Intravenous dosing of tocilizumab in patients younger than two years of age with systemic juvenile idiopathic arthritis

The anti-interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years.Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period. The primary end point was comparability of pharmacokinetics during the main evaluation period to that of the previous trial (in patients aged 2-17 years), and the secondary end point was safety; pharmacodynamics and efficacy end points were exploratory. Descriptive comparisons for pharmacokinetics, pharmacodynamics, safety, and efficacy were made with sJIA patients aged 2 to 17 years weighing < 30 kg (n = 38) who received tocilizumab 12 mg/kg IV Q2W in the previous trial (control group).Eleven patients (mean age, 1.3 years) received tocilizumab during the main evaluation period. The primary end point was met: tocilizumab exposures for patients younger than 2 were within the range of the control group (mean [±SD] μg/mL concentration at the end-of-dosing interval [Cmin]: 39.8 [±14.3] vs 57.5 [±23.3]; maximum concentration [Cmax] postdose: 288 [±40.4] vs 245 [±57.2]). At week 12, pharmacodynamic measures were similar between patients younger than 2 and the control group; mean change from baseline in Juvenile Arthritis Disease Activity Score-71 was - 17.4 in patients younger than 2 and - 28.8 in the control group; rash was reported by 14.3 and 13.5% of patients, respectively. Safety was comparable except for the incidence of serious hypersensitivity reactions (27.3% in patients younger than 2 vs 2.6% in the control group).Tocilizumab 12 mg/kg IV Q2W provided pharmacokinetics, pharmacodynamics, and efficacy in sJIA patients younger than 2 comparable to those in patients aged 2 to 17 years. Safety was comparable except for a higher incidence of serious hypersensitivity events in patients younger than 2 years.Juvenile idiopathic arthritis.ClinicalTrials.gov, NCT01455701 . Registered, October 20, 2011, Date of enrollment of first participant: October 26, 2012

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings

Fetal ultrasound parameters: Reference values for a local perspective

Background: Fetal biometry, with the help of ultrasonography (USG) provides the most reliable and important information about fetal growth and well-being. Frequently used parameters for fetal measurements by this method are the biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). These fetal dimensions depend upon the racial demographic characteristics, nutrition, genetics and many more environmental factors of a particular population. Aims: The purpose of the present investigation was to define and analyze these fetal biometric parameters in our local population and to compare them with the given norms. Methods: This cross-sectional study with convenience sampling was conducted on a total of 425 fetuses with a period of gestation between 18 to 38 weeks. Descriptive statistics was used to calculate the mean with standard deviation and 95% confidence interval (CI) for each fetal parameter in each gestational week. Results: Mean of BPD and FL in our population are similar to the mean values given by Hadlock throughout the pregnancy, except near the end of the third trimester where our population shows a slightly lower range of mean values. HC and AC fall below the lower range of Hadlock as early as 24 weeks of pregnancy. Conclusions: Fetal biometric parameters in the studied population are at the lower range of established nomograms by Hadlock on white fetuses, more so with the progression of pregnancy

Expression analysis of γ-tocopherol methyl transferase genes and α-tocopherol content in developing seeds of soybean [<i>Glycine max</i> (L.) Merr.]

267-273Soybean, Glycine max (L.) Merr., besides being rich source of protein and oil, is a good source health promoting substances viz., isoflavones, anthocyanins and tocopherols, the latter are composed of four isoforms α-, β-, γ- and δ-tocopherols. Due to the potent antioxidant property and nutraceutical relevance of α-tocopherol, increasing its levels endogenously by modulating γ-tocopherol methyl transferase (γ-TMT) gene expression has gained significant attention in recent years. Despite having γ-tocopherol as the predominant form, its conversion into highly active α-tocopherol is the limiting step in soybean seeds; the step which is catalyzed by γ-tocopherol methyl transferase enzyme. Based on the differences in amino acid sequence at NH2-domain, the γ-TMT is classified as γ-TMT1, γ-TMT2 and γ-TMT3. Expression of these γ-TMT genes was studied in developing soybean seeds of two contrasting genotypes with respect to α-tocopherol content, namely Bragg (‘high’) and DS-2706 (‘low’). Among γ-TMT, significantly higher (P γ-TMT3 was observed in Bragg genotype than in DS-2706 at 50 days after flowering (DAF). A positive correlation was observed between γ-TMT3 gene expression and α-tocopherol accumulation (14 µg/g seed) in Bragg at 50 DAF than in DS-2706. The study may prove useful in greater understanding of temporal differences in the α-tocopherol accumulation and γ-TMT3 gene expression in seeds and the distinct roles of γ-TMT genes in soybean

Comparative Analysis of Tocopherol Biosynthesis Genes and Its Transcriptional Regulation in Soybean Seeds

Tocopherols composed of four isoforms (α, β, γ, and δ) and its biosynthesis comprises of three pathways: methylerythritol 4-phosphate (MEP), shikimate (SK) and tocopherol-core pathways regulated by 25 enzymes. To understand pathway regulatory mechanism at transcriptional level, gene expression profile of tocopherol-biosynthesis genes in two soybean genotypes was carried out, the results showed significantly differential expression of 5 genes: 1-deoxy-d-xylulose-5-P-reductoisomerase (DXR), geranyl geranyl reductase (GGDR) from MEP, arogenate dehydrogenase (TyrA), tyrosine aminotransferase (TAT) from SK and γ-tocopherol methyl transferase 3 (γ-TMT3) from tocopherol-core pathways. Expression data were further analyzed for total tocopherol (T-toc) and α-tocopherol (α-toc) content by coregulation network and gene clustering approaches, the results showed least and strong association of γ-TMT3/tocopherol cyclase (TC) and DXR/DXS, respectively, with gene clusters of tocopherol biosynthesis suggested the specific role of γ-TMT3/TC in determining tocopherol accumulation and intricacy of DXR/DXS genes in coordinating precursor pathways toward tocopherol biosynthesis in soybean seeds. Thus, the present study provides insight into the major role of these genes regulating the tocopherol synthesis in soybean seeds

Comparative Analysis of Tocopherol Biosynthesis Genes and Its Transcriptional Regulation in Soybean Seeds

Tocopherols composed of four isoforms (α, β, γ, and δ) and its biosynthesis comprises of three pathways: methylerythritol 4-phosphate (MEP), shikimate (SK) and tocopherol-core pathways regulated by 25 enzymes. To understand pathway regulatory mechanism at transcriptional level, gene expression profile of tocopherol-biosynthesis genes in two soybean genotypes was carried out, the results showed significantly differential expression of 5 genes: 1-deoxy-d-xylulose-5-P-reductoisomerase (DXR), geranyl geranyl reductase (GGDR) from MEP, arogenate dehydrogenase (TyrA), tyrosine aminotransferase (TAT) from SK and γ-tocopherol methyl transferase 3 (γ-TMT3) from tocopherol-core pathways. Expression data were further analyzed for total tocopherol (T-toc) and α-tocopherol (α-toc) content by coregulation network and gene clustering approaches, the results showed least and strong association of γ-TMT3/tocopherol cyclase (TC) and DXR/DXS, respectively, with gene clusters of tocopherol biosynthesis suggested the specific role of γ-TMT3/TC in determining tocopherol accumulation and intricacy of DXR/DXS genes in coordinating precursor pathways toward tocopherol biosynthesis in soybean seeds. Thus, the present study provides insight into the major role of these genes regulating the tocopherol synthesis in soybean seeds