Pre-B-cell development in the absence of λ5 in transgenic mice expressing a heavy-chain disease protein

AbstractBackground: Heavy-chain diseases (HCDs) are human lymphoproliferative neoplasias that are characterized by the secretion of truncated immunoglobulin heavy chains devoid of light chains. We have previously proposed — by analogy to the process by which mutated growth factor receptors can be oncogenic — that because the genetic defects in HCDs result in the production of abnormal membrane-associated heavy chains lacking an antigen-binding domain, these abnormal B-cell antigen receptors might engage in ligand-independent signalling. Normal pre-B-cell development requires the presence of the pre-B-cell receptor, formed by the association of μ heavy chains with two polypeptides — so-called surrogate light chains, Vpre-B and λ5 — that are homologous to the variable and constant portions of immunoglobulin light chains, respectively. To assess whether amino-terminal truncation of membrane-associated heavy chains results in their constitutive activation, we have examined the ability of a HCD-associated μ protein to promote pre-B-cell development in transgenic mice.Results When the μ HCD transgene is introduced into SCID mice, CD43− pre-B cells develop normally. To determine whether this pre-B-cell development requires surrogate light chains, we backcrossed mice expressing full-length or truncated μ transgenes with λ5-deficient mice. Our results show that the truncated heavy chain, but not the normal chain, is able to promote pre-B-cell development in the absence of λ5. We also show that truncated μ chains spontaneously aggregate at the surface of bone marrow cells.Conclusion Expression of the truncated μ heavy chain overrides a tightly controlled step of pre-B-cell development, which strongly suggests that a constitutive signal is delivered by the truncated μ chain disease protein. The self-aggregation of μ chain disease proteins might account for this constitutive activation. We conclude that amino-terminal truncation of heavy chains could play a role in the genesis of HCD neoplasia if it occurs at an appropriate stage of B-cell differentiation, namely in a mature B cell

Differences in pelvic floor morphology between continent, stress urinary incontinent, and mixed urinary incontinent elderly women : an MRI study

Aims To compare magnetic resonance imaging (MRI) of the pelvic floor musculature (PFM), bladder neck and urethral sphincter morphology under three conditions (rest, PFM maximal voluntary contraction (MVC), and straining) in older women with symptoms of stress (SUI) or mixed urinary incontinence (MUI) or without incontinence. Methods This 2008–2012 exploratory observational cohort study was conducted with community-dwelling women aged 60 and over. Sixty six women (22 per group), mean age of 67.7 ± 5.2 years, participated in the study. A 3 T MRI examination was conducted under three conditions: rest, PFM MVC, and straining. ANOVA or Kruskal–Wallis tests (data not normally distributed) were conducted, with Bonferroni correction, to compare anatomical measurements between groups. Results Women with MUI symptoms had a lower PFM resting position (M-Line P = 0.010 and PC/H-line angle P = 0.026) and lower pelvic organ support (urethrovesical junction height P = 0.013) than both continent and SUI women. Women with SUI symptoms were more likely to exhibit bladder neck funneling and a larger posterior urethrovesical angle at rest than both continent and MUI women (P = 0.026 and P = 0.008, respectively). There were no significant differences between groups on PFM MVC or straining. Conclusions Women with SUI and MUI symptoms present different morphological defects at rest. These observations emphasize the need to tailor UI interventions to specific pelvic floor defects and UI type in older women

Responsiveness and clinical utility of the geriatric self-efficacy index for urinary incontinence

OBJECTIVES: To report on the responsiveness testing and clinical utility of the 12-item Geriatric Self-Efficacy Index for Urinary Incontinence (GSE-UI). DESIGN: Prospective cohort study. SETTING: Six urinary incontinence (UI) outpatient clinics in Quebec, Canada. PARTICIPANTS: Community-dwelling incontinent adults aged 65 and older. MEASUREMENTS: The abridged 12-item GSE-UI, measuring older adults' level of confidence for preventing urine loss, was administered to all new consecutive incontinent patients 1 week before their initial clinic visit, at baseline, and 3 months posttreatment. At follow-up, a positive rating of improvement in UI was ascertained from patients and their physicians using the Patient's and Clinician's Global Impression of Improvement scales, respectively. Responsiveness of the GSE-UI was calculated using Guyatt's change index. Its clinical utility was determined using receiver operating curves. RESULTS: Eighty-nine of 228 eligible patients (39.0%) participated (mean age 72.6+5.8, range 65–90). At 3-month follow-up, 22.5% of patients were very much better, and 41.6% were a little or much better. Guyatt's change index was 2.6 for patients who changed by a clinically meaningful amount and 1.5 for patients having experienced any level of improvement. An improvement of 14 points on the 12-item GSE-UI had a sensitivity of 75.1% and a specificity of 78.2% for detecting clinically meaningful changes in UI status. Mean GSE-UI scores varied according to improvement status (P<.001) and correlated with changes in quality-of-life scores (r=0.7, P<.001) and reductions in UI episodes (r=0.4, P=.004). CONCLUSION: The GSE-UI is responsive and clinically useful

Paneth Cell Alterations During Ischemia-reperfusion, Follow-up, and Graft Rejection After Intestinal Transplantation

BACKGROUND Ischemia-reperfusion (IR) injury is inevitable during intestinal transplantation (ITx) and executes a key role in the evolution towards rejection. Paneth cells (PC) are crucial for epithelial immune defense and highly vulnerable to IR injury. We investigated the effect of ITx on PC after reperfusion (T0), during follow-up, and rejection. Moreover, we investigated whether PC loss was associated with impaired graft homeostasis. METHODS Endoscopic biopsies, collected according to center-protocol and at rejection episodes, were retrospectively included (n=28 ITx, n=119 biopsies) Biopsies were immunohistochemically co-stained for PC (lysozyme) and apoptosis, and PC/crypt and lysozyme intensity were scored. RESULTS We observed a decrease in PC/crypt and lysozyme intensity in the first week after ITx (W1) compared to T0. There was a tendency towards a larger decline in PC/crypt (p=0.08) and lysozyme intensity (p=0.08) in W1 in patients who later developed rejection compared to patients without rejection. Follow-up biopsies showed that the PC number recovered, whereas lysozyme intensity remained reduced. This persisting innate immune defect may contribute to the well-known vulnerability of the intestine to infection. There was no clear evidence that PC were affected throughout rejection. CONCLUSION This study revealed a transient fall in PC numbers in the early post-ITx period, but a permanent reduction in lysozyme intensity following ITx. Further research is needed to determine the potential clinical impact of PC impairment after ITx

Characteristics of Suicide Attempts in Anorexia and Bulimia Nervosa: A Case–Control Study

Objective: Compared to other eating disorders, anorexia nervosa (AN) has the highest rates of completed suicide whereas suicide attempt rates are similar or lower than in bulimia nervosa (BN). Attempted suicide is a key predictor of suicide, thus this mismatch is intriguing. We sought to explore whether the clinical characteristics of suicidal acts differ between suicide attempters with AN, BN or without an eating disorders (ED). Method: Case-control study in a cohort of suicide attempters (n = 1563). Forty-four patients with AN and 71 with BN were compared with 235 non-ED attempters matched for sex, age and education, using interview measures of suicidal intent and severity. Results: AN patients were more likely to have made a serious attempt (OR = 3.4, 95 % CI 1.4–7.9), with a higher expectation of dying (OR = 3.7,95 % CI 1.1–13.5), and an increased risk of severity (OR = 3.4,95 % CI 1.2–9.6). BN patients did not differ from the control group. Clinical markers of the severity of ED were associated with the seriousness of the attempt. Conclusion: There are distinct features of suicide attempts in AN. This may explain the higher suicide rates in AN. Higher completed suicide rates in AN may be partially explained by AN patients ’ higher desire to die and their more severe and lethal attempts

The Utility of Urodynamic Studies in Neuro-Urological Patients

Introduction: The utility of a clinical tool lies in its clinical performance evaluation and describes the relevance and usefulness of that tool in a medical setting. The utility of urodynamic and video-urodynamic studies in the management of specific urodynamic profiles in the diagnosis, treatment, and prognostic approach in neuro-urological patients is the focus of the current review. Methods: For this narrative review, a PubMed® search was performed by cross-referencing the keywords “urodynamics”, “neurogenic bladder”, “utility”, “clinical utility” and “clinical performance” with various terms related to the management of neurogenic lower urinary tract dysfunction. Clinical practice guidelines and landmark reviews from the most renowned experts in the field were also used. Analysis: Assessment of the utility of urodynamic study was performed during the diagnostic, therapeutic and prognostic steps of the neuro-urological patients’ management. We focused on its clinical performance in the identification and evaluation of several unfavorable events, such as neurogenic detrusor overactivity, detrusor-sphincter dyssynergia, elevated detrusor leak point pressure and the presence of vesico-ureteral reflux, which may be indicators for a higher risk for the development of urological comorbidities. Conclusion: Despite the paucity of existing literature assessing the utility of urodynamic study—specifically video-urodynamic study—in neuro-urological patients, it does remain the gold standard to assess lower urinary tract function precisely in this patient category. With regard to its utility, it is associated with high clinical performance at every step of management. The feedback on possible unfavorable events allows for prognostic assessment and may lead us to question current recommendations