A paracrine role for chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) in mediating chemotactic activation of CRTH2+ CD4+ T helper type 2 lymphocytes

Activation of human CRTH2(+) CD4(+) T helper type 2 (Th2) cells with anti-CD3/anti-CD28 led to time-dependent production of prostaglandin D(2) (PGD(2)) which peaked at 8 hr. The production of PGD(2) was completely inhibited by cotreatment with the cyclo-oxygenase inhibitor diclofenac (10 microm) but was not affected by cotreatment with ramatroban, a dual antagonist of both the thromboxane-like prostanoid (TP) receptor and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Supernatants from activated CRTH2(+) CD4(+) Th2 cells caused a concentration-dependent increase in the migration of naive CRTH2(+) CD4(+) Th2 cells compared to supernatants from unstimulated CRTH2(+) CD4(+) Th2 cells. The level of chemotactic activity peaked at 8 hr after activation, corresponding to the peak levels of PGD(2), but production of chemotactic activity was only partially inhibited by the cyclo-oxygenase inhibitor diclofenac. In contrast, ramatroban completely inhibited the chemotactic responses of naive Th2 cells to supernatants from activated CRTH2(+) CD4(+) Th2 cells collected up to 8 hr after activation, although supernatants collected 24 hr after activation were less sensitive to inhibition by ramatroban. The selective TP antagonist SQ29548 did not inhibit migration of Th2 cells, implicating CRTH2 in this response. These data suggest that CRTH2 plays an important paracrine role in mediating chemotactic activation of Th2 cells. Interestingly, although PGD(2) is produced from Th2 cells and contributes to this paracrine activation, it appears that additional CRTH2 agonist factors are also produced by activated Th2 cells and the production of these factors occurs independently of the cyclo-oxygenase pathway of the arachidonic acid metabolism.     

The characteristics of recovery sleep when recovery opportunity is restricted

STUDY OBJECTIVES: The aim of this study was to investigate the recovery of sleep and waking functions following one night of total sleep deprivation, when recovery opportunity was either augmented or restricted. DESIGN: The 9-day laboratory study involved a baseline night, a night of sleep loss (approximately 40 h) followed by 5 nighttime recovery sleep periods. Recovery consisted of either five 9-h sleep opportunities or five 6-h sleep opportunities. SETTING: All data collection took place in a controlled laboratory environment at the Centre for Sleep Research. PARTICIPANTS: A total of n = 20 healthy adults (18-35 yrs) participated in the study. RESULTS: Each sleep period was recorded using a standard polysomnographic EEG montage. Waking functions were assessed every 2 hours during all wake periods, using a 10 minute psychomotor vigilance task (PVT) and a subjective alertness visual analogue scale (VAS). Sleep analyses indicated that across the week TST, SOL, REM, and sleep efficiency varied significantly between the 2 conditions, but amounts of SWS did not. Waking functions in the 9-h condition recovered after one sleep period. In the 6-h condition however, mean response time on the PVT was 10% below baseline and subjective alertness 20% below baseline for the entire recovery period. CONCLUSIONS: The results suggest that TST is a key factor in determining recovery. When recovery opportunity is restricted, both sleep variables and measures of waking functions do not recover.     

p150/95 (CD11c/CD18) expression is required for the development of experimental autoimmune encephalomyelitis

p150/95 (CD11c/CD18, CR4) is a member of the beta(2)-integrin family of adhesion molecules and is considered an important phagocytic receptor. The role of p150/95 in the development of central nervous system demyelinating diseases, including multiple sclerosis, remains unexplored. To determine p150/95-mediated mechanisms in experimental autoimmune encephalomyelitis (EAE), we performed EAE using CD11c-deficient (CD11c(-/-)) mice. EAE in CD11c(-/-) mice was significantly attenuated and characterized by markedly reduced spinal cord T-cell infiltration and interferon-gamma production by these cells. Adoptive transfer of antigen-restimulated T cells from wild-type to CD11c(-/-) mice produced significantly attenuated EAE, whereas transfer of CD11c(-/-) antigen-restimulated T cells to control mice induced a very mild, monophasic EAE. T cells from MOG(35-55) peptide-primed CD11c(-/-) mice displayed an unusual cytokine phenotype with elevated levels of interleukin (IL)-2, IL-4, and IL-12 but reduced levels of interferon-gamma, tumor necrosis factor-alpha, IL-10, IL-17, and transforming growth factor-beta compared with control mice. Overall, CD11c(-/-) T cells from primed mice proliferated comparably to that of control T cells on MOG(35-55) restimulation. Our results indicate that expression of p150/95 is critical on both T cells as well as other leukocytes for the development of demyelinating disease and may represent a novel therapeutic target for multiple sclerosis.     

Malignancy in Renal Transplant Recipients Exposed to Cyclophosphamide Prior to Transplantation for the Treatment of Native Glomerular Disease

Study Objective

To evaluate the risk of posttransplantation malignancy in renal transplant recipients exposed to pretransplantation cyclophosphamide for the treatment of glomerular nephropathy (GN).

Design

Retrospective cohort study.

Setting

Tertiary academic medical center.

Patients

Six hundred adult renal transplant recipients were transplanted between 1993 and 2014; 54 patients were exposed to pretransplantation cyclophosphamide for treatment of GN (GN‐CYC group), and 546 patients with polycystic kidney disease were not exposed to pretransplantation cyclophosphamide (PKD group).

Measurement and Main Results

Data were collected retrospectively from electronic medical records. The primary outcome was occurrence of posttransplantation malignancy. During a median follow‐up of 5.5 years, 130 patients developed malignancy (incidence rate 3.5 events per 100 person‐yrs). Exposure to cyclophosphamide before transplantation was significantly associated with malignancy after transplantation (adjusted hazard ratio [aHR] 2.20, 95% confidence interval [CI] 1.16–4.22, p=0.02), specifically skin cancer (aHR 2.24, 95% CI 1.09–4.60, p=0.03). Malignancy risk in the GN‐CYC group was higher in the setting of lymphocyte‐depleting induction (alemtuzumab; aHR 4.53, 95% CI 0.99–20.72, p=0.05) compared with basiliximab induction. Incidences of death‐censored graft loss and mortality were similar between the GN‐CYC and PKD groups.

Conclusion

In our observational study, renal transplant recipients exposed to pretransplantation cyclophosphamide appeared to have a higher risk of developing a malignancy compared with unexposed renal transplant recipients. Further investigation into the impact of pretransplantation immunosuppression on malignancy, particularly the compounded effect with lymphocyte‐depleting induction, is warranted.     

Competencies and skills for remote and rural maternity care: a review of the literature

AIM: This paper reports a review of the literature on skills, competencies and continuing professional development necessary for sustainable remote and rural maternity care. BACKGROUND: There is a general sense that maternity care providers in rural areas need specific skills and competencies. However, how these differ from generic skills and competencies is often unclear. METHODS: Approaches used to access the research studies included a comprehensive search in relevant electronic databases using relevant keywords (e.g. 'remote', 'midwifery', 'obstetrics', 'nurse-midwives', education', 'hospitals', 'skills', 'competencies', etc.). Experts were approached for (un-)published literature, and books and journals known to the authors were also used. Key journals were hand searched and references were followed up. The original search was conducted in 2004 and updated in 2006. FINDINGS: Little published literature exists on professional education, training or continuous professional development in maternity care in remote and rural settings. Although we found a large literature on competency, little was specific to competencies for rural practice or for maternity care. 'Hands-on' skills courses such as Advanced Life Support in Obstetrics and the Neonatal Resuscitation Programme increase confidence in practice, but no published evidence of effectiveness of such courses exists. CONCLUSION: Educators need to be aware of the barriers facing rural practitioners, and there is potential for increasing distant learning facilitated by videoconferencing or Internet access. They should also consider other assessment methods than portfolios. More research is needed on the levels of skills and competencies required for maternity care professionals practising in remote and rural areas.     

Advanced Gynecologic Laparoscopy in a Fast-Track Ambulatory Surgery Center

Background/Objectives:

It has been shown that major gynecologic laparoscopy is safe in hospital ambulatory settings, but there is little data to suggest the same in freestanding ambulatory surgery centers. This study evaluates the safety and efficacy of advanced gynecologic laparoscopic surgery using a fast-track model in freestanding ambulatory surgery centers and discusses our institution protocols.

Methods:

Retrospective, multicenter review was conducted of major gynecologic surgeries from August 1^st 2010 to September 30^th 2011 in 3 surgical centers with one primary surgeon. All patients were treated for symptomatic uterine leiomyomas and/or endometriosis. Primary outcome measures were unplanned admissions and discharge within 23 hours.

Results:

One hundred and thirty-four patients underwent major laparoscopic gynecologic surgery with a total of 160 procedures: 77 stage IV endometriosis treatment including 7 disk excisions of endometriosis from the large bowel, 3 ureteroneocystostomies and 1 partial bladder resection, 38 myomectomies, and 34 hysterectomies including 12 modified radical hysterectomies. The overall unplanned admission rate was 4.5%. One hundred and thirty-one patients (97.7%) were discharged within 24 hours after surgery. Three patients (2.2%) were transferred to the hospital postoperatively: 1 patient for observation of postoperative anemia and 2 patients for postoperative fever. Three patients (2.2%) were admitted to the hospital after discharge: 1 patient for postoperative ileus, 1 patient for postoperative fever, and 1 patient with septic pelvic thrombophlebitis. These postoperative issues all resolved without complication, and all patients had an uneventful follow-up.

Conclusions:

With appropriate resources and an experienced surgeon, advanced laparoscopic surgery can be safely performed in a fast-track ambulatory surgery center with a high rate of discharge within 23 hours and low unplanned readmission rate.     

Geographical and ecological analyses of childhood acute leukaemias and lymphomas in north-west England

Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology.     

Multi-Modality Imaging in the Evaluation and Treatment of Tricuspid Regurgitation

Purpose of review

The goal of this review is to cover the epidemiology of tricuspid regurgitation (TR), anatomy of the tricuspid valve (TV), and the mechanisms and modern treatment of TR. The focus will be on the role of echocardiography, cardiac CT, and MRI to determine the mechanism, severity, and management strategies of TR.

Recent findings

The evaluation and management of TR is a rapidly growing field with significant advances in both imaging and interventions. Important advances have been made to understand TV anatomy and physiology in 3D echo, CT, and MRI. Additional understanding of the abnormal outcomes in both primary TR and secondary TR have been appreciated. Multiple transcatheter devices have reached the stage of early trials in high surgical risk cohorts with favorable initial findings.

Summary

TR is a significant cardiovascular problem and vastly undertreated in the present era. There has been tremendous growth in knowledge of mechanisms of TR, its prognostic implications, timing of intervention, and development of novel treatment strategies. Multimodality imaging plays a key role in evaluation and treatment of this condition.