4, chronic thromboembolic pulmonary hypertension in 5, and other pulmonary hypertension in 2). The percent change in these parameters

6 months after treatment with pulmonary artery vasodilators (beraprost in 8 and sildenafil in 3) was assessed. There was a correlation between the relative change in right ventricular systolic pressure (RVSP) and the relative changes in left ventricular outflow tract velocity-time integral (r = -0.730, P = 0.011) and mitral valve velocity-time integral (r = -0.621, P = 0.041). However, there was no correlation between the relative change in RVSP and the relative changes in left ventricular ejection selleck screening library fraction, left ventricular diastolic dimension, and systolic blood pressure. The relative change in RVSP was also correlated with the relative change in early diastolic myocardial velocity at the medial mitral annulus (r = -0.675, P = 0.023). Reduction of RVSP by pulmonary artery vasodilators might increase left ventricular preload, leading to an increase in stroke volume. Right ventricular load reduction might improve left

ventricular diastolic function in patients with pulmonary hypertension, possibly through altered interventricular septal performance.”
“In the literature, the enamelin gene ENAM has been repeatedly designated as a possible candidate for caries susceptibility. Here, we checked whether ENAM variants could increase caries susceptibility. To this aim, we sequenced coding exons and exon-intron boundaries of ENAM in 250 children with a severe caries phenotype and in 149 caries-free patients from 9 French hospital groups. In total, 23 single-nucleotide polymorphisms (SNPs) were found, but none appeared to be responsible for a direct change of ENAM function. Six SNPs had a high minor allele frequency (MAF) and 6 others were identified for the first time.

LYMs consist of a signal peptide, three consecutive LysMs, separa

LYMs consist of a signal peptide, three consecutive LysMs, separated by cysteine pairs, and a C-terminal region without see more any known signature, whose length allows the distinction between the two types, and which may be followed by a glycosylphosphatidylinositol (GPI) anchor

motif. We analyzed a representative of each type, MtLYM1 and MtLYM2, from Medicago truncatula at the biochemical level and with respect to their expression patterns and observed some similarities but also marked differences. MtLYM1 and MtLYM2 proved to be very different with regard to abundance and apparent molecular mass on SDS-PAGE. Both undergo several post-translational modifications, including N-glycosylation and the addition of a GPI anchor, which would position the proteins at the outer face of the plasma membrane. Only MtLYM2, but not MtLYM1, showed specific

binding to biotinylated N-acetylchitooctaose in a manner similar to CEBiP, which belongs to the same type. We postulate that LYM2-type proteins likely function in the perception of chitin-related molecules, whereas possible functions of LYM1-type proteins remain to be elucidated. (C) 2011 Elsevier Masson SAS. All rights reserved.”
“It has been known that C-13-labeling technique is quite useful in estimating the metabolic fluxes. Although check details the program-based flux analysis is powerful, it is not easy to be confident with the result obtained without experiences and exhaustive trial and errors based on statistical analysis for the confidence intervals in practice. It is, therefore, quite important to grasp the relationship between the fluxes and the C-13-labeled isotopomer distribution to get deeper insight into the metabolic flux analysis. In the present research, it was shown explicitly how the isotopomer distribution changes with respect to the fluxes in relation to the labeling patterns of the substrate, where either labeled glucose, acetate, or pyruvate was used as a

carbon source. Some of the analytical expressions were derived based on the matrix representation, and they were utilized Givinostat Cytoskeletal Signaling inhibitor for analysis. It was shown that the isotopomer pattern does not necessarily change uniformly with respect to fluxes, but changes in a complicated way in particular for the case of using pyruvate as a carbon source where some isotopomers do not necessarily change monotonically. It was shown to be quite important to grasp how the isotopomer pattern changes with respect to fluxes and the labeling pattern of the substrate for flux determination and the experimental design. It was also shown that the mixture of [1-C-13] acetate and [2-C-13] acetate should not be used from the information index point of view. Some of the experimental data were evaluated from the present approach. It was also shown that the isotopomer distribution is less sensitive to the bidirectional fluxes in the reversible pathway. (C) 2010 Elsevier B.V. All rights reserved.”
“Study Design.

0 degrees C +/- 2 degrees C before contouring followed by body te

0 degrees C +/- 2 degrees C before contouring followed by body temperature (37.2 degrees C +/- 2 degrees C). Each rod was 5 mm in diameter and 200 mm long. The rods were mounted over graph paper in fixed positions and photographed to measure displacement

of the tip as a function of the curvature.

Results. Statistically significant shape loss of the rods manufactured from all the tested materials was found. The hand contoured CPTi rods displayed considerably higher loss of curvature over time than Ti-6Al-4V and SS rods at all tested temperature conditions. Preliminary autoclaving at 135 degrees C before contouring tended to amplify this effect, in particular 1 cycle of autoclaving. If the number of preliminary autoclaving cycles was higher (5-10), a tendency of

decrease of shape loss effect was observed in Ti-6Al-4V and CPTi rods.

Conclusion. Ralimetinib concentration The shape of the hand contoured CPTi rods was the least stable of the rods across all applied temperature conditions. The SS and Ti-6Al-4V rods were more stable than CPTi rods. Autoclaving before handcontouring tended to increase rods’ shape loss.”
“Influenza can selleck chemicals llc be transmitted through respirable (small airborne particles), inspirable (intermediate size), direct-droplet-spray, and contact modes. How these modes are affected by features of the virus strain (infectivity, survivability, transferability, or shedding profiles), host population (behavior, susceptibility, or shedding profiles), and environment (host density, surface area to volume ratios, or host movement patterns) have only recently

come under investigation. A discrete-event, continuous-time, stochastic transmission model was constructed to analyze the environmental processes through which a virus passes from one person to another via different transmission modes, and explore which factors increase or decrease different modes of transmission. With the exception of the inspiratory route, each route on its own can cause high transmission in isolation Quisinostat of other modes. Mode-specific transmission was highly sensitive to parameter values. For example, droplet and respirable transmission usually required high host density, while the contact route had no such requirement. Depending on the specific context, one or more modes may be sufficient to cause high transmission, while in other contexts no transmission may result. Because of this, when making intervention decisions that involve blocking environmental pathways, generic recommendations applied indiscriminately may be ineffective; instead intervention choice should be contextualized, depending on the specific features of people, virus strain, or venue in question.

Our results support recent indications that antibodies binding to

Our results support recent indications that antibodies binding to the “”stalk”" GSK1838705A mouse region of hemagglutinin are found in the human population and exert evolutionary pressure on the virus.

Our computational approach provides a possible method for identifying antigenic escape through evolution in this region, which in some cases will not be identified by the hemagglutinin inhibition assay.”
“Rationale A variety of behavioral procedures have been developed to assess cannabinoid activity in mice; however, the feasibility of establishing Delta(9)-THC as a discriminative stimulus in mice has not been documented.

Objective One goal was to establish Delta(9)-THC as a discriminative stimulus in mice; after having done so, another goal was to examine the in vivo mechanism of action of Delta(9)-THC with other cannabinoids and noncannabinoids.

Materials and methods C57BL/6J mice (n=8) were trained to discriminate Delta(9)-THC (10 mg/kg i.p.) from vehicle while responding under a fixed ratio 30 schedule of food presentation.

Results Mice satisfied the discrimination criteria in 18-98 (median=67) sessions and the discriminative stimulus effects of Delta(9)-THC were dose-dependent (ED(50)=2.6 mg/kg). CP 55940 and WIN 55212-2 dose-dependently increased Delta(9)-THC-appropriate

responding to 100% (ED(50)=0.032 and R788 0.45 mg/kg, respectively), whereas methanandamide and a variety of noncannabinoids (cocaine, ethanol, and ketamine) produced a maximum of 34% Delta(9)-THC-appropriate responding. The cannabinoid CB(1) antagonist SR 141716A (rimonabant) surmountably antagonized the discriminative effects of Delta(9)-THC, next CP 55940, and WIN 55212-2; methanandamide did not significantly modify the Delta(9)-THC discriminative stimulus.

Conclusions The discriminative stimulus effects of Delta(9)-THC, CP 55940, and WIN 55212-2 are mediated by the same (i.e., CB(1)) receptors, whereas the effects of methanandamide or a metabolite of

methanandamide are mediated at least in part by non-CB(1) receptors. The discriminative stimulus effects of Delta(9)-THC in mice could be used to evaluate mechanisms of cannabinoid activity with approaches (e.g., inducible knockouts) currently unavailable in nonmurine species.”

Proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases, binds to low-density lipoprotein (LDL) receptors, leading to their accelerated degradation and to increased LDL cholesterol levels. We report three phase 1 studies of a monoclonal antibody to PCSK9 designated as REGN727/SAR236553 (REGN727).


In healthy volunteers, we performed two randomized, single ascending-dose studies of REGN727 administered either intravenously (40 subjects) or subcutaneously (32 subjects), as compared with placebo.