Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4<sup>+</sup> T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system <i>in</i> <i>vivo</i>. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation

Vortical and Wave Modes in 3D Rotating Stratified Flows: Random Large Scale Forcing

Utilizing an eigenfunction decomposition, we study the growth and spectra of energy in the vortical and wave modes of a 3D rotating stratified fluid as a function of $\epsilon = f/N$. Working in regimes characterized by moderate Burger numbers, i.e. $Bu = 1/\epsilon^2 < 1$ or $Bu \ge 1$, our results indicate profound change in the character of vortical and wave mode interactions with respect to $Bu = 1$. As with the reference state of $\epsilon=1$, for $\epsilon < 1$ the wave mode energy saturates quite quickly and the ensuing forward cascade continues to act as an efficient means of dissipating ageostrophic energy. Further, these saturated spectra steepen as $\epsilon$ decreases: we see a shift from $k^{-1}$ to $k^{-5/3}$ scaling for $k_f < k < k_d$ (where $k_f$ and $k_d$ are the forcing and dissipation scales, respectively). On the other hand, when $\epsilon > 1$ the wave mode energy never saturates and comes to dominate the total energy in the system. In fact, in a sense the wave modes behave in an asymmetric manner about $\epsilon = 1$. With regard to the vortical modes, for $\epsilon \le 1$, the signatures of 3D quasigeostrophy are clearly evident. Specifically, we see a $k^{-3}$ scaling for $k_f < k < k_d$ and, in accord with an inverse transfer of energy, the vortical mode energy never saturates but rather increases for all $k < k_f$. In contrast, for $\epsilon > 1$ and increasing, the vortical modes contain a progressively smaller fraction of the total energy indicating that the 3D quasigeostrophic subsystem plays an energetically smaller role in the overall dynamics.Comment: 18 pages, 6 figs. (abbreviated abstract

Arthroscopic Treatment of Acetabular Retroversion With Acetabuloplasty and Subspine Decompression: A Matched Comparison With Patients Undergoing Arthroscopic Treatment for Focal Pincer-Type Femoroacetabular Impingement.

BackgroundGlobal acetabular retroversion is classically treated with open reverse periacetabular osteotomy. Given the low morbidity and recent success associated with the arthroscopic treatment of femoroacetabular impingement (FAI), there may also be a role for arthroscopic treatment of acetabular retroversion. However, the safety and outcomes after hip arthroscopic surgery for retroversion need further study, and the effect of impingement from the anterior inferior iliac spine (subspine) in patients with retroversion is currently unknown.HypothesisArthroscopic treatment for global acetabular retroversion will be safe, and patients will have similar outcomes compared with a matched group undergoing arthroscopic treatment for focal pincer-type FAI.Study designCohort study; Level of evidence, 2.MethodsPatients undergoing hip arthroscopic surgery for symptomatic global acetabular retroversion were prospectively enrolled and compared with a matched group of patients undergoing arthroscopic surgery for focal pincer-type FAI. Both groups underwent the same arthroscopic treatment protocol. All patients were administered patient-reported outcome (PRO) measures, including the 12-item Short-Form Health Survey (SF-12) Physical Component Summary (PCS) and a Mental Component Summary (MCS), modified Harris Hip Score (mHHS), Hip disability and Osteoarthritis Outcome Score (HOOS), and visual analog scale (VAS) for pain preoperatively and at 1 year postoperatively.ResultsThere were no differences in age, sex, or body mass index between 39 hips treated for global acetabular retroversion and 39 hips treated for focal pincer-type FAI. There were no major or minor complications in either group. Patients who underwent arthroscopic treatment for global acetabular retroversion demonstrated similar significant improvements in postoperative PRO scores (scores increased by 17 to 43 points) as patients who underwent arthroscopic treatment for focal pincer-type FAI. Patients treated for retroversion who also underwent subspine decompression had greater improvement than patients who did not undergo subspine decompression for the HOOS-Pain (33.7 ± 15.3 vs 22.5 ± 17.6, respectively; P = .046) and HOOS-Quality of Life (49.7 ± 18.8 vs 34.6 ± 22.0, respectively; P = .030) scores.ConclusionArthroscopic treatment for acetabular retroversion is safe and provides significant clinical improvement similar to arthroscopic treatment for pincer-type FAI. Patients with acetabular retroversion who also underwent arthroscopic subspine decompression demonstrated greater improvements in pain and quality of life outcomes than those who underwent arthroscopic treatment without subspine decompression

Which activities threaten independent living of elderly when becoming problematic : inspiration for meaningful service robot functionality

Purpose: In light of the increasing elderly population and the growing demand for home care, the potential of robot support is given increasing attention. In this paper, an inventory of activities was made that threaten independent living of elderly when becoming problematic. Results will guide the further development of an existing service robot, the Care-O-bot®. Method: A systematic literature search of PubMed was performed, focused on the risk factors for institutionalization. Additionally, focus group sessions were conducted in the Netherlands, United Kingdom and France. In these focus group sessions, problematic activities threatening the independence of elderly people were discussed. Three separate target groups were included in the focus group sessions: (1) elderly persons (n = 41), (2) formal caregivers (n = 40) and (3) informal caregivers (n = 32). Results: Activities within the International Classification of Functioning domains mobility, self-care, and interpersonal interaction and relationships were found to be the most problematic. Conclusions: A distinct set of daily activities was identified that may threaten independent living, but no single activity could be selected as the main activity causing a loss of independence as it is often a combination of problematic activities that is person-specific. Supporting the problematic activities need not involve a robotic solution Read More: http://informahealthcare.com/doi/abs/10.3109/17483107.2013.840861Peer reviewe

Sustainability assessment of electrokinetic bioremediation compared with alternative remediation options for a petroleum release site

Sustainable management practices can be applied to the remediation of contaminated land to maximise the economic, environmental and social benefits of the process. The Sustainable Remediation Forum UK (SuRF-UK) have developed a framework to support the implementation of sustainable practices within contaminated land management and decision making. This study applies the framework, including qualitative (Tier 1) and semi-quantitative (Tier 2) sustainability assessments, to a complex site where the principal contaminant source is unleaded gasoline, giving rise to a dissolved phase BTEX and MTBE plume. The pathway is groundwater migration through a chalk aquifer and the receptor is a water supply borehole. A hydraulic containment system (HCS) has been installed to manage the MTBE plume migration. The options considered to remediate the MTBE source include monitored natural attenuation (MNA), air sparging/soil vapour extraction (AS/SVE), pump and treat (PT) and electrokinetic-enhanced bioremediation (EK-BIO). A sustainability indictor set from the SuRF-UK framework, including priority indicator categories selected during a stakeholder engagement workshop, was used to frame the assessments. At Tier 1 the options are ranked based on qualitative supporting information, whereas in Tier 2 a multi-criteria analysis is applied. Furthermore, the multi-criteria analysis was refined for scenarios where photovoltaics (PVs) are included and amendments are excluded from the EK-BIO option. Overall, the analysis identified AS/SVE and EK-BIO as more sustainable remediation options at this site than either PT or MNA. The wider implications of this study include: (1) an appraisal of the management decision from each Tier of the assessment with the aim to highlight areas for time and cost savings for similar assessments in the future; (2) the observation that EK-BIO performed well against key indicator categories compared to the other intensive treatments; and (3) introducing methods to improve the sustainability of the EK-BIO treatment design (such as PVs) did not have a significant effect in this instance

Changes in and predictors of length of stay in hospital after surgery for breast cancer between 1997/98 and 2004/05 in two regions of England: a population-based

BACKGROUND Decreases in length of stay (LOS) in hospital after breast cancer surgery can be partly attributed to the change to less radical surgery, but many other factors are operating at the patient, surgeon and hospital levels. This study aimed to describe the changes in and predictors of length of stay (LOS) in hospital after surgery for breast cancer between 1997/98 and 2004/05 in two regions of England. METHODS Cases of female invasive breast cancer diagnosed in two English cancer registry regions were linked to Hospital Episode Statistics data for the period 1st April 1997 to 31st March 2005. A subset of records where women underwent mastectomy or breast conserving surgery (BCS) was extracted (n = 44,877). Variations in LOS over the study period were investigated. A multilevel model with patients clustered within surgical teams and NHS Trusts was used to examine associations between LOS and a range of factors. RESULTS Over the study period the proportion of women having a mastectomy reduced from 58% to 52%. The proportion varied from 14% to 80% according to NHS Trust. LOS decreased by 21% from 1997/98 to 2004/05 (LOSratio = 0.79, 95%CI 0.77-0.80). BCS was associated with 33% shorter hospital stays compared to mastectomy (LOSratio = 0.67, 95%CI 0.66-0.68). Older age, advanced disease, presence of comorbidities, lymph node excision and reconstructive surgery were associated with increased LOS. Significant variation remained amongst Trusts and surgical teams. CONCLUSION The number of days spent in hospital after breast cancer surgery has continued to decline for several decades. The change from mastectomy to BCS accounts for only 9% of the overall decrease in LOS. Other explanations include the adoption of new techniques and practices, such as sentinel lymph node biopsy and early discharge. This study has identified wide variation in practice with substantial cost implications for the NHS. Further work is required to explain this variation

Assessment of 1183 screen-detected, category 3B, circumscribed masses by cytology and core biopsy with long-term follow up data

Discrete masses are commonly detected during mammographic screening and most such lesions are benign. For lesions without pathognomonically benign imaging features that are still regarded likely to be non-malignant (Tabar grade 3) reliable biopsy results would be a clinically useful alternative to mammographic surveillance. Appropriate institutional guidelines for ethical research were followed. Between Jan 1996–Dec 2005 grade 3B discrete masses detected in the setting of a large, population based, breast cancer screening programme are included. Patient demographics, fine needle aspiration biopsy (FNAB), core and surgical biopsy results are tabulated. The final pathology of excised lesions was obtained. Information regarding interval cancers was obtained from the State Cancer Registry records and also through long term follow-up of clients in subsequent rounds of screening. A total of 1183 lesions, mean diameter of 13.3 mm (±8.3 mm) and mean client age of 55.1 years (±8.8 years) are included. After diagnostic work up, 98 lesions (8.3%) were malignant, 1083 were non-malignant and a final histologic diagnosis was not established in two lesions. In the 27 months after assessment, no interval cancers were attributable to these lesions and during a mean follow up of 54.5 months, available in 84.9% of eligible women, only one cancer has developed in the same quadrant as the original lesion, although the two processes are believed to be unrelated. FNAB performed in 1149 cases was definitive in 80.5% cases (882 benign, 43 malignant) with a negative predictive value (NPV) of 99.8% (880 of 882) and a positive predictive value (PPV) of 95.2% (40 of 42, both intraductal papillomas). Core biopsy was performed in 178 lesions, mostly for indefinite cytology. Core biopsy was definitive in 79.8% cases (57% benign 22% malignant) with a PPV of 100% and NPV of 99.0%. In experienced hands FNAB is an accurate first line diagnostic modality for the assessment of 3B screen-detected discrete masses, providing definitive results in 80.5% of cases. When used as a second line modality, core biopsy had a similarly high rate of definitive diagnosis at 79.8%. The stepwise approach to the use of FNAB and core biopsy would reduce substantially the proportion of cases requiring surgical diagnostic biopsy. Given the low probability of malignancy and the imperative to limit the morbidity associated with cancer screening, the demonstration of the reliability of FNAB as a minimally invasive but highly accurate test for this particular subset of screen-detected lesions has significant clinical utility

Prognostic factors in metaplastic carcinoma of the breast: A multi-institutional study

Background: Metaplastic breast carcinoma (MBC) is a rare type of breast cancer that has basal-like characteristics and is perceived to have poorer prognosis when compared with conventional no specific type/ductal carcinomas (ductal/NST). However, current data on MBC are largely derived from small case series or population-based reports. This study aimed to assess the clinicopathological features and outcome of MBC identified through an international multicentre collaboration. Methods: A large international multicentre series of MBC (no=405) with histological confirmation and follow-up information has been included in this study. The prognostic value of different variables and outcome has been assessed and compared with grade, nodal status and ER/HER2 receptor-matched ductal/NST breast carcinoma. Results: The outcome of MBC diagnosed in Asian countries was more favourable than those in Western countries. The outcome of MBC is not different from matched ductal/NST carcinoma but the performance of the established prognostic variables in MBC is different. Lymph node stage, lymphovascular invasion and histologic subtype are associated with outcome but tumour size and grade are not. Chemotherapy was associated with longer survival, although this effect was limited to early-stage disease. In this study no association between radiotherapy and outcome was identified. Multivariate analysis of MBC shows that histologic subtype is an independent prognostic feature. Conclusions: This study suggests that MBC is a heterogeneous disease. Although the outcome of MBC is not different to matched conventional ductal/NST breast carcinoma, its behaviour is dependent on the particular subtype with spindle cell carcinoma in particular has an aggressive biological behaviour. Management of patients with MBC should be based on validated prognostic variables

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m2. Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m2, the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m2. Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m2 and grade 2 in two, one who received a cumulative dose of 960 mg m2 and the other a cumulative dose of 600 mg m2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m2. Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m2, we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated

A pilot randomised controlled trial of personalised care for depressed patients with symptomatic coronary heart disease in South London general practices: the UPBEAT-UK RCT protocol and recruitment.

ABSTRACT: Background: Community studies reveal people with coronary heart disease (CHD) are twice as likely to be depressed as the general population and that this co-morbidity negatively affects the course and outcome of both conditions. There is evidence for the efficacy of collaborative care and case management for depression treatment, and whilst NICE guidelines recommend these approaches only where depression has not responded to psychological, pharmacological, or combined treatments, these care approaches may be particularly relevant to the needs of people with CHD and depression in the earlier stages of stepped care in primary care settings. Methods: This pilot randomised controlled trial will evaluate whether a simple intervention involving a personalised care plan, elements of case management and regular telephone review is a feasible and acceptable intervention that leads to better mental and physical health outcomes for these patients. The comparator group will be usual general practitioner (GP) care. 81 participants have been recruited from CHD registers of 15 South London general practices. Eligible participants have probable major depression identified by a score of ≥8 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D) together with symptomatic CHD identified using the Modified Rose Angina Questionnaire. Consenting participants are randomly allocated to usual care or the personalised care intervention which involves a comprehensive assessment of each participant’s physical and mental health needs which are documented in a care plan, followed by regular telephone reviews by the case manager over a 6-month period. At each review, the intervention participant’s mood, function and identified problems are reviewed and the case manager uses evidence based behaviour change techniques to facilitate achievement of goals specified by the patient with the aim of increasing the patient’s self efficacy to solve their problems. Depressive symptoms measured by HADS score will be collected at baseline and 1, 6- and 12 months post randomisation. Other outcomes include CHD symptoms, quality of life, wellbeing and health service utilisation. Discussion: This practical and patient-focused intervention is potentially an effective and accessible approach to the health and social care needs of people with depression and CHD in primary care. Trial registration: ISRCTN21615909