Design and synthesis of new fused carbazole-imidazole derivatives as anti-diabetic agents: In vitro α-glucosidase inhibition,kinetic, and in silico studies

Twenty three fused carbazole–imidazoles 6a–w were designed, synthesized, and screened as new α-glucosidase inhibitors. All the synthesized fused carbazole-imidazoles 6a-w were found to be more active than acarbose (IC₅₀?=?750.0?±?1.5?µM) against yeast α-glucosidase with IC₅₀ values in the range of 74.0?±?0.7–298.3?±?0.9?µM. Kinetic study of the most potent compound 6v demonstrated that this compound is a competitive inhibitor for α-glucosidase (K_i value?=?75?µM). Furthermore, the in silico studies of the most potent compounds 6v and 6o confirmed that these compounds interacted with the key residues in the active site of α-glucosidase.     

The adrenomedullin receptor acts as clearance receptor in pulmonary circulation

Adrenomedullin (AM) is a powerful pulmonary vasodilator with antimitogenic properties. We investigated the role of the AM receptor (AMR) and the calcitonin gene-related peptide type-1 receptor (CGRP1R) in regulating pulmonary vascular AM levels. The AMR antagonist hAM(22-52) (120 nmol/L) significantly elevated AM release compared with controls to 250% after 2 h in isolated rat lungs and to 830% after 4 h in pulmonary artery endothelial cells (PAEC). CGRP1R blockade had no effect. AMR blockade did not influence prepro-AM mRNA levels nor did inhibition of protein synthesis by cycloheximide (0.01 mg/mL) abolish the effect of the AMR antagonist. Radioligand-binding studies with PAEC membranes revealed a decrease by 44% of the AMR density in response to AMR antagonism. Altogether, the pulmonary vascular AMR represents not only a functionally active, but also a clearance receptor; its expression is constitutively stimulated by basal AM. This identifies a novel mechanism for controlling pulmonary AM levels.     

End-of-life issues as perceived by Lebanese judges

Objectives: to assess the attitudes of judges in Beirut, Lebanon, regarding end-of-life issues such as assisted suicide and withholding or withdrawing life-sustaining treatment.
Subjects and Methods: 85% of all currently acting and in-training judges and public prosecutors in Beirut (N =135) were surveyed using a mailed questionnaire that assessed attitudes toward intervention in five hypothetical cases. The associations of attitudes, on a scale from least to most 'sympathetic' toward assisting those who desire to end their lives, were measured by a variety of personal, social and professional variables.
Results: younger individuals, and those who have not yet been formally appointed as judges, were significantly more sympathetic to withdrawal or withholding of life-sustaining devices when patients or their proxies requested it, and more in support of assisted suicide. Gender, religious denomination, religious practice, and personal experience with prolonged illness leading to death among close friends or family, were generally not significant predictors of respondents' attitudes. Years of experience as a judge correlated strongly with age and may have contributed to its predictive effect.
Discussion and conclusions: a relatively more sympathetic attitude among younger judges, many of them women, and among trainees, may reflect a historical evolution in younger age-groups in Lebanon today. A survey of opinions in the public may help reach a more conclusive understanding in this regard. In any case, judges in Lebanon will remain important partners in the debate, as they will continue to be the final interpreters of the letter of the law in end-of-life issues.     

Bis‐ and Tetrakis(carboxylato)platinum(IV) Complexes with Mixed Axial Ligands – Synthesis,Characterization, and Cytotoxicity

A series of twelve novel diamminetetrakis(carboxylato)platinum(IV) and 18 novel bis(carboxylato)dichlorido(ethane‐1,2‐diamine)platinum(IV) complexes with mixed axial carboxylato ligands was synthesized and characterized by multinuclear ¹H‐, ¹³C‐, ¹⁵N‐, and ¹⁹⁵Pt‐NMR spectroscopy. Their cytotoxic potential was evaluated (by MTT assay) against three human cancer cell lines derived from ovarian teratocarcinoma (CH1/PA‐1), lung (A549), and colon carcinoma (SW480). In the cisplatin‐sensitive CH1/PA‐1 cancer cell line, diamminetetrakis(carboxylato)platinum(IV) complexes showed IC₅₀ values in the low micromolar range, whereas, for the most lipophilic compounds of the bis(carboxylato)dichlorido(ethane‐1,2‐diamine)platinum(IV) series, IC₅₀ values in the nanomolar range were found.     

La TEP au 18F-FDG dans le diagnostic et le suivi évolutif des plasmocytomes solitaires

AimTo assess the role of [¹⁸F]FDG-PET in solitary plasmacytoma with regards to staging, therapeutic follow-up and monitoring.Patients and methodsTwenty consecutive patients were included in the present study when following conditions were met: (i) solitary plasmacytoma histologically confirmed (bone, n = 16; extramedullary, n = 4); (ii) [¹⁸F]FDG-PET scan from July 2004 to April 2009. The clinical follow-up was over than 2 years for 13 patients. Ten patients underwent a post-therapy PET scan. PET scans were visually analysed.ResultsPET scan enabled confirmation of all main lesions (sensitivity: 100%) and also detected infra-clinical lesions in eight cases. Follow-up for more than 2 years showed a progression disease into myeloma in five from six cases (83%) with infraclinical lesions at the baseline PET scan. Among 10 patients who underwent post-therapeutic PET scan, six experienced a complete response at the main lesion site and four experienced a partial response.ConclusionFDG-PET may play an important role in plasmacytoma staging and enables detection of smaller lesions (otherwise undetected).     

Évaluation de méthodes automatiques de segmentation des volumes tumoraux en tomographie par émission de positons par comparaison avec des contours manuels réalisés par un groupe d’experts

Objective

Set up a framework for evaluating automatic segmentation methods of tumour volumes on PET images.

Patient and methods

This study was performed with PET images of 18 patients with non-Hodgkin's lymphoma. One target lesion per patient was pointed out. Each lesion was then three times manually delineated by five experts. Four automatic methods (the application of a threshold of 42% of the maximum SUV, the MIP-based method, the Daisne et al. method and the Nestle et al. method) were evaluated by comparison with the set of manual delineations.

Results

From the manual delineations, we have concluded to a moderate intra-operator variability and to a reduced interoperator reproducibility. From statistical tests performed on various quantitative criteria, there was no significant difference between the MIP-based method, the Daisne et al. method and the Nestle et al. one. The application of a threshold of 42% of the maximum SUV appears to be less efficient.

Conclusion

This work proposes a comparison and an evaluation protocol for segmentation methods. The generated data set will be distributed online for the community to simplify the evaluation of any new method of segmentation.