Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice

Flk-1(+) endothelial progenitors contribute critically to the definitive onset of hematopoiesis during embryogenesis. Recent studies have suggested that adult sources of endothelial cells also possess hematopoietic activity. In this study, we sought to determine whether transplantation of primary vascular endothelial cells (ECs) could enhance the hematopoietic recovery and survival of irradiated mice. C57Bl6 mice were exposed to sublethal and lethal doses of irradiation and were subsequently given transplants of either primary murine brain-derived ECs (MBECs) or fetal blood-derived ECs (FBECs). Mice that received a transplant with MBECs alone demonstrated accelerated BM cellular recovery, radioprotection of BM c-kit(+)sca-1(-)lin(-) progenitors and enhanced regeneration of c-kit(+)sca-1(+)lin(-) (KSL) stem/progenitor cells following irradiation compared with controls. MBEC transplantation also facilitated the recovery of circulating white blood cell and platelet counts following radiation exposure. Remarkably, 57% of mice that received a transplant with MBECs alone survived long term following 1050 cGy exposure, which was 100% lethal in control mice. FBEC transplantation was also associated with increased survival compared with controls, although these mice did not survive in the long term. These data suggest that reestablishment of endothelial cell activity can improve the hematopoietic recovery and survival of irradiated mice.     

Targeted treatment using monoclonal antibodies and tyrosine-kinase inhibitors in pregnancy

An expanding knowledge of the signalling pathways involved in the cell cycle has led to great improvements in the understanding of the molecular events involved in carcinogenesis. The past decade has seen substantial advances with the introduction of several classes of targeted therapeutics for the treatment of various cancers and autoimmune disorders. However, the question arises as to whether pregnant women can take advantage of these new treatments in view of the potential risks to the fetus. Published work suggests that biological agents, like traditional treatments, have the potential to affect the fetus, and should, therefore, be used with caution during pregnancy. However, when targeted treatment is clearly indicated the magnitude of the risk to the fetus might not reach that of standard chemotherapy. In circumstances where better alternative treatments do not exist, or where failure to use targeted treatments would result in suboptimum patient care or survival, the risk-benefit analysis might favour the use of potentially effective molecular treatment during pregnancy.     

Urolithiasis in pregnancy

The presentation of urolithiasis is often dramatic, but rarely is it more anxiety provoking than during pregnancy. The evaluation and the intervention are often approached with trepidation as the health of the mother and the fetus must be taken into account. The typical diagnostic course and surgical management used in the nonpregnant population must be reevaluated in the expectant mother. Failure to promptly diagnose and manage urolithiasis during pregnancy may have adverse consequences for mother and child. The authors present a review of the relevant anatomic and physiologic changes of pregnancy as they affect stone disease and outline options for radiologic evaluation and surgical management.     

Blunted humoral response to influenza vaccination in patients exposed to zidovudine plus trimethoprim-sulfamethoxazole

STUDY OBJECTIVES: To determine as proof of principle the effect of combination exposure to zidovudine plus trimethoprim-sulfamethoxazole (TMP-SMX) on humoral immune responses to influenza vaccination in patients with human immunodeficiency virus (HIV). DESIGN: Prospective, open-label trial. SETTING: University-affiliated infectious diseases outpatient clinic. PATIENTS: Twenty-three HIV-infected adults receiving antiretroviral therapy, with CD4+ cell counts greater than 350 cells/mm3 and undetectable viral loads. INTERVENTION: Patients were assigned to one of four treatment groups: zidovudine (6 patients), TMP-SMX (7), zidovudine plus TMP-SMX (5), or neither drug (5); TMP-SMX was given as a 28-day course. Patients were subsequently immunized with the yearly influenza vaccine, and humoral responses were compared among groups 20-24 days after vaccination. MEASUREMENTS AND MAIN RESULTS: Antibody responses to influenza A and B were measured, and total and activated T and B cell percentages in the peripheral blood were determined. Mean influenza B-specific serum immunoglobulin (Ig)G titers were significantly lower in patients receiving TMP-SMX alone (0.98 +/- 0.60 reference value, p=0.010) or the combination of zidovudine plus TMP-SMX (0.73 +/- 0.29 reference value, p=0.003) compared with those receiving neither drug (1.95 +/- 0.38 reference value). This corresponded to a significantly lower percentage of patients in the combination group that achieved immunoprotective titers to influenza B compared with the group who received neither drug (control group; 20% vs 100%, p=0.048). In addition, the relationship between serum IgG titer and CD4+ cell count was statistically significantly different for patients exposed to zidovudine plus TMP-SMX versus control patients for both influenza A and B (F statistics 8.72 and 11.70, respectively, compared with critical F value 7.26 for p<0.025). Likewise, the relationship between influenza B serum IgG and CD4+ cell count was different among patients who received TMP-SMX versus those who did not receive TMP-SMX (F statistic 5.95 compared with critical F value 4.56 for p<0.025). No significant differences were observed among T and B cell percentages in the blood. CONCLUSION: Combination exposure to zidovudine plus TMP-SMX causes a clinically significant suppression of humoral immune responses to influenza vaccination in HIV-infected patients.     

Tuberculosis,focussed tools and the right schools: estimated impact and cost of a targeted student screening programme for tuberculosis infection

Background

The World Health Organization (WHO) recommends targeted screening for latent tuberculosis infection (LTBI) among high-risk populations. Recent studies that evaluate targeted school-based programmes in low burden settings are scarce.

Aims

To evaluate a school screening programme for recently arrived migrant students from moderate and high tuberculosis (TB) burden countries and estimate (1) the number of cases of active TB that were prevented and (2) the cost per case of active TB prevented.

Methods

Students were screened with tuberculin skin tests (TST) at schools with a high migrant population intake. Those with positive results were referred for specialist evaluation. Outcomes were retrospectively assessed using 5 years of prospectively collected data. Cost data were collected. Main outcomes measured were the number of children were diagnosed with LTBI who completed treatment, and programme costs.

Results

Of 4728 student screened, 295 (6.2%) were diagnosed with LTBI. Of these, 273 (92.5%) were offered preventive therapy, 242 (82.0%) commenced and 204 (69.2%) completed therapy. The number needed to screen (NNS) was 23 per completed course of preventive treatment for LTBI. Assuming a 10% lifetime risk of reactivation, the NNS was 386 per case of TB disease notification avoided. The cost of screening was A$23 932 per case of TB disease avoided.

Conclusions

This TB strategy is supported by the high rate of TB infection in the student group, the treatment uptake and completion rates. Cost–benefit is linked with lifetime risk of TB reactivation. Targeted school screening programmes represent an important opportunity for TB control in low-burden settings.     

Strategies to enhance physical activity in people with Rheumatoid Arthritis: A Delphi survey

Introduction

Managing symptoms, resisting functional decline and maintaining health and independence are key motivators for people with Rheumatoid Arthritis (RA) who successfully engage with physical activity (PA). To inform PA support for people with RA the aim was to determine whether the broader RA population share similar beliefs and strategies regarding PA to those who report successful engagement.

Methods

A modified two-stage Delphi approach. 200 patients from four National Health Service rheumatology departments received a postal questionnaire containing statements relating to engagement with PA derived from prior interview data from physically active individuals with RA. Statements rated as agree or strongly agree by >50% of respondents were retained and the same respondents asked to rate and prioritize potential PA intervention components. Ethical approval: Oxford C Research Ethics Committee (ref 13/SC/0418).

Results

Questionnaire one received 49 responses (11 males, 37 females, 1 unknown), mean age 65 years (range 29–82). Low levels of PA were reported by 60% of respondents. Questionnaire two responses (n = 36) indicated that a PA intervention should include information about prevention of RA symptoms worsening and benefits of PA for joints; help participants to achieve improved pain management and a feeling of being in control of their RA. For PA maintenance it was important that medication controlled symptoms, and PA instructors understood RA to ensure safety.

Conclusions

A key factor to consider when designing a PA intervention for people with RA is that education from a knowledgeable instructor should underpin programme delivery alongside effective medication. Programmes may need tailoring based on demographics; this should be explored in future studies.     

Additional lesions identified by genomic microarrays are associated with an inferior outcome in low-risk chronic lymphocytic leukaemia patients

We explored the relevance of genomic microarrays (GM) in the refinement of prognosis in newly diagnosed low-risk chronic lymphocytic leukaemia (CLL) patients as defined by isolated del(13q) or no lesions by a standard 4 probe fluorescence in situ hybridization (FISH) analysis. Compared to FISH, additional lesions were detected by GM in 27 of the 119 patients (22.7%). The concordance rate between FISH and GM was 87.4%. Discordant results between cytogenetic banding analysis (CBA) and GM were observed in 45/119 cases (37.8%) and were mainly due to the intrinsic characteristics of each technique. The presence of additional lesions by GM was associated with age > 65 years (p = 0.047), advanced Binet stage (p = 0.001), CLL-IPI score (p < 0.001), a complex karyotype (p = 0.004) and a worse time-to-first treatment in multivariate analysis (p = 0.009). Additional lesions by GM were also significantly associated with a worse time-to-first treatment in the subset of patients with wild-type TP53 and mutated IGHV (p = 0.025). In CLL patients with low-risk features, the presence of additional lesions identified by GM helps to identify a subset of patients with a worse outcome that could be proposed for a risk-adapted follow-up and for early treatment including targeted agents within clinical trials.