“
“Within the last years, a rapidly growing number

of polyphenolic compounds with neuroprotective effects have been described. Many efforts have been made to explore the mechanisms behind the neuroprotective action of polyphenols. However, many pathways see more and mechanisms considered for mediating these effects are rather general than specific. Moreover, despite the beneficial effects of polyphenols in experimental treatment of neurodegeneration, little has been achieved in bringing them into routine clinical applications. In this review, we have summarized the protective effects of polyphenols against neurodegeneration, and we have also discussed some of the barricades in translating these biochemical compounds, into relevant therapeutics for neurodegenerative diseases. (C) 2012 Elsevier B.V. All rights reserved.”
“ObjectiveWe sought to assess the disutility associated with diabetes in the kidney transplant population.\n\nMethodsWe enrolled 233 kidney transplant recipients age 18-74 from a Midwestern hospital outpatient department. Recipients with multiple or multi-organ transplants, those with laboratory evidence that suggests acute cellular damage (creatinine-kinase>200U/L), or a diagnosis of acute renal failure or acute rejection were excluded from the analysis (n=33). Participants health-related quality of life (HRQOL) were

evaluated using the Euro-QoL-5 Dimension (EQ-5D), Health Utility Index Mark III (HUI-III), and the Short Selleckchem Anlotinib Form-6D (SF-6D), which was calculated from the generic section (SF-12) of the Kidney Disease Quality of Life 36 (KDQOL-36). We estimated health utilities associated with diabetes using general linear modeling after adjusting for demographic,

socioeconomic, and clinical characteristics.\n\nResultsThe adjusted health disutilities associated with diabetes were clinically and statistically significant: EQ-5D (=0.05; p<0.01), HUI-III (=0.09; p<0.01), and SF-6D (=0.04, p<0.01). There was no difference between diabetic patients with good glycemic control (mean serum glucose <126mg/dL in the three months prior to enrollment) and patients AZD1480 research buy with poor glycemic control.\n\nConclusionsAmong kidney transplant patients between the ages of 18-74, non-diabetics have significantly higher HRQOL scores on the EQ-5D, HUI-III, and SF-6D compared with patients with diabetes.”
“Objective To investigate the attenuating effect of curcumin, an anti-inflammatory compound derived from dietary spice turmeric (Curcuma longa) on the pro-inflammatory insulin-resistant state in 3T3-L1 adipocytes. Methods Glucose uptake rate was determined with the [(3)H] 2-deoxyglucose uptake method. Expressions of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by quantitative RT-PCR analysis and ELISA. Nuclear transcription factor kappaB p65 (NF-kappa B p65) and mitogen-activated protein kinase (MAPKs) were detected by Western blot assay.

Results The focus selleck chemicals llc group participants classified good dying into 2 domains: a feeling of completion of the individual life and dying within the community. Reported barriers to palliative care provision were socio-economic consequences of being seriously ill, taboos on dying and being ill, restricted access to adequate medical-technical care, equation of religion with medicine, and the faulty implementation of palliative care policy by government.

The addition of telemedicine to Nigeria’s palliative care practice appears problematic, due to irregular bandwidth, poor network coverage, and unstable power supply obstructing interactivity and access to information. However, a tele-education ‘lite’ scenario seemed viable in Nigeria, wherein low-tech educational networks are central that build on non-synchronous online communication. Discussion Nigerian health care professionals’ concepts on good dying/a good death and barriers and opportunities for palliative care provision were, for the greater part, similar to prior findings from other studies in Africa. Information for and education of patient, family, and community are essential to further improve palliative care in Africa. Telemedicine can only BEZ235 inhibitor help if low-tech solutions are

applied that work around network coverage problems by focusing on non-synchronous online communication.”
“IL-10 is vastly studied for its anti-inflammatory properties on most immune cells. However, it has been reported that IL-10 activates B cells, up-regulates their MHC class II molecules and prevents apoptosis. As MARCH1 was shown to be responsible for the intracellular sequestration of MHC class II molecules in dendritic cells and monocytes in response to IL-10, we set out to clarify the role of this ubiquitin ligase in B cells. Here, we demonstrate in mice that splenic follicular B cells represent the

major cell population that up-regulate MHC II molecules in the presence of IL-10. Activation of these cells through TLR4, CD40 or the IL-10 receptor caused selleck kinase inhibitor the down-regulation of MARCH1 mRNA. Accordingly, B cells from MARCH1-deficient mice do not up-regulate I-A(b) in response to IL-10. In all, our results demonstrate that IL-10 can have opposite effects on MARCH1 regulation in different cell types. (C) 2012 Elsevier Ltd. All rights reserved.”
“Stenosis of the common bile duct may be either due to benign (chronic pancreatitis) or malignant (cholangiocarcinoma, pancreatic adenocarcinoma) conditions. The benign nature of the stricture should be first confirmed in order to ensure appropriate therapy. Therefore, the identification of markers allowing discrimination between malignant and benign biliary stenosis would be very valuable in clinical practice. To this intent, we performed a proteomic analysis of bile samples from patients having a biliary stenosis caused by pancreatic adenocarcinoma.

(C) 2011 Elsevier Ltd. All rights reserved.”
“Prospective trials comparing tandem autologous stem cell transplantation (ASCT) with ASCT followed by allogeneic stem cell transplantation (AlloSCT) have shown mixed results with regard to progression-free and overall survival rates. Thus, AlloSCT, although a potentially curative treatment, is not regarded as a standard treatment for multiple myeloma by most experts in the field. Strategies to improve the therapeutic index of the conditioning regimens have the potential to improve outcomes. Other approaches to modulate graft-versus-host disease while DNA Damage inhibitor preserving or improving a graft-versus-myeloma

effect could elevate AlloSCT to mainstream treatment. These approaches include vaccines, monoclonal antibodies, and adoptive Vorinostat immunotherapies.”
“Foot-and-mouth disease

(FMD) is a highly contagious disease affecting cloven-hoofed animals and causes severe economic loss and devastating effect on international trade of animal or animal products. Since FMD outbreaks have recently occurred in some Asian countries, it is important to understand the relationship between diverse immunogenomic structures of host animals and the immunity to foot-and-mouth disease virus (FMDV). We performed genome wide association study based on high-density bovine single nucleotide polymorphism (SNP) chip for identifying FMD resistant loci in Holstein cattle. Among 624532 SNP after quality control, we found that 11 SNPs on 3 chromosomes (chr17, 22, and 15) were significantly associated with the trait at the p.adjust smaller than 0.05 after PERMORY test. Most significantly associated SNPs were located on chromosome 17, around the genes Myosin XVIIIB and Seizure related 6 homolog (mouse)-like, which

were associated with lung cancer. Based on the known function of the genes nearby the significant SNPs, the FMD resistant animals might have ability to improve their innate immune response to FMDV infection.”
“Chara myosin is plant myosin responsible for cytoplasmic streaming and moves actin filaments at 60 mu m/s, which is the fastest of all myosins examined. The neck of the myosin molecule has usually mechanical and regulatory roles. The neck of Chara myosin is supposed to bind six light chains, but, at present, we have no knowledge about them. We found Ca++-calmodulin activated Chara myosin motility and its Z-DEVD-FMK datasheet actin-activated ATPase, and actually bound with the Chara myosin heavy chain, indicating calmodulin might be one of candidates for Chara myosin light chains. Antibody against essential light chain from Physarum myosin, and antibodies against Chara calmodulin and chicken myosin light chain from lens membranes reacted with 20 kDa. and 18 kDa polypeptides of Chara myosin preparation, respectively. Correspondingly, column purified Chara myosin had light chains of 20 kDa, and 18 kDa with the molar ratio of 0.7 and 2.5 to the heavy chain, respectively.

(c) 2011 Elsevier B.V. All rights reserved.”
“In magnetic nanoparticle hyperthermia for cancer treatment, controlling the heat distribution and temperature elevations is an immense challenge in clinical applications. In this study we evaluate magnetic nanofluid transport and heat distribution induced by commercially available

magnetic nanoparticles injected into the extracellular space of biological tissue using agarose gel with porous structures similar AZD1480 in vitro to human tissue. The nanofluid distribution in the gel is examined via digital images of the nanofluid spreading in the gel. A radio-frequency electromagnetic field is applied to the gel following the nanofluid injection and the initial rates of temperature rise at various locations are measured to obtain the specific absorption rate (SAR) distribution. By adjusting the gel concentration and injection flow rate, the results have demonstrated that a relatively low injection rate leads to a spherically shaped nanofluid distribution in the gels which is desirable for controlling temperature click here elevations. The SAR distribution shows that the nanoparticle distribution in the gel is not uniform with a high concentration of the nanoparticles close to the

injection site. We believe that the experimental study is the first step towards providing guidance for designing better treatment selleck compound protocol for future clinical applications.”
“The genus Capripoxvirus within the family Poxviridae comprises three closely

related viruses, namely goat pox, sheep pox and lumpy skin disease viruses. This nomenclature is based on the animal species from which the virus was first isolated, respectively, goat, sheep and cattle. Since capripoxviruses are serologically identical, their specific identification relies exclusively on the use of molecular tools. We describe here the suitability of the G-protein-coupled chemokine receptor (GPCR) gene for use in host-range grouping of capripoxviruses. The analysis of 58 capripoxviruses showed three tight genetic clusters consisting of goat pox, sheep pox and lumpy skin disease viruses. However, a few discrepancies exist with the classical virus-host origin nomenclature: a virus isolated from sheep is grouped in the goat poxvirus; clade and vice versa. Intra-group diversity was further observed for the goat pox and lumpy skin disease virus isolates. Despite the presence of nine vaccine strains, no genetic determinants of virulence were identified on the GPCR gene. For sheep poxviruses, the addition or deletion of 21 nucleic acids (7 aa) was consistently observed in the 5′ terminal part of the gene. Specific signatures for each cluster were also identified.

MMP-9, but not MMP-2 activity was detected in AMCM. AMCM-induced tubular cell EMT in C1.1 cells was inhibited selleckchem by broad-spectrum MMP inhibitor (GM6001), MMP-2/9 inhibitor, and in AMCM after MMP-9 removal by monoclonal Ab against MMP-9. AMCM-induced EMT in primary tubular epithelial cells was inhibited by MMP-2/9 inhibitor. MMP-9 induced tubular cell EMT in both C1.1 cells and primary tubular epithelial cells. Furthermore, MMP-9 induced tubular cell EMT in C1.1 cells to an extent similar to transforming growth factor-beta. Transforming growth factor-beta-induced tubular cell EMT in C1.1 cells was inhibited by MMP-2/9 inhibitor. Our in vitro study provides evidence that MMPs, specifically

MMP-9, secreted by effector macrophages can induce tubular cell EMT and thereby contribute to renal fibrosis. (Am J Pathol 2010,176:1256-1270; DOI: 10.2353/ajpath.2010.090188)”
“Background: Japanese encephalitis (JE) caused by Japanese encephalitis virus (JEV) accounts for acute illness and death. However, few studies https://www.selleckchem.com/products/R406.html have been conducted to unveil the potential pathogenesis mechanism of JEV. Dendritic cells (DCs) are the most

prominent antigen-presenting cells (APCs) which induce dual humoral and cellular responses. Thus, the investigation of the interaction between JEV and DCs may be helpful for resolving the mechanism of viral escape from immune surveillance and JE pathogenesis.\n\nResults: We examined the alterations of phenotype and function

of DCs including bone marrow-derived THZ1 cell line DCs (bmDCs) in vitro and spleen-derived DCs (spDCs) in vivo due to JEV P3 wild strain infection. Our results showed that JEV P3 infected DCs in vitro and in vivo. The viral infection inhibited the expression of cell maturation surface markers (CD40, CD80 and CD83) and MHC., and impaired the ability of P3-infected DCs for activating allogeneic naive T cells. In addition, P3 infection suppressed the expression of interferon (IFN)-alpha and tumor necrosis factor (TNF)-alpha but enhanced the production of chemokine (C-C motif) ligand 2 (CCL2) and interleukin (IL)-10 of DCs. The infected DCs expanded the population of CD4+ Foxp3+ regulatory T cell (Treg).\n\nConclusion: JEV P3 infection of DCs impaired cell maturation and T cell activation, modulated cytokine productions and expanded regulatory T cells, suggesting a possible mechanism of JE development.”
“Renal hemosiderosis is a rare cause of renal failure and, as a result, may not be diagnosed unless a detailed history, careful interpretation of blood parameters and renal biopsy with special staining is done. Here, we present a rare case of renal hemosiderosis presenting with renal failure.”
“We have evaluated the effect of bracing in scoliosis on coronal alignment in a cohort of patients. Current literature has not described the specific effect of bracing on the 3D shape of the scoliotic curves.

(C) 2014 Elsevier Inc. All rights reserved.”
“A consensus nested PCR was used to screen diagnostic samples from approximately 70 reptiles for the presence of adenoviruses (AdV) in the years 2006-2007. Classical virus isolation methods were also used with all samples. After adenoviruses were detected in a group of helodermatid lizards

in a Danish zoo, a follow-up study was also carried out on lizards from this group (10 Mexican beaded lizards and 24 Gila monsters) over the period of a year. Adenoviruses were detected LB-100 in a total of 26 lizards and snakes by PCR. The PCR amplicons from all positive animals were sequenced and the resulting polymerase gene sequences were used for phylogenetic analysis. Altogether six Agamid AdVs were amplified, with a minimal sequence variation between one another and between these and GenBank Agamid AdVs. The sequence obtained from one of the Gila monsters is identical with the GenBank Helodermatid AdV, while the sequences from

the Mexican beaded lizards differ from this. In a snake collection we have detected a new AdV from an Asp viper. All of the above mentioned adenoviruses Cluster in the Atadenovirus genus. However, the sequence Selleck Tozasertib from a new Varanid AdV detected in this study clusters; outside this genus. On cell culture, viruses were isolated from three of the AdV positive helodermatid lizards (one Mexican beaded lizard and two Gila monsters)and identified as AdVs based on electron microscopy and PCR and sequencing using cell culture supernatant. This is the first report of the successful isolation of a lizard AdV. (C) 2008 Elsevier B.V. All rights reserved.”
“P>Background:\n\nThe current management of thyroid lymphomas (TL) includes the combined use of chemotherapy and radiotherapy, with surgery mainly

confined to diagnosis through an open biopsy following ultrasound-guided fine-needle aspiration cytology (US-FNAC).\n\nAims:\n\nTo analyse the clinical presentation and methods of diagnosis of TL, its Selleck MK2206 pitfalls and the management of these tumours presenting with compression symptoms and airway obstruction.\n\nMethods:\n\nA retrospective review of nine patients diagnosed with TL at Guy’s and St Thomas Hospital NHS Foundation Trust in London over the past 5 years.\n\nResults:\n\nNine consecutive patients were identified with the diagnosis of TL, and seven (78%) of them being women and with a mean age of 65 years. All patients presented with an anterior neck mass while four (44.4%) presented with stridor and vocal cord palsy. Two (22.2%) presented with a hoarse voice, dysphagia, and only one patient had a B symptom of weight loss. FNAC was diagnostic in three patients (33.3%) and a report of multi-nodular goitre in one patient. There was clinical suspicion of TL in three patients (33.3%).

Pharmacophores are associated with binding sites of proteins and characterize the arrangement of chemical and physical features that govern the modes of interactions of different ligands within the binding sites. Methods designed to infer pharmacophores computationally have been successfully applied in drug discovery pipelines.

Virtual high-throughput screening (HTS), lead optimization, PP2 research buy and de novo drug design are just a few areas in which pharmacophores are actively used. This review surveys different computational methods to elucidate pharmacophores and discuss their utilization in drug discovery applications. Drug Dev Res 72: 17-25, 2011. (C) 2010 Wiley-Liss, Inc.”
“Preterm birth (PTB), defined as any birth occurring before 37 weeks of gestation, occurs in only 12% of all births, yet accounts for nearly half of long-term neurological morbidity, and 60%-80% of perinatal mortality. The single most common cause of PTB is intrauterine infection. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is both upregulated by

inflammatory cytokines and capable of increasing myometrial smooth muscle tone. We hypothesized, therefore, that ET-1 is a critical component of the parturition cascade in the setting of infection-associated Panobinostat inhibitor PTB. In our previous work, we have shown that blockade of ET-I synthesis through the use of the metalloproteinase inhibitor phosphoramidon results in control of preterm labor. In the current work, we showed that blockade of ET-I action with 5-50 mg/kg i.p. 3-(3-carboxybenzyl)-1-((6-ethylbenzo[d][1,3]dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (HJP272), a putative novel selective ETA-receptor antagonist (IC50, 70 nmol/L), prevents PTB induced with selleck screening library up to 50 mg/kg of i.p. lipopolysaccharide in a mouse model. This is the first report, to our knowledge, of control of infection-associated PTB with a specific ETA-receptor antagonist. The identification of a novel effective therapy for PTB could have important clinical implications.”
“PURPOSE. To assess the effects

of intravitreal bevacizumab injections in the treatment of subfoveal choroidal neovascularization (CNV) associated with pattern dystrophy (PD) of the retinal pigment epithelium.\n\nMETHODS. The study was a prospective, nonrandomized, openlabel, interventional clinical trial in which 12 patients were prospectively enrolled. Patients with a diagnosis of PD complicated by subfoveal CNV were considered for the study. All patients underwent a complete ophthalmic examination, including ETDRS visual acuity measurement, electroretinogram, electrooculogram, optical coherence tomography, and fluorescein angiography. The treatment protocol began with a loading dose of three consecutive injections at 1-month intervals, followed by injections administered as needed, according to OCT parameters and angiographic features observed during a 24-month follow-up period.

Conclusions: Few studies on menopause have been conducted in HIV-infected buy Navitoclax women compared with HIV-uninfected women. Many questions regarding age of menopause onset, frequency of menopausal

symptoms and associated complications such as bone disease and cardiovascular disease, and efficacy of treatment among HIV-infected women remain. The incidence and severity of some of these factors may be increased in the setting of HIV and cART.”
“The establishment of biocontrol agents is critical for success of biological control strategies. Predator-in-First (PIF) is a prophylactic control strategy that aims to establish predators before the appearance of pests in an agro-ecosystem. PIF uses the ability

of generalist phytoseiid mites to survive, develop and reproduce on pollen and thus establish in the absence of prey. The early establishment of populations of natural enemies helps control the pests at their incipient stage of infestation. The current study was undertaken to screen pepper cultivars for their ability to support populations of the predatory mite Amblyseius Selleck SHP099 swirskii Athias-Henriot in the absence of prey. Twenty-nine pepper cultivars (11 hot and 18 sweet) were tested through a series of experiments, and four cultivars (7141, 992-7141, FPP7039 and FPP9048) were found to sustain A. swirskii populations throughout the study period. The initial application of pollen was important for establishment and maintenance of the predatory mites within the greenhouse system. Among the three screening experiments, high densities of mites were obtained in the experiment where 20 mites were released per plant,

even reaching densities of [100 mites/plant. Recovery of predatory mites was significantly higher (ca. 2-3 fold) on the four pepper cultivars when predatory mites www.selleckchem.com/products/baricitinib-ly3009104.html were mass released using an indirect method (banker plants) than when they were released directly on the seedlings, suggesting an advantage of passive continuous release. Future work will evaluate the selected pepper cultivars with the PIF strategy under greenhouse and field production conditions.”
“A simple and rapid isocratic high-performance liquid chromatographic (HPLC) method has been developed for the determination of seven alpha-keto acids, glyoxylic acid, pyruvic acid, 2-oxobutyric acid, 3-methyl-2-oxobutyric acid, 2-oxoglutaric acid, 2-oxohexanoic acid, and phenylpyruvic acid using meso silbenediamine as derivatizing reagent in the blood samples. The chromatographic separation was achieved with methanol-water-acetonitrile-tetrahydrofuran (38.4:60:1:0.6, v/v/v/v) as the mobile phase, a C18 column, and UV detection at 255 nm. Linear calibration curves were obtained with 0.2 to 100 mu g/mL. The limits of detection and quantitation were obtained within the range 0.07-0.2 mu g/mL and 0.21-0.6 mu g/mL, respectively.

The results demonstrate that BRUV was more efficient at surveying the entire fish community, specifically invertebrate carnivores, generalist carnivores and cartilaginous species. On the other hand, RUV was more effective at surveying microinvertebrate carnivores. High variability CDK inhibitors in clinical trials in the RUV data resulted in the method requiring a greater number of samples to achieve the same diagnostic power as BRUV. However, RUV required a shorter deployment and post-sampling video analysis time, making it more time efficient. Baited remote underwater video was more sensitive in the detection of differences in abundance between habitat

types, while the RUV data were more prone to an intra-species methodological bias linked to the percentage of reef visible in the frame of view. The scale of the response to the presence of bait was inconsistent among species, indicating that behaviour determined the area selleck surveyed within the bait plume of BRUV. The benefits gained by sampling the fish community with RUV do not outweigh those obtained by altering the community through the presence of bait. However, in combination, the 2 methods are highly effective at monitoring the

subtidal fish communities in the Agulhas bioregion of South Africa.”
“BACKGROUND: Invasive pancreatic carcinoma generally appears as poorly defined mass reflecting the infiltrative growth. We aimed to identify the histological and immunohistochemical features in a rare case of pancreatic carcinoma showing exophytic growth.\n\nMETHODS: A 67-year-old woman presented with a mass of 5.0 cm in diameter in the pancreatic head. Preoperative computed tomography revealed a well-demarcated, primarily solid mass with a central low-density area. Magnetic resonance cholangiopancreatography revealed neither encasement nor dilation of the main

pancreatic check details duct. An incorrect preoperative diagnosis was made of solid pseudopapillary tumor of the pancreas. Elevated serum carcinoembryonic antigen (CEA) levels and abnormal FDG positron emmission tomography accumulation suggested that the tumor had malignant potential requiring a pancreatoduodenectomy.\n\nRESULTS: The head of the pancreas contained a well-circumscribed encapsulated mass of 5.0 cm in diameter, comprising 50% adenocarcinoma, with mucinous carcinoma in the center and anaplastic carcinoma at the periphery. The anaplastic carcinoma comprised pleomorphic cells (PCs) and pleomorphic giant cells (PGCs). The PGCs phagocytozed mononuclear PCs and lymphocytes adjacent to the capsule without infiltrating the capsule itself. Immunohistochemistry revealed that the anaplastic carcinoma cells including PGCs were positive for the tumor antigen Mucin 1 and CEA but negative for vimentin.

In such a system, the excited dye chromophore is reduced by different tetraorganylborate anions. Upon irradiation at 488 nm, reductive carbonboron bond cleavage occurs, producing reactive radicals, which start the chain reaction. The efficiency of bond-breaking processes was found to be dependent on the nature of both the acceptors and the donors. The experimental results show that the photoinitiating ability of the

tested photoredox pairs were controlled by both the driving force of the electron-transfer process between the electron donor and BAY 73-4506 the electron acceptor and the reactivity of the free radical that resulted from the secondary reactions occurring after the photoinduced electron-transfer Vorinostat inhibitor process. Using the nanosecond flash photolysis method, we studied the spectral and kinetic characteristics of the triplet state of cyanine dye and determined the rate constants of the triplet quenching by phenyltrialkylborate salts. The results obtained show that the tetramethylammonium phenyl-tri-n-butylborate (TB7) has a faster electron-transfer rate than the tetramethylammonium n-butyltriphenylborate (TB2) salt, which bore only one

butyl group attached to the boron. The relative initiator efficiency of the triphenylbutylborate salts, as compared to the corresponding phenyltrialkylborate salts with a common chromophore, was determined. (C) 2011 Wiley Periodicals, Inc. J Appl Polym Sci 123: 3535-3544, 2012″
“The relationship between target volume and adverse radiation effects (AREs) at low prescription doses requires elucidation. The development of AREs in three series of patients treated in the Gamma Knife is analysed in relation to prescription dose and target volume.

There were three groups. In group 1, there were of 275 patients with meningiomas; in group 2, 132 patients with vestibular schwannomas; and in group 3, 107 patients with arteriovenous malformations (AVMs). The minimum follow-up

for each group was more than 24 months. All patients were followed up at six monthly intervals. The selleck compound patients with tumours received a prescription dose of 12 Gy, which was varied to protect normal structures but not in relation to tumour volume per se. The desired AVM prescription dose was 25 Gy, but this was also reduced to protect normal structures and to keep the total dose within certain pre-defined limits. All AREs refer to intra-parenchymal increased perilesional T2 signal on MR irrespective of clinical correlation.

There was no relationship between tumour volume and the development of ARE in the tumour groups. There was a highly significant relationship between target volume and the development of ARE for the AVMs with their much higher dose.