Broadened ligand responsiveness of androgen receptor mutants obtained by random amino acid substitution of H874 and mutation hot spot T877 in prostate cancer

In a subset of endocrine therapy-resistant prostate cancers, amino acid substitutions H874Y, T877A and T877S, which broaden ligand specificity of the ligand binding domain (LBD) of the androgen receptor (AR), have been detected. To increase our knowledge of the role of amino acid substitutions at these specific positions in prostate cancer, codons 874 and 877 were subjected to random mutagenesis. AR mutants were screened in a yeast readout system for responsiveness to 5 alpha-dihydrotestosterone, progesterone and dehydroepiandrosterone. At position 874, only the histidine to tyrosine substitution could broaden AR ligand specificity. At position 877, 4 ligand specificity broadening substitutions were found: T877A, T877S, T877C and T877G. The latter 2 were not found in prostate cancer. The AR mutants were tested in mammalian (Hep3B) cells for responsiveness to 13 different ligands. All mutants displayed their own ligand specificity spectrum. Importantly, AR(H874Y) and AR(T877A) could be activated by cortisol. According to the 3-dimensional structure of the AR LBD, T877 interacts directly with the 17 beta-hydroxyl group of androgens. All amino acid substitutions identified at position 877 had smaller side chains than the threonine in the wild-type receptor, indicating that increased space in the ligand binding pocket is important in broadened ligand specificity. Because H874 does not interact directly with the ligand, its substitution by a tyrosine is expected to change the ligand binding pocket conformation indirectly. For T877C and T877G substitutions, 2-point mutations are required, and for H874Y, T877A and T877S substitutions, only a 1-point mutation is sufficient. This most likely explains that the latter 3 have been found in prostate cancer.     

Non-word repetition and non-word discrimination in Swedish preschool children

By looking at data on expressive phonology, non-word repetition, non-word discrimination and phonological sensitivity in two groups of Swedish children, the common basis for tasks tapping into different levels of phonological processing is discussed. Two studies were performed, one including children with language impairment (LI) and one including children with normal language development (NL). A discrimination task consisting of non-word pairs differing in one phoneme was developed. In both groups there was a significant correlation between non-word repetition and phoneme identification. In children with LI phoneme identification was significantly correlated with expressive phonology. In children with NL non-word repetition correlated significantly with non-word discrimination, which was linked both to rhyme recognition and phoneme identification. Non-word discrimination might be equally useful as non-word repetition as an early screening tool and would circumvent the confounding factor of an expressive phonological impairment as well as decrease the amount of complicating factors involved in scoring procedures.     

Endotoxin-induced cytokine production of monocytes of third-trimester pregnant women compared with women in the follicular phase of the menstrual cycle

OBJECTIVE: Little is known about the function of the innate immune response during pregnancy. We therefore investigated monocyte cytokine production, as a measure of monocyte function, in pregnant women compared with nonpregnant women. STUDY DESIGN: Whole blood of women in the follicular phase (day 5-6) and of healthy pregnant women (30 weeks) was collected and stimulated with endotoxin (2 microg/mL). After incubation for 4 hours (37 degrees C, 5% carbon dioxide), red blood cells were lysed and white blood cells were permeabilized, followed by staining with anti-CD14 (fluorescein isothiocyanate labeled) and with phycoerythrin-labeled tumor necrosis factor-alpha, interleukin-1beta, or interleukin-12. The cells were analyzed by flow cytometry after fixation. Results are expressed as a percentage cytokine producing cells after endotoxin stimulation. Statistical analysis was performed with the Mann-Whitney U test (P <.05). RESULTS: Compared with the percentage endotoxin-induced cytokine producing peripheral monocytes in women in the follicular phase, this percentage in pregnancy was decreased for interleukin-12 (mean 6.63 +/- 1.34 vs 3.34 +/- 0.87, P <.05) and tumor necrosis factor-alpha (mean 50.20 +/- 5.80 vs 31.29 +/- 5.57, P >.05). No significant difference was seen in the production of interleukin-1beta (mean 58.22 +/- 11.09 vs 47.18 +/- 7.88, P >.05). CONCLUSION: The percentage of interleukin-12 and tumor necrosis factor-alpha producing monocytes is decreased in pregnant women compared with nonpregnant women, suggesting that pregnancy is a proinflammatory state.     

Substrate specificity of adenovirus protease

The adenovirus protease, adenain is functionally required for virion uncoating and virion maturation and release from the infected cell. In addition to hydrolysis of precursor proteins at specific consensus sites, adenain has also been observed to cleave viral proteins at other sites. Here we re-examine the sequences in the consensus sites and also the phenomena of cleavage at other sites on viral proteins II, 100K, V, VI and VII. An examination of the eight residues flanking the scissile bond in 274 consensus sites from 36 different adenovirus serotypes in the DNA sequence databanks provided the following main conclusions: (1) two types of consensus sites, type 1, (M,I,L)XGX-G and type 2, (M,I,L)XGG-X, (2) the variant positions P(3) and P(1) never contained C,P,D,H,W,Y and C,P,G,M amino acids, respectively in type 1, (3) the variant positions P(3) and P(1)' never contained C,D,L,W and C,P,D,Q,H,Y,W amino acids, respectively in type 2, and (4) the thiol forming C residue occurred only twice within the eight residues flanking the scissile bond and that in the P(4)' position. Six unusual serotypes had (M,L,I)XAT-G as the PVII consensus site. Adenain has been proposed to cleave protein VI at an unknown site in the course of virion uncoating. The cleavage of capsid protein VI in the absence of a consensus site is confirmed here in vitro using recombinant adenain. Virion proteins II, V and VII and the nonstructural protein 100K were also digested in vitro into discrete fragments by recombinant adenain. We conclude that adenain preferentially cleaves viral proteins at their consensus sites, but is capable, in vitro of cleavages at other discrete sites which resemble the consensus cleavage sites.     

Psychosocial and demographic correlates of the discontinuation of in vitro fertilization

In this study, we investigated the relationship between psychosocial factors assessed pre-treatment and the discontinuation of in vitro fertilisation (IVF) treatment after one year.

A cohort study was performed in a Dutch fertility clinic and included 667 couples. Demographic characteristics, scores for psychosocial factors, discontinuation rates, reasons for discontinuation and outcome data of the treatment were measured. Discontinuation due to personal reasons was differentiated from discontinuation because of changing a clinic or physicians’ advice. The results showed that 37.5% of the couples became pregnant, while 40 (6%) discontinued IVF treatment because of personal reasons. A sample size of 288 women remained for analysis. A longer duration of infertility, less perceived social support in women and higher scores on acceptance of infertility in both men and women were significantly correlated with discontinuation. Multivariate analysis, using these variables including the age of the women, showed that these factors could explain 29% of the discontinuation.

These results point to a differentiation between couples who choose positively choose to discontinue treatment and those discontinuing from a more negative perspective. Opportunities to tailor interventions to this second group of couples need to be investigated.     

A Cross-Country Network Analysis of Adolescent Resilience

PurposeIn situations of adversity, young people draw on individual, relational, and contextual (community and cultural) resources to foster their resilience. Recent literature defines resilience as a capacity that is underpinned by a network of interrelated resources. Although empirical studies show evidence of the value of a network approach, little is known regarding how different country contexts influence which resources are most critical within a resource network and how resources interact for adolescent resilience.MethodsNetwork analysis was conducted with data from studies that had used the Child and Youth Resilience Measure. Regularized partial correlation networks of 17 resources were estimated for 14 countries (Botswana, Canada, China, Colombia, Equatorial Guinea, India, Indonesia, Italy, Jordan, New Zealand, the Philippines, Romania, South Africa, and Syrian refugees living in Jordan). The sample size was 18,914 (mean age = 15.70 years, 48.8% female).ResultsWe observed mostly positive associations between the resources of interest. The salience and strength of associations between resources varied by country. The most central resource across countries was having supportive caregivers during stressful times because this resource had the most and strongest positive associations with other resources.ConclusionsThis study gives first empirical evidence from multiple countries that an interplay of social–ecological resources (such as individual skills, peer, caregiver and community support, and educational aspirations and opportunities) matter for adolescent resilience. Across countries, caregiver support appears to be most central for adolescent resilience. Future resilience interventions might apply this network approach to identify important, contextually relevant resources that likely foster additional resources.     

Feasibility of health-related quality of life (HRQoL) assessment for cancer patients using electronic patient-reported outcome (ePRO) in daily clinical practice

Quality of Life Research - Routine Electronic Monitoring of Health-Related Quality of Life (HRQoL) (REMOQOL) in clinical care with real-time feedback to physicians could help to enhance...     

Prevalences of dementia and cognitive impairment among older people in sub-Saharan Africa: a systematic review

Objective

To perform a systematic review of the literature on the prevalence of cognitive impairment and dementia in sub-Saharan Africa.

Methods

Five electronic databases were searched for relevant abstracts and to identify papers eligible for full-text review. A study was included if two authors agreed that it had a cohort, case–control or cross-sectional design and reported population-level data; was limited to black African adults older than 50 years or described as “elderly” or “old”; reported data for individuals residing in sub-Saharan Africa; and reported at least one measure of cognitive impairment or clinical outcomes relevant to cognitive decline. References of papers included in our study were searched to identify additional candidate publications. Disagreements about inclusion were adjudicated during discussions involving all authors. Data were extracted independently by two authors, using a form developed by the authors and tested on a sample of papers.

Findings

A total of 2320 unique papers was found; the full text of 87 was reviewed. Nineteen papers featuring 11 cross-sectional studies were included; all were published during 1995–2011. Studies occurred in Benin, Botswana, the Central African Republic, the Congo and Nigeria and enrolled approximately 10 500 participants. The prevalence of dementia ranged from 0%, in Nigeria, to 10.1% (95% confidence interval, CI: 8.6–11.8), also in Nigeria. The prevalence of cognitive impairment ranged from 6.3%, in Nigeria, to 25% (95% CI: 21.2–29.0), in the Central African Republic.

Conclusion

Prevalences of dementia and cognitive impairment in sub-Saharan Africa varied widely, with few published studies revealed by the literature search.