Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees

Steroid 21-hydroxylase deficiency is among the most common inborn errors of metabolism in man. Characterization of mutations in the 21- hydroxylase gene (CYP21) has permitted genetic diagnosis, facilitated by the polymerase chain reaction (PCR). The most common mutation is conversion of an A or C at nt656 to a G in the second intron causing aberrant splicing of mRNA. Homozygosity for nt656G is associated with profoundly deficient adrenal cortisol and aldosterone synthesis, secondary hypersecretion of adrenal androgens, and a severe form of congenital adrenal hyperplasia (CAH) characterized by ambiguous genitalia and/or sodium wasting in newborns. During the course of genetic analysis of CYP21 mutations in CAH families, we and others have noticed a number of relatives genotyped as nt656G homozygotes, yet showing no clinical signs of disease. A number of lines of evidence have led us to propose that the putative asymptomatic nt656G/G individuals are incorrectly typed due to dropout of one haplotype during PCR amplification of CYP21. For prenatal diagnosis, we recommend that microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nt656.      

Observed Externalizing Behavior: A Developmental Comparison of Genetic and Environmental Influences Across Three Samples

Estimates of genetic and environmental influences on externalizing behavior are markedly inconsistent. In an attempt to refine and extend our knowledge of externalizing behavior, the current study examined the etiology of externalizing behavior using observational data in middle childhood and adolescence from three twin and sibling samples. Observational ratings offer a unique perspective on externalizing behavior rarely examined within behavioral genetic designs. Shared environmental influences were significant and moderate to large in magnitude across all three samples (i.e., 44, 77, and 38%), while genetic influences (31%) were significant only for the adolescent sample. All three samples showed greater shared environmental influences and less genetic influence than is typically found when examining self-, parent-, and teacher-reports of externalizing behavior. These findings are consistent with other reports that have found evidence for shared environmental influences on measures of child externalizing behavior—in direct contrast to a commonly held perception that shared environmental factors do not have significant influences on behavior beyond early childhood.     

In search of security: the latent structure of the Adult Attachment Interview revisited

Building on Roisman, Fraley, and Belsky, who produced evidence for two modestly correlated dimensions (i.e., dismissing and preoccupied states of mind) underlying individual differences in attachment as assessed by the Adult Attachment Interview using the Main and Goldwyn classification system, this report replicates and extends relevant evidence in a large sample of adults (N = 842) who completed the Adult Attachment Interview coded using Kobak's Adult Attachment Interview Q-Sort. Principal components analysis of item-level Q-Sort data yielded two state of mind (dismissing vs. free to evaluate and preoccupied vs. not) and two inferred experience (maternal and paternal) components that were associated with two domains of theoretical significance to attachment theory: interpersonal functioning in a romantic context and symptoms of psychopathology. Results revealed distinctive behavioral correlates of dismissing versus preoccupied states of mind and emphasize the differential predictive significance for developmental adaptation of attachment states of mind versus adults' recollections of their early experiences. Implications for adult attachment methodology and theory are discussed.     

Tremelimumab (anti-CTLA4) mediates immune responses mainly by direct activation of T effector cells rather than by affecting T regulatory cells

Cytotoxic T Lymphocyte Antigen 4 (CTLA4) blockade has shown antitumor activity against common cancers. However, the exact mechanism of immune mediation by anti-CTLA4 remains to be elucidated. Further understanding of how CTLA4 blockade with tremelimumab mediates immune responses may allow a more effective selection of responsive patients. Our results show that tremelimumab enhanced the proliferative response of T effector cells (Teff) upon TCR stimulation, and abrogated Treg suppressive ability. In the presence of tremelimumab, frequencies of IL-2-secreting CD4(+) T cells and IFN-γ-secreting CD4(+) and CD8(+) T cells were increased in response to polyclonal activation and tumor antigens. Importantly, Treg frequency was not reduced in the presence of tremelimumab, and expanded Tregs in cancer patients treated with tremelimumab expressed FoxP3 with no IL-2 release, confirming them as bona fide Tregs. Taken together, this data indicates that tremelimumab induces immune responses mainly by direct activation of Teff rather than by affecting Tregs.     

Motivation-based intervention to promote colonoscopy screening: an integration of a fear management model and motivational interviewing

Colorectal cancer (CRC) screening rates have been low despite effectiveness of screening in reducing CRC mortality. This article outlines the theoretical background and development of an innovative, telephone-based risk communication designed to promote screening among individuals at increased risk for familial CRC. This ongoing intervention integrates the Extended Parallel Process Model of fear management and the motivational interviewing counselling style. Tailoring and implementation intentions are incorporated. The primary outcome is self-reported colonoscopy within nine months following intervention. If proven effective, the remote intervention could be broadly disseminated to individuals at increased familial CRC risk, especially those in geographically underserved areas.     

Variations in GP–patient communication by ethnicity,age, and gender: evidence from a national primary care patient survey

Background

Doctor–patient communication is a key driver of overall satisfaction with primary care. Patients from minority ethnic backgrounds consistently report more negative experiences of doctor–patient communication. However, it is currently unknown whether these ethnic differences are concentrated in one gender or in particular age groups.

Aim

To determine how reported GP–patient communication varies between patients from different ethnic groups, stratified by age and gender.

Design and setting

Analysis of data from the English GP Patient Survey from 2012–2013 and 2013–2014, including 1 599 801 responders.

Method

A composite score was created for doctor–patient communication from five survey items concerned with interpersonal aspects of care. Mixed-effect linear regression models were used to estimate age- and gender-specific differences between white British patients and patients of the same age and gender from each other ethnic group.

Results

There was strong evidence (P<0.001 for age by gender by ethnicity three-way interaction term) that the effect of ethnicity on reported GP–patient communication varied by both age and gender. The difference in scores between white British and other responders on doctor–patient communication items was largest for older, female Pakistani and Bangladeshi responders, and for younger responders who described their ethnicity as ‘Any other white’.

Conclusion

The identification of groups with particularly marked differences in experience of GP–patient communication — older, female, Asian patients and younger ‘Any other white’ patients — underlines the need for a renewed focus on quality of care for these groups.