Insight into the pathogenesis of chronic lymphocytic leukemia (CLL) through analysis of IgVH gene usage and mutation status in familial CLL

To address the proposition that familial B-cell chronic lymphocytic leukemia (CLL) may exhibit a more restricted phenotype than sporadic CLL with respect to immunoglobulin gene usage or ontogenic development, we compared immunoglobulin (Ig) heavy chain variable region (VH) gene usage and IgVH mutation status in 327 patients with CLL from 214 families with 724 patients with sporadic cases. The frequency of mutated CLL was higher in familial CLL (P < .001), and there was evidence of intrafamilial concordance in mutation status (P < .001). The repertoire and frequency of IgVH usage was, however, not significantly different between familial and sporadic CLL. Furthermore, IgVH usage was not correlated between affected members of the same family. These observations provide evidence that familial CLL is essentially indistinguishable from sporadic CLL, favoring a genetic basis to disease development in general rather than a simple environmental etiology.     

Modeling the site-specific variation of selection patterns along lineages

The unambiguous footprint of positive Darwinian selection in protein-coding DNA sequences is revealed by an excess of nonsynonymous substitutions over synonymous substitutions compared with the neutral expectation. Methods for analyzing the patterns of nonsynonymous and synonymous substitutions usually rely on stochastic models in which the selection regime may vary across the sequence but remains constant across lineages for any amino acid position. Despite some work that has relaxed the constraint that selection patterns remain constant over time, no model provides a strong statistical framework to deal with switches between selection processes at individual sites during the course of evolution. This paper describes an approach that allows the site-specific selection process to vary along lineages of a phylogenetic tree. The parameters of the switching model of codon substitution are estimated by using maximum likelihood. The analysis of eight HIV-1 env homologous sequence data sets shows that this model provides a significantly better fit to the data than one that does not take into account switches between selection patterns in the phylogeny at individual sites. We also provide strong evidence that the strength and the frequency of occurrence of selection might not be estimated accurately when the site-specific variation of selection regimes is ignored.     

Evaluating a Psychoeducational,Therapeutic Group for Parents of Children with Autism Spectrum Disorder

The current study aimed to review and evaluate a three-session psychoeducational and psychotherapeutic group programme for parents of children with autism spectrum disorder (ASD). The group programme was facilitated through an ASD diagnostic and intervention service within a Northern Ireland Health and Social Care Trust over a 12-month period, throughout which time 83 parents attended a three-session course covering various aspects of ASD-specific material. Knowledge of ASD, understanding of behavioural management techniques and parental self-efficacy were measured through pre-course and post-course questionnaires, completed by the parents. Participants also completed a questionnaire regarding their experience following course attendance. The data were analysed using a mixed-methods approach. Results from pre-course and post-course analysis showed that parental understanding of the social deficits and the cognitive and behavioural difficulties associated with ASD significantly increased following course attendance. Course attendance also significantly increased parental understanding of the strategies used to support a child with ASD and parental self-efficacy. Client experience questionnaires were analysed using thematic analysis, with themes centring on the importance of peer and professional support, timeliness of intervention and relevance of information covered within the course. The parents' evaluation of the course was rated predominantly as a positive experience. The importance of parents receiving involvement through an intervention programme is explored and the results are discussed in relation to potential impact on service provision, identifying future need and areas for further research.     

A survey of fertility and sexual health following allogeneic haematopoietic stem cell transplantation in New South Wales,Australia

Four hundred and twenty‐one adult allogeneic haematopoietic stem cell transplant (HSCT) survivors participated in a cross‐sectional study to assess sexual dysfunction and infertility post‐transplant. Survey instruments included the Sydney Post‐Blood and Marrow Transplant (BMT) Survey, Functional Assessment of Cancer Treatment (FACT) – BMT, the Depression, Anxiety, Stress Scales (DASS 21), the Chronic Graft‐versus‐Host Disease (cGVHD) Activity Assessment‐ Patient Self Report (Form B), the Lee cGVHD Symptom Scale and The Post‐Traumatic Growth Inventory. Most HSCT survivors reported sexual difficulties (51% of males; 66% of females). Men reported erectile dysfunction (79%) and decreased libido (61·6%) and women reported loss of libido (83%), painful intercourse (73%) and less enjoyment of sex (68%). Women also commonly reported vaginal dryness (73%), vaginal narrowing (34%) and vaginal irritation (26%). Woman had much higher rates of genital cGvHD than men (22% vs. 5%). Age and cGVHD were significantly associated with sexual dysfunction. Few survivors had children following transplant (3·3%). However, for those of reproductive age at HSCT, 22% reported trying to conceive, with 10·3% reporting success. This study is the largest to date exploring sexual function in survivors of allo‐HSCT. This data provides the basis for health service reform to better meet the needs of HSCT survivors, including evidence to support counselling and education both pre‐ and post‐transplant.     

Identification of circulating antigen-specific CD4+ T lymphocytes with a CCR5+, cytotoxic phenotype in an HIV-1 long-term nonprogressor and in CMV infection

Antigen-specific CD4+ effector T cells primarily provide help for B-cell antibody responses and CD8+ cytotoxic T-lymphocyte (CTL) responses. We have found an expanded population of HIV-1 p24-specific, T-cell receptor V beta 17+, CD4+ T lymphocytes, defined by in vitro proliferative and interferon-gamma responses to a 15-mer Gag peptide, in the peripheral blood of an individual with long-term nonprogressive HIV-1 infection. Ex vivo, these cells were CCR5+ and CCR7-, consistent with an effector/memory function. Surprisingly, these cells highly expressed several proteins characteristic of cytotoxic lymphocytes, including TIA-1 (T-cell intracellular antigen 1; GMP-17/NKG7), granzymes A and B, CD161 (NKRP-1), and CD244 (C1.7/2B4). Following in vitro peptide stimulation, these cells produced interleukin 2 (IL-2) and intracellular CD40L, suggesting possible helper function, in addition to induction of perforin and cytotoxicity. A subset of cytomegalovirus (CMV)-specific CD4+ T cells in healthy adults similarly expressed these CTL markers and CCR5, ex vivo. Furthermore, this distinct subset of CD4+ T cells was significantly elevated in healthy CMV-seropositive adults, compared with CMV-seronegative individuals. These results suggest that CCR5+ CD4+ CTL may be a major effector mechanism of the immune response to viral infections in humans. Moreover, expression of CCR5 may render them particularly susceptible to cytopathic effects during progressive HIV-1 infection.