Characterization of agonist-induced motilin receptor trafficking and its implications for tachyphylaxis

The motilin receptor (MR) is a member of the seven-transmembrane receptor family and is expressed throughout the gastrointestinal tract of humans and other species. Motilin, the natural MR peptide ligand, has profound stimulatory effects on gastrointestinal contractility, indicating a therapeutic potential for MR modulators. However, long-term clinical use of certain MR agonists is limited by tachyphylaxis, a reduced responsiveness to repeated compound exposure. This study was meant to characterize the ligand-induced endocytosis of MR and to test whether receptor trafficking contributes to tachyphylaxis. A cell-based assay was developed by fusing a green fluorescent protein (GFP) moiety to the motilin receptor, and high-content biology instrumentation was used to quantify time and dose dependence of MR-GFP endocytosis. Maximal internalization of MR-GFP was induced after 45 min of constant exposure to 80 nM motilin. This process was disrupted by nocodazole, suggesting an essential role for microtubules. Internalized MR-GFP vesicles disappeared within 15 to 45 min of motilin withdrawal but did not overlap with the lysosomal compartment, indicating that MR-GFP escaped degradation and was recycled back to the plasma membrane. It is noteworthy that the kinetics of MR-GFP redistribution varied substantially when stimulated with motilin, erythromycin, 6,9-hemiacetal 8,9-anhydro-4'-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B (ABT-229), or N-[(1S)-1-[[[(1S)-1-(aminocarbonyl)-3-phenylpropyl]amino]carbonyl]-3-phenylpropyl]-2'-(1,3-benzodioxol-5-ylmethyl)tetrahydro-1',3'-dioxo-spiro[piperidine-4,5'(6'H)-[1H][1,2,4]triazolo[1,2-a]pyridazine]-8'-carboxamide (BMS-591348) at equipotent doses for Ca(2+)-mobilization. Retardation of the intracellular MR-GFP sorting cycle seemed to correlate with the tachyphylaxis-inducing properties of each compound, but not its EC(50). These results indicate that MR internalization, desensitization, and resensitization are ligand-dependent and that appropriate screening strategies may enable the development of small molecule agonists with ideal combinations of these distinct properties.     

Familial breast cancer registry program in patients referred to the cancer institute of Iran

Introduction: Annually a considerable number of people die because of breast cancer, a common diseaseamong women also in Iran. Identifying risk factors and susceptible people can lead to prevention or at leastearly diagnosis. Among susceptibility risks, 5-10% of patients have a family history predisposing factor whichcan influence the risk of incidence among the family. Having a registry program can be a more practical wayto screen high risk families for preventive planning. Method: Based on inclusion criteria, a questionnaire wasprepared and after a pilot study on a small number of patients, actual data were collected on 400 patients andprocessed in SPSS 16.0. Results: Totally, 28.2%of the patients were younger than 40 years old and 36.8% hadthe included criteria for familial breast cancer (FBC). 102 patient’s samples could be compared for receptorpresentation. Similar to other studies, the number of triple negative breast cancers increased as the age decreased.Conclusion: The high percentage of patients with FBC among 400 cases in this study demonstrates that in orderto design an infrastructural diagnostic protocol and screening of patients with FBC, a precise survey related tofrequency and founder mutations of FBC is needed nationwide.     

Application of asymmetric Sharpless aminohydroxylation in total synthesis of natural products and some synthetic complex bio-active molecules

This report illustrates the applications of Asymmetric Sharpless Aminohydroxylation (ASAH) in the stereoselective synthesis of vicinal amino alcohols as important intermediates in the total synthesis of complex molecules and natural products with significant biological activities. The ASHA allows the regio- syn-selective synthesis of 1,2-amino alcohols via reaction of alkenes with salts of N-halosulfonamides, -amides and -carbamates employing osmium tetroxide (OsO₄) as an efficient catalyst. In this reaction, chirality is induced via the addition of dihydroquinine- and dihydroquinidine as derived chiral ligands.

This work shows applications of Asymmetric Sharpless Aminohydroxylation (ASAH) in the stereoselective synthesis of vicinal amino alcohols as important intermediates in the total synthesis of complex molecules and natural products with significant biological activities.     

Visceral leishmaniasis among children in an endemic area of northwestern Iran between 2016 and 2017: An epidemiological study

Objective: To clarify the epidemiological aspects of visceral leishmaniasis in Kaleybar and Khoda-Afarin districts, north-west of Iran.Methods: A total of 1 420 human(children under 12 years) samples, 101 domestic dogs samples(Canis familiaris), and 577 female sand fly samples were collected. Sera of human and dogs were tested using the direct agglutination test, and sand flies were identified at species level using the microscopic method. Furthermore, a structured questionnaire was applied to evaluate the correlation between the potential risk factors and the related clinical signs/symptoms with the human and dogs' seropositivity.Results: Totally, 2.18% of human samples were positive at titers≥1: 800; among them, 13 cases(41.94%) were above 1:3 200, and clinical symptoms were observed in all of them except for an 11-year old girl. Anti-Leishmania infantum antibodies were found at titer≥1: 320 in 9.90% of dogs' samples, half of them had at least one sign of canine visceral leishmaniasis. Moreover, 10 Phlebotomus species were identified in the study areas, and Phlebotomus(Larroussius) major group was the predominant species. There are significant correlations between the presence of anti-Leishmania infantum antibodies and the fever(P0.001), anemia(P=0.001) and weight loss(P=0.016) in children. On the other hand, significant correlations were revealed between the Leishmania infection and the shelter(P=0.039), cutaneous lesion(P=0.005), lymphadenopathy(P=0.001) and weight loss(P0.001) in the infected dogs.Conclusions: Visceral Leishmania infection is prevalent in rural areas of Kaleybar and KhodaAfar districts located in East-Azerbaijan province, therefore active detection and treatment of visceral leishmaniasis cases should not be neglected.     

Three horizontal muscle surgery for large-angle esotropia: success rate and dose-effect ratio

Non-simulator-based examination methods of the fundal examination have shown to be cost-effective. We reviewed different non-simulator-based direct fundoscopy examination methods used in undergraduate curricula and their outcomes. PubMed (MEDLINE) and Cochrane Database of Systematic Reviews were searched using standard Medical Subject Heading (MeSH) terms ophthalmoscopy, medical education, undergraduate medical education, medical student, educational assessment and learning. The search included publications until 28th February 2019. We obtained 34 articles after screening abstracts; of them, 12 articles were included in the qualitative synthesis. The studies were comprised of diverse teaching methods which included fundal photograph matching with corresponding eye, continuous education using community-based eye clinics, formal instructions and demonstrations prior to skills training, ophthalmoscopy skills practice using eye pathologies, teaching versus conventional ophthalmoscopy and group-based teaching. We concluded that non-simulator-based techniques such as use of fundal photograph matching of an eye of a volunteer, introduction to eye pathologies, smaller student groups and formal instructions with video demonstrations prior to skills training were highly effective in teaching direct ophthalmoscopy for undergraduate medical students.