A Scalable High-Yielding and Selective Oxidative Heck Cross-Coupling – A Key Step for the Synthesis of trans- Stilbenes

A selective oxidative Heck cross-coupling method was developed and optimized as a pivotal step for a synthetic route leading to the trans-stilbene framework. The developed method and synthesis were needed in a SAR study in progress that concerned design and development of an inhibitor for the human cell xCT antiporter system. The developed oxidative Heck cross-coupling method was examined with a variety of substrates and reagents to produce a library of different substituted trans-stilbenes, which revealed the method to hold a very good tolerance for an assortment of functional groups. The final synthetic route was successfully scaled-up (from mg scale) and performed in a 150 g (>1000×up-scaled) batch run to obtain an overall yield of 73 % (over three steps), which corresponds to a mean step yield of 90 %. The inhibitor candidate DC10 [(E)-5-(2-([1,1′-biphenyl]-4-yl)vinyl)-2-hydroxy-benzoic acid] was produced in multi-gram quantities (≈33 g) that subsequently was forwarded for animal efficacy and toxicology studies. The scaled-up process constitutes the first example of an oxidative Heck cross-coupling on >100-gram scale.publishedVersio

Importance of Sex Differences in Impulse Control and Addictions

Background Nursing students are expected to deliver holistic care in their upcoming career. Developing spirituality during nursing training is poorly understood. Objectives The current study aimed to explore the process of developing spirituality among Iranian nursing undergraduates. Patients and Methods The study employed Grounded theory approach and purposive sampling with maximum variation to select the participants among undergraduate nursing students in their fourth-year of study in the nursing school of Tehran University of Medical Sciences. Data were gathered through semi structured interviews with nineteen nursing students and one faculty member (n = 20). Strauss and Corbin approach was selected for data analysis. Results Data analysis revealed that developing spirituality during nursing education is an intuitive development including three stages: early frustration, intuitive development through hardship and seeking meaning and fulfilment. This process is influenced by educational/caring environment as well as role models. Conclusions Upbringing capable nurses to deliver spiritual care require supportive environment and influential role models to encourage students’ spiritual development. Developing spiritually may end in delivering spiritual care and provide nursing students with inner strength for better confrontation with serious situations common in their upcoming career

Экономическая эффективность ранней диагностики и реабилитации при заболеваниях желчевыводящей системы у детей в Республике Беларусь

экономика медицинскаяжелчных путей болезниздравоохранение Республики Беларус

Oestradiol levels and superoxide dismutase activity in age-related cataract: a case-control study.

Background: It has been suggested that the higher prevalence of cataract in women is caused by a withdrawal effect of oestrogen at menopause. In vitro studies have demonstrated protection of serum oestradiol (E2) against oxidative stress through upregulation of antioxidant enzymes, including superoxide dismutase (SOD). The purpose of the present study was to investigate E2 levels and SOD erythrocyte activity in patients with age-related cataract. Methods: The studied subjects consisted of 103 patients with age-related cataract and 22 controls. Cataracts were classified as nuclear, cortical, or posterior subcapsular. Blood samples were collected and data on smoking, hormonal use, diabetes and age at menarche/menopause was obtained for all individuals. Serum oestradiol analyses were performed with radioimmunoassay (RIA) and SOD activity was measured in erythrocyte lysates. Results: A negative correlation between age and E2 concentration was seen in a linear regression analysis. No correlation was seen between SOD activity and age or gender and no correlation between E2 levels and SOD activity was found using multiple linear regression. The mean level of E2 for all male subjects was 50.1 +/- 16.3 pmol/L, significantly higher compared to 13.8 +/- 11.8 pmol/L for postmenopausal women. Conclusion: The present study does not support a role for E2-induced effects on SOD in cataract formation. The findings of higher E2 levels in men than in postmenopausal women may suggest that decreased oestrogen at menopause is partially responsible for the gender-related difference in cataract prevalence. However, the latter can only be verified through prospective randomized trials using hormonal replacement therapy

A mutation in POLE predisposing to a multi-tumour phenotype

Somatic mutations in the POLE gene encoding the catalytic subunit of DNA polymerase epsilon have been found in sporadic colorectal cancers (CRCs) and are most likely of importance in tumour development and/or progression. Recently, families with dominantly inherited colorectal adenomas and colorectal cancer were shown to have a causative heterozygous germline mutation in the proofreading exonuclease domain of POLE. The highly penetrant mutation was associated with predisposition to CRC only and no extra-colonic tumours were observed. We have identified a mutation in a large family in which the carriers not only developed CRC, they also demonstrate a highly penetrant predisposition to extra-intestinal tumours such as ovarian, endometrial and brain tumours. The mutation, NM_006231.2:c.1089C>A, p.Asn363Lys, also located in the proofreading exonuclease domain is directly involved in DNA binding. Theoretical prediction of the amino acid substitution suggests a profound effect of the substrate binding capability and a more severe impairment of the catalytic activity compared to the previously reported germline mutation. A possible genotype to phenotype correlation for deleterious mutations in POLE might exist that needs to be considered in the follow-up of mutation carriers

Factors limiting the establishment of a chaparral oak, Quercus durata Jeps. in grassland

Presented at the Symposium on Oak Woodlands and Hardwood Rangeland Management, October 31 - November 2, 1990, Davis, California.We studied factors that restrict colonization of grassland by Quercus durata Jeps., an oak commonly found in chaparral on serpentine soils. The study site contained a chaparral/ grassland border that had been stable for at least 50 years. Monitoring of acorns planted in the chaparral understory and grassland revealed that, although initial seedling emergence was similar in the different sites, seedling survival was much higher in the chaparral. No seedling in the open grassland survived beyond the third year of the study, while 25 percent in the chaparral understory were still alive at the end of 6 years. The differences in survival could not be explained by differences in animal activity and herbivory. Rather, the high solar radiation load on seedlings in the grassland appeared to play a major role in mortality. Experimental shading of seedlings in the grassland with light shade cloth increased seedling survival.Keywords: seedling mortality, seedling surviva

Reduction of the HIV-1 reservoir in resting CD4+ T-lymphocytes by high dosage intravenous immunoglobulin treatment: a proof-of-concept study

<p>Abstract</p> <p>Background</p> <p>The latency of HIV-1 in resting CD4⁺T-lymphocytes constitutes a major obstacle for the eradication of virus in patients on antiretroviral therapy (ART). As yet, no approach to reduce this viral reservoir has proven effective.</p> <p>Methods</p> <p>Nine subjects on effective ART were included in the study and treated with high dosage intravenous immunoglobulin (IVIG) for five consecutive days. Seven of those had detectable levels of replication-competent virus in the latent reservoir and were thus possible to evaluate. Highly purified resting memory CD4⁺T-cells were activated and cells containing replication-competent HIV-1 were quantified. HIV-1 from plasma and activated memory CD4⁺T-cells were compared with single genome sequencing (SGS) of the <it>gag </it>region. T-lymphocyte activation markers and serum interleukins were measured.</p> <p>Results</p> <p>The latent HIV-1 pool decreased with in median 68% after IVIG was added to effective ART. The reservoir decreased in five, whereas no decrease was found in two subjects with detectable virus. Plasma HIV-1 RNA ≥ 2 copies/mL was detected in five of seven subjects at baseline, but in only one at follow-up after 8–12 weeks. The decrease of the latent HIV-1 pool and the residual plasma viremia was preceded by a transitory low-level increase in plasma HIV-1 RNA and serum interleukin 7 (IL-7) levels, and followed by an expansion of T regulatory cells. The magnitude of the viral increase in plasma correlated to the size of the latent HIV-1 pool and SGS of the <it>gag </it>region showed that viral clones from plasma clustered together with virus from activated memory T-cells, pointing to the latent reservoir as the source of HIV-1 RNA in plasma.</p> <p>Conclusion</p> <p>The findings from this uncontrolled proof-of-concept study suggest that the reservoir became accessible by IVIG treatment through activation of HIV-1 gene expression in latently-infected resting CD4⁺T-cells. We propose that IVIG should be further evaluated as an adjuvant to effective ART.</p