Gene conversion in human rearranged immunoglobulin genes

Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V<sub>H</sub> segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V<sub>H</sub> replacements with no addition of untemplated nucleotides at the V<sub>H</sub>–V<sub>H</sub> joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V<sub>H</sub> replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion

Current management strategies for patellofemoral pain: an online survey of 99 practising UK physiotherapists

Background: Patellofemoral pain (PFP) is considered one of the commonest forms of knee pain. This study aimed to identify how physiotherapists in the United Kingdom (UK) currently manage patellofemoral pain (PFP), particularly in relation to exercise prescription, and response to pain. Methods: An anonymous survey was designed with reference to previous surveys and recent systematic reviews. Practising UK physiotherapists who treat patients with PFP were invited to take part via an invitation email sent through professional networks, the ‘interactive Chartered Society of Physiotherapy (iCSP)’ message board, and social media (Twitter). Descriptive statistics were used to analyse the data. Results: A total of 99 surveys were completed. Responders reported a wide range of management strategies, including a broad selection of type and dose of exercise prescription. The five most common management strategies chosen were: closed chain strengthening exercises (98%); education and advice (96%); open chain strengthening exercises (76%); taping (70%) and stretches (65%). Physiotherapists with a special interest in treating PFP were statistically more likely to manage patients with orthotics (P=0.02) and bracing (P=0.01) compared to physiotherapists without a special interest. Approximately 55% would not prescribe an exercise if it was painful. Thirty-one percent of physiotherapists would advise patients not to continue with leisure and/or sporting activity if they experienced any pain. Conclusion: Current UK practice in the management strategies of PFP is variable. Further high quality research on which to inform physiotherapy practice is warranted for this troublesome musculoskeletal condition

Differential Genetic Susceptibility to Child Risk at Birth in Predicting Observed Maternal Behavior

This study examined parenting as a function of child medical risks at birth and parental genotype (dopamine D4 receptor; DRD4). Our hypothesis was that the relation between child risks and later maternal sensitivity would depend on the presence/absence of a genetic variant in the mothers, thus revealing a gene by environment interaction (GXE). Risk at birth was defined by combining risk indices of children's gestational age at birth, birth weight, and admission to the neonatal intensive care unit. The DRD4-III 7-repeat allele was chosen as a relevant genotype as it was recently shown to moderate the effect of environmental stress on parental sensitivity. Mothers of 104 twin pairs provided DNA samples and were observed with their children in a laboratory play session when the children were 3.5 years old. Results indicate that higher levels of risk at birth were associated with less sensitive parenting only among mothers carrying the 7-repeat allele, but not among mothers carrying shorter alleles. Moreover, mothers who are carriers of the 7-repeat allele and whose children scored low on the risk index were observed to have the highest levels of sensitivity. These findings provide evidence for the interactive effects of genes and environment (in this study, children born at higher risk) on parenting, and are consistent with a genetic differential susceptibility model of parenting by demonstrating that some parents are inherently more susceptible to environmental influences, both good and bad, than are others

New Approaches to Preventing, Diagnosing, and Treating Neonatal Sepsis

Karen Edmond and Anita Zaidi highlight new approaches that could reduce the burden of neonatal sepsis worldwide

Turbomachinery high speed modal balancing: Modeling and testing of scale rotors

The object of this work is the application of a modal balancing approach to turbomachinery rotors. The investigation was carried out on a small commercial rotor dynamic test bench suitably modified to represent in scale a typical turbomachinery balancing problem. Software based on literature theoretical formulations was developed for both the more widespread influence coefficient method and modal balancing. The modal balancing software was coupled with a finite element rotor dynamic code in order to determine the modal shapes necessary to impose the orthogonality conditions and calculate the modal calibration sets. Results of the two approaches were compared both in terms of balancing quality and in terms of time to balance the rotor. The test results highlighted essential information for an eventual true scale industrial application of the modal method and also interesting new aspects such as the possibility of balancing modes out of the operating speed range

How do we explain painful chronic non-traumatic knee conditions to children and adolescents? A multiple-method study to develop credible explanations

Abstract Background Perceived diagnostic uncertainty can leave adolescents confused about their condition and impede their ability to understand ?what's wrong with me?. Our aim is to develop credible explanations about the condition for adolescents suffering from non-traumatic knee pain. Methods This multiple-method study integrated findings from two systematic literature searches of qualitative and quantitative studies, an Argumentative Delphi with international experts (n?=?16) and think-aloud interviews with adolescents (n?=?16). Experts provided feedback with arguments on how to communicate credible explanations to meet adolescents' needs; we analysed feedback using thematic analysis. The explanations were tailored based on the adolescent end-users' input. Results We screened 3239 titles/abstracts and included 16 papers exploring diagnostic uncertainty from adolescents' and parents' perspectives. Five themes were generated: (1) understanding causes and contributors to the pain experience, (2) feeling stigmatized for having an invisible condition, (3) having a name for pain, (4) controllability of pain, and (5) worried about something being missed. The Argumentative Delphi identified the following themes: (1) multidimensional perspective, (2) tailored to adolescents, (3) validation and reassurance, and (4) careful wording. Merging findings from the systematic search and the Delphi developed three essential domains to address in credible explanations: ?What is non-traumatic knee pain and what does it mean??, ?What is causing my knee pain?? and ?How do I manage my knee pain?? Conclusions Six credible explanations for the six most common diagnoses of non-traumatic knee pain were developed. We identified three domains to consider when tailoring credible explanations to adolescents experiencing non-traumatic knee pain. Significance This study provides credible explanations for the six most common diagnoses of non-traumatic knee pain. Additionally, we identified three key domains that may need to be addressed to reduce diagnostic uncertainty in adolescents suffering from pain complaints. Based on our findings, we believe that clinicians will benefit from exploring adolescents' own perceptions of why they experience pain and perceived management strategies, as this information might capture important clinical information when managing these young individuals