Enhanced Bioavailability of Fenoterol Transdermal Systems in Rabbits

The pharmacokinetic and bioavailability of fenoterol, a B2 adrenergic agonist were studied to determine the feasibility of enhanced transdermal delivery. Fenoterol has been widely used to treat asthmatic patients. Two fenoterol formulations were studied; the first was a liquid formulation of fenoterol in Transcutol: Oleic acid in a ratio 1:1(F1), while the second was a matrix system of fenoterol in Duro-tak® 87-2074 adhesive with 10% 1-dodecyl-2-pyrrolidinone as an enhancer (F2). For comparison, control matrix with fenoterol without any enhancer (F3) was also tested. The tested formulations were applied to the shaved back skin of rabbits using HILL TOP CHAMBER® in case of liquid formula. Blood samples were collected via auricle central vein for 24 hours and the plasma concentrations of fenoterol were determined by LC-MS/MS method. Pharmacokinetic parameters were calculated using the WinNonlin computer program. The results showed a maximum concentration of fenoterol in plasma of 514.8 ng/ml after application of the liquid formula while its AUC0-∞ amounted to be 485972(ng*min/ml) with a dose of 3mg/kg. The transdermal matrix prepared with 10% 1-dodecyl-2-pyrollidinone had a Cmax of 219 ng/ml and AUC0-∞ was 124636 (ng*min/ml) which is significantly higher than that obtained after application of the control patch without any enhancer. Therefore, the transdermal systems will offer an efficient drug delivery system for the treatment of bronchial asthma

Does preincubational in ovo injection of buffers or antioxidants improve the quality and hatchability in long-term stored eggs?

peer reviewedA hypothesis was tested that providing buffer solutions or antioxidants during egg storage may help embryos in combating the harmful effect of longer holding periods. Hatching eggs were obtained from a breeder flock (35 wk) and stored for 13 d before setting. In experiment 1, the eggs were injected (d 4) with bicarbonate buffer solution (BBS) or PBS. For experiment 2, l-carnitine (LC), vitamin E (VE), and vitamin C (VC) were injected (d 7) at 3 different doses. The egg internal quality characteristics were evaluated at 2-d intervals after injection and the remaining eggs were incubated for 21 d under standard conditions. At 21 d, hatchability was recorded and unhatched eggs were broken open to assess the fertility and stage of embryonic mortality. No differences were noted in albumen pH due to using buffer solutions or antioxidants except for a decreased pH at 2 d postinjection of the high dose of VC (75 mg). In ovo injection of BBS increased the albumen index and Haugh unit at d 6 postinjection; however, the response to PBS was not different from that in the control group. In ovo injection of antioxidants did not influence the albumen index, Haugh unit, and yolk index; however, the yolk percentage was partly affected. Irrespective of the dosage, hatchability was greatly decreased following in ovo injection of buffers or antioxidants (as low as 4.3 vs. 87.5% in control), with the highest mortality percentage recorded at early embryonic stages (d 0 to 6). Data suggested that, despite improvement in certain egg internal qualities, preincubational in ovo injection of BBS, PBS, LC, VE, or VC was associated with a profoundly decreased hatchability for which the underlying mechanism(s) remain(s) to be clarified

Effects of Long-term Induced Hyperthyroidism on Egg Quality Traits in Cobb 500 Broiler Breeder Hens

Published data on 4-week-long administration of exogenous thyroxine in broiler breeder hens to decline the cold-induced ascites in their progeny suggest that the long-term maternal hyperthyroidism would affect egg quality characteristics traits in Cobb 500 broiler breeder hens. Seventy 47-w-old broiler breeder Cobb 500 hens (5 replicates and 7 hens each) were assigned in separate cages and allotted to two treatments, control and hyperthyroid. Thyroxine was orally administered to the hyperthyroid group (0.3 mg hen/day) for a period of 100 days consecutively. Simultaneously, distilled water was orally administered to the control group. The blood sampling was done every two weeks to analyze T3, T4, and estrogen assays, using commercially kits and the egg quality attributes were evaluated for weeks 0, 3, 6, 9, and 12. Thyroxine treatment resulted in an increase in plasma concentration of T4; however, the T3 level and estrogen were not affected. The results of this study showed that the long-term administration of thyroxine had adverse effect on the most of egg quality traits in broiler breeder hens; although the results may be distinct for treatments that using other birds, doses and duration of treatments, among the different egg quality traits of broiler breeder hens evaluated in this research. Therefore, further studies should be done to make a final conclusion to use of long-term maternal hyperthyroidism treatment to reduce the ascites incidence

Comprehensive detection of recurring genomic abnormalities : a targeted sequencing approach for multiple myeloma

Recent genomic research efforts in multiple myeloma have revealed clinically relevant molecular subgroups beyond conventional cytogenetic classifications. Implementing these advances in clinical trial design and in routine patient care requires a new generation of molecular diagnostic tools. Here, we present a custom capture next-generation sequencing (NGS) panel designed to identify rearrangements involving the IGH locus, arm level, and focal copy number aberrations, as well as frequently mutated genes in multiple myeloma in a single assay. We sequenced 154 patients with plasma cell disorders and performed a head-to-head comparison with the results from conventional clinical assays, i.e., fluorescent in situ hybridization (FISH) and single-nucleotide polymorphism (SNP) microarray. Our custom capture NGS panel had high sensitivity (>99%) and specificity (>99%) for detection of IGH translocations and relevant chromosomal gains and losses in multiple myeloma. In addition, the assay was able to capture novel genomic markers associated with poor outcome such as bi-allelic events involving TP53. In summary, we show that a multiple myeloma designed custom capture NGS panel can detect IGH translocations and CNAs with very high concordance in relation to FISH and SNP microarrays and importantly captures the most relevant and recurrent somatic mutations in multiple myeloma rendering this approach highly suitable for clinical application in the modern era

Detection of Echinococcus multilocularis in Carnivores in Razavi Khorasan Province, Iran Using Mitochondrial DNA

Echinococcus multilocularis causes alveolar echinococcosis, a serious zoonotic disease present in many areas of the world. The parasite is maintained in nature through a life cycle in which adult worms in the intestine of carnivores transmit infection to small mammals, predominantly rodents, via eggs in the feces. Humans may accidentally ingest eggs of E. multilocularis through contact with the definitive host or by direct ingestion of contaminated water or foods, causing development of a multivesicular cyst in the viscera, especially liver and lung. We found adult E. multilocularis in the intestine and/or eggs in feces of all wild carnivores examined and in some stray and domestic dogs in villages of Chenaran region, northeastern Iran. The life cycle of E. multilocularis is being maintained in this area by wild carnivores, and the local population and visitors are at risk of infection with alveolar echinococcosis. Intensive health initiatives for control of the parasite and diagnosis of this potentially fatal disease in humans, in this area of Iran, are needed

Predkliničke studije [61Cu]ATSM kao PET radiofarmaka za snimanje fibrosarkoma

[61Cu]diacetyl-bis(N4-methylthiosemicarbazone) ([61Cu]ATSM) was prepared using in house-made diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) ligand and [61Cu]CuCl2 produced via the natZn(p,x)61Cu (180 μA proton irradiation, 22 MeV, 3.2 h) and purified by a ion chromatography method. [61Cu]ATSM radiochemical purity was >98%, as shown by HPLC and RTLC methods. [61Cu]ATSM was administered into normal and tumor bearing rodents for up to 210 minutes, followed by biodistribution and co-incidence imaging studies. Significant tumor/non-tumor accumulation was observed either by animal sacrification or imaging. [61Cu]ATSM is a positron emission tomography (PET) radiotracer for tumor hypoxia imaging.[61Cu]diacetil-bis(N4-metiltiosemikarbazon) ([61Cu]ATSM) dobiven je iz liganda diacetil-bis(N4-metiltiosemikarbazona) (ATSM) pripravljenog u vlastitom laboratoriju i [61Cu]CuCl2 dobivenog iz natZn(p,x)61Cu (180 μA protonskim zračenjem, 22 MeV, 3.2 h). [61Cu]ATSM je čišćen ionskom kromatografijom. Prema HPLC i RTLC radiokemijska čistoća bila je > 98%. [61Cu]ATSM je davan zdravim glodavcima i glodavcima s tumorom tijekom 210 minuta te je praćena biodistribucija. Žrtvovanjem testiranih životinja te snimanjem primijećena je značajna razlika u akumulaciji [61Cu]ATSM u tumorskom tkivu u odnosu na zdravo tkivo. [61Cu]ATSM je pogodan za dijagnostiku hipoksije tumora pozitron emisijskom tomografijom (PET)

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine

Erratum: COMPARE CPM-RMI trial: Intramyocardial transplantation of autologous bone marrow-derived CD133+ cells and MNCs during CABG in patients with recent MI: A phase II/III, multicenter, placebo-controlled, randomized, double-blind clinical trial. (Cell Journal (2018) 20:3 (449) DOI: 10.22074/cellj.2018.5197)

This article published in Cell J (Yakhteh), Vol 20, No 2, Jul-Sep 2018, on pages 267-277, four affiliations (1, 4, 5, and 10) were changed based on authors request. © 2018 Royan Institute (ACECR). All rights reserved

COMPARE CPM-RMI Trial: Intramyocardial transplantation of autologous bone marrow-derived CD133+ Cells and MNCs during CABG in patients with recent MI: A Phase II/III, multicenter, placebo-controlled, randomized, double-blind clinical trial

Objective: The regenerative potential of bone marrow-derived mononuclear cells (MNCs) and CD133+ stem cells in the heart varies in terms of their pro-angiogenic effects. This phase II/III, multicenter and double-blind trial is designed to compare the functional effects of intramyocardial autologous transplantation of both cell types and placebo in patients with recent myocardial infarction (RMI) post-coronary artery bypass graft. Materials and Methods: This was a phase II/III, randomized, double-blind, placebo-controlled trial COMPARE CPM-RMI (CD133, Placebo, MNCs - recent myocardial infarction) conducted in accordance with the Declaration of Helsinki that assessed the safety and efficacy of CD133 and MNCs compared to placebo in patients with RMI. We randomly assigned 77 eligible RMI patients selected from 5 hospitals to receive CD133+ cells, MNC, or a placebo. Patients underwent gated single photon emission computed tomography assessments at 6 and 18 months post-intramyocardial transplantation. We tested the normally distributed efficacy outcomes with a mixed analysis of variance model that used the entire data set of baseline and between-group comparisons as well as within subject (time) and group�time interaction terms. Results: There were no related serious adverse events reported. The intramyocardial transplantation of both cell types increased left ventricular ejection fraction by 9 95% confidence intervals (CI): 2.14% to 15.78%, P=0.01 and improved decreased systolic wall thickening by -3.7 (95% CI: -7.07 to -0.42, P=0.03). The CD133 group showed significantly decreased non-viable segments by 75% (P=0.001) compared to the placebo and 60% (P=0.01) compared to the MNC group. We observed this improvement at both the 6- and 18-month time points. Conclusion: Intramyocardial injections of CD133+ cells or MNCs appeared to be safe and efficient with superiority of CD133+ cells for patients with RMI. Although the sample size precluded a definitive statement about clinical outcomes, these results have provided the basis for larger studies to confirm definitive evidence about the efficacy of these cell types (Registration Number: NCT01167751). © 2018 Royan Institute (ACECR). All Rights Reserved

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND: Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. METHODS: We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. FINDINGS: Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. INTERPRETATION: As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed