Interaction of stem cell factor and its receptor c-kit mediates lodgment and acute expansion of hematopoietic cells in the murine spleen

The phenotypes of mice that harbor a defect in the genes encoding either stem cell factor (SCF) or its receptor, c-kit, indicate that this ligand/receptor pair is necessary for maintenance of normal hematopoiesis in the adult. Our objective was to determine whether SCF, like erythropoietin, is necessary for acute erythroid expansion during recovery from hemolytic anemia. Monoclonal antibody ACK2, which recognizes the murine c-kit receptor, was used to selectively block the hematopoietic growth-promoting effects of SCF. Mice were treated with phenylhydrazine on day 0 and day 1 to induce hemolytic anemia and also received no antibody, control IgG, or ACK2 on day 0. The mice were killed on day 3 and the hematocrit (Hct), reticulocyte count, and numbers of erythroid and myeloid hematopoietic progenitor cells (colony- forming unit-erythroid [CFU-E], burst-forming unit [BFU]-E, and CFU- granulocyte-macrophage [GM]) were quantitated in the femoral marrow and spleen using hematopoietic colony-forming assays. Induction of hemolytic anemia with phenylhydrazine resulted in a drop in the Hct from approximately 50% to 30%, and an approximate 8- to 10-fold increase in the reticulocyte count. The numbers of CFU-E increased modestly in the femur, and approximately 25- to 50-fold in the spleen, in comparison with normal mice. BFU-E and CFU-GM values did not increase in the femur but expanded 6- to 10-fold in the spleen, in comparison with normal mice. This confirms that much of the erythroid expansion in response to hemolytic anemia occurs in the murine spleen. Neutralizing quantities of the ACK2 antibody reduced femoral CFU-E, BFU- E, and CFU-GM content to less than half that found in phenylhydrazine- treated control mice and nearly totally ablated splenic hematopoiesis. These results suggest that c-kit receptor function may be required for optimal response to acute erythropoietic demand and that erythropoiesis in the splenic microenvironment is more dependent on SCF/c-kit receptor interaction than is erythropoiesis in the marrow microenvironment. Because expansion of late erythropoiesis in the spleen was preferentially blocked, we tested the hypothesis that homing of more primitive hematopoietic cells to the spleen was dependent on c-kit receptor function. Lethally irradiated mice were injected with marrow cells obtained from mice that had received phenylhydrazine plus control IgG or with marrow cells obtained from mice that had received phenylhydrazine plus ACK2. In parallel experiments, normal murine marrow cells were treated in vitro with control IgG or with ACK2 and were injected into lethally irradiated mice. The fraction of BFU-E and CFU-GM retrieved from the marrow and spleen of the recipient mice 4 hours later was reduced by approximately 75% when progenitor cells had been exposed to ACK2, in comparison with control IgG. These data suggest that interaction of SCF with the c-kit receptor affects the homing behavior of hematopoietic progenitor cells in the adult animal.     

Meta-analysis: anticholinergics, but not β-agonists, reduce severe exacerbations and respiratory mortality in COPD

BACKGROUND: Anticholinergics and beta2-agonists have generally been considered equivalent choices for bronchodilation in chronic obstructive pulmonary disease (COPD). OBJECTIVE: To assess the safety and efficacy of anticholinergics and beta2-agonists in COPD. DESIGN: We comprehensively searched electronic databases from 1966 to December 2005, clinical trial websites, and references from selected reviews. We included randomized controlled trials of at least 3 months duration that evaluated anticholinergic or beta2-agonist use compared with placebo or each other in patients with COPD. MEASUREMENTS: We evaluated the relative risk (RR) of exacerbations requiring withdrawal from the trial, severe exacerbations requiring hospitalization, and deaths attributed to a lower respiratory event. RESULTS: Pooled results from 22 trials with 15,276 participants found that anticholinergic use significantly reduced severe exacerbations (RR 0.67, confidence interval [CI] 0.53 to 0.86) and respiratory deaths (RR 0.27, CI 0.09 to 0.81) compared with placebo. Beta2-agonist use did not affect severe exacerbations (RR 1.08, CI 0.61 to 1.95) but resulted in a significantly increased rate of respiratory deaths (RR 2.47, CI 1.12 to 5.45) compared with placebo. There was a 2-fold increased risk for severe exacerbations associated with beta2-agonists compared with anticholinergics (RR 1.95, CI 1.39 to 2.93). The addition of beta2-agonist to anticholinergic use did not improve any clinical outcomes. CONCLUSION: Inhaled anticholinergics significantly reduced severe exacerbations and respiratory deaths in patients with COPD, while beta2-agonists were associated with an increased risk for respiratory deaths. This suggests that anticholinergics should be the bronchodilator of choice in patients with COPD, and beta2-agonists may be associated with worsening of disease control.     

The rising rate of admissions for tonsillitis and neck space abscesses in England, 1991–2011

Introduction

Sore throats and tonsillitis represent a considerable health burden as well as a significant source of expenditure for the National Health Service (NHS). As part of the recent NHS savings drive, the introduction of ‘procedures of low clinical effectiveness’ (PoLCE) lists has reinforced a large reduction in the number of tonsillectomies performed. We carried out a cross-sectional study of trends in emergency sore throat admissions in the context of the number of tonsillectomies performed.

Methods

Hospital Episode Statistics (HES) data were extracted. Office for National Statistics data were also used.

Results

Between 1991 and 2011, the overall tonsillectomy rate fell by 44%. In the same time, the admission rate for tonsillitis rose by 310% (Pearson’s r=–0.67, p=0.01). The peritonsillar abscess admission rate rose by 31% (r=–0.79, p<0.01). Between 1996 and 2011, the overall tonsillectomy rate fell by 41% and the retro and parapharyngeal abscess admission rate rose by 39% (r=–0.55, p=0.026). There was a 14% overall increase in tonsillectomy and sore throat associated bed days. This was despite the large fall in tonsillectomy numbers and the reduction in length of hospital stay.

Conclusions

Efforts to reduce the tonsillectomy rate are correlated with a significant rise in emergency admissions. The rise in the retro and parapharyngeal abscess rate is perhaps most alarming given the very high mortality of these conditions. Bed day data suggest that no net saving has been made despite the new measures.     

Overview on SARS in Asia and the World

Severe Acute Respiratory Syndrome (SARS) is the first major novel infectious disease to hit the international community in the 21st century. It originated in southern China in November 2002, reached Hong Kong in February 2003 and spread rapidly thereafter to 29 countries/regions on five continents. At the end of the epidemic, the global cumulative total was 8098 with 774 deaths. Seven Asian countries/regions were among the top ten on the list. Mainland China and Hong Kong, SAR, accounted for 87% of all cases and 84% of all deaths. Severe acute respiratory syndrome is caused by a novel coronavirus. It has alarmed the world with its infectivity and significant morbidity and mortality, its lack of a rapid, reliable diagnostic test and lack of effective specific treatment and vaccination. The adverse impact on travel and business around the world, particularly in Asia, has been enormous. Some lessons learnt from this epidemic included: (1) any outbreak of infectious disease can rapidly spread around the world by air travel; (2) early reporting of the outbreak to neighbouring countries/regions and the World Health Organization is essential to prevent international spread; and (3) infection control, tracing and quarantine of contacts are essential to control the epidemic. Many questions remain unanswered, including the origin and pathogenesis of the novel coronavirus, the natural history and the best specific treatment of the disease. The SARS‐CoV has probably jumped from an animal host to humans. There is an urgent need to evaluate the human–animal habitat in southern China and to remove animal reservoirs if found.