Molecular insights into stress erythropoiesis

PURPOSE OF REVIEW: In addition to its essential role in baseline erythropoiesis, the hormone erythropoietin drives the erythropoietic response to hypoxic stress. A mechanistic understanding of stress erythropoiesis would benefit multiple clinical settings, and may aid in understanding leukemogenesis. RECENT FINDINGS: The spectrum of progenitors targeted by the erythropoietin receptor is broader during stress than during baseline erythropoiesis. Further, the requirement for erythropoietin receptor signaling is more stringent during stress. However, erythropoietin receptor signaling has been mostly studied in vitro, where it is difficult to relate signaling events to stress-dependent changes in erythroid homeostasis. Here we review advances in flow cytometry that allow the identification and study of murine erythroid precursors in hematopoietic tissue as they are responding to stress in vivo. The death receptor Fas and its ligand, FasL, are coexpressed by early splenic erythroblasts, suppressing erythroblast survival and erythropoietic rate. During stress, erythropoietin receptor signaling downregulates erythroblast Fas and FasL, consequently increasing erythropoietic rate. SUMMARY: Erythropoietic rate is regulated at least in part through the erythropoietin receptor-mediated survival of splenic early erythroblasts. Future research will delineate how multiple antiapoptotic pathways, potentially activated by the erythropoietin receptor, interact to produce the remarkable dynamic range of erythropoiesis.     

Changes in gene expression pattern following granulocyte colony-stimulating factor administration to normal stem cell sibling donors

Granulocyte colony-stimulating factor (G-CSF) is widely used for the mobilization of hematopoietic stem cells from normal donors. The mechanism of induced mobilization has recently been elucidated. Treatment with G-CSF is considered safe; however, long-term effects are largely unknown. The aim of this study was, therefore, to determine whether it leads to significant changes in gene expression modifications. Affymetrix Gene Chip array technology was used. Samples were collected before and at various time points (up to 9 months) after mobilization. The expression levels of 122 genes were transiently modified before and after mobilization (p < 0.05). Fifty-three genes belonging to cell growth, proliferation and communication gene ontology categories were upregulated, while 69 genes were downregulated. Conclusion: The administration of G-CSF is associated with transient DNA and gene expression modifications in the lymphocytes of normal mobilized donors. A long-term follow-up of stem cell donors is recommended.     

Medical response of a physician and two nurses to the mass-casualty event resulting in the Phi Phi Islands from the tsunami

The Phi Phi Islands are isolated islands located about one hour by ship from the mainland in Krabi province of Thailand. There is a small medical facility where the director is the one physician that provides care to residents and tourists. This small medical facility faced an enormous mass casualty incident due to the 2004 Tsunami. The hospital was damaged by the Tsunami wave and was not functional, one crew member died and another was injured. Medical care and evacuation posed a unique problem in the Phi Phi Islands due to remoteness, limited medical resources, lack of effective communication with the main land and the large number of victims. An alternative medical facility was located in a nearby hotel. The crew included the medical director, two nurses, two additional staff members, 10 local volunteers, and hotel staff members. The medical crew had to treat 600-700 casualties in 24 hours. Most of the victims were mildly injured, but approximately 100 (15%) of the victims could not walk due to their injuries. The medical director, made a conscious decision to initially treat only circulation ("C") problems, by controlling external hemorrhages. This decision was driven by the lack of equipment and personnel to deal with airway ("A") and breathing ("B") problems. In the post-disaster debriefing, the Phi Phi Island hospital physician noted five major lessons concerning disaster management in such extreme situation in a small facility located in a remote area: (1) effective resistant communication facilities must be ensured; (2) clear, simple "evacuation plans" should be made in advance; (3) plans should be made to ensure automatic reinforcement of remote areas with evacuation vehicles, medical equipment and medical personnel; (4) efficient cooperation with medical volunteers must be planned and drilled; and (5) every team member of such a hospital must participate in an educational program and periodic drills should be done to improve the disaster and emergency medicine capabilities. This case report is an example for caregivers all over the world, of an amazing lesson of leadership and courage.     

Disaster healthcare system management and crisis intervention leadership in Thailand--lessons learned from the 2004 Tsunami disaster

INTRODUCTION: Quarantelli established criteria for evaluating the effectiveness of disaster management. OBJECTIVES: The objectives of this study were to analyze the response of the healthcare system to the Tsunami disaster according to the Quarantelli principles, and to validate these principles in a scenario of a disaster due to natural hazards. METHODS: The Israeli Defense Forces (IDF) Home Front Command Medical Department sent a research team to study the response of the Thai medical system to the disaster. The analysis of the disaster management was based on Quarantelli's 10 criteria for evaluating the management of community disasters. Data were collected through personal and group interviews. RESULTS: The three most important elements for effective disaster management were: (1) the flow of information; (2) overall coordination; and (3) leadership. Although pre-event preparedness was for different and smaller scenarios, medical teams repeatedly reported a better performance in hospitals that recently conducted drills. CONCLUSIONS: In order to increase effectiveness, disaster management response should focus on: (1) the flow of information; (2) overall coordination; and (3) leadership.     

Exercise induced muscle blood flow is decreased in Charcot–Marie–Tooth disease type 1 polyneuropathy: a power Doppler analysis

Background and purpose

Intramuscular blood flow increases during physical activity and may be quantified immediately following exercise using power Doppler sonography. Post-exercise intramuscular blood flow is reduced in patients with muscular dystrophy, associated with disease severity and degenerative changes. It is not known if intramuscular blood flow is reduced in patients with neuropathy, nor if it correlates with muscle strength and structural changes. The aim was to determine whether blood flow is reduced in patients with polyneuropathy due to Charcot–Marie–Tooth disease type 1 (CMT1) and to compare more affected distal to less affected proximal muscles.

Methods

This was a cross-sectional study including 21 healthy volunteers and 17 CMT patients. Power Doppler ultrasound was used to quantify post-exercise intramuscular blood flow in distal (gastrocnemius) and proximal (elbow flexor) muscles. Intramuscular blood flow was compared to muscle echo intensity, muscle strength, disease severity score, patient age and electromyography.

Results

Polyneuropathy patients showed reduced post-exercise blood flow in both gastrocnemius and elbow flexors compared to controls. A more prominent reduction was seen in the gastrocnemius (2.51% vs. 10.34%, p < 0.0001) than in elbow flexors (4.48% vs. 7.03%, p < 0.0001). Gastrocnemius intramuscular blood flow correlated with muscle strength, disease severity and age. Receiver operating characteristic analysis showed that quantification of intramuscular blood flow was superior to echo intensity for detecting impairment in the gastrocnemius (area under the curve 0.962 vs. 0.738, p = 0.0126).

Conclusion

Post-exercise intramuscular blood flow is reduced in CMT1 polyneuropathy. This reduction is present in both impaired distal and minimally affected proximal muscles, indicating it as an early marker of muscle impairment due to neuropathy.     

Real-world experience with belantamab mafodotin therapy for relapsed/refractory multiple myeloma: A multicentre retrospective study

Belantamab mafodotin, an immuno-conjugate targeting B-cell maturation antigen, showed single-agent activity in phase 1 and 2 studies, and was recently approved for heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. Real-world data and long-term follow-up are scarce. We conducted a multisite retrospective study aimed to assess safety and efficacy of belantamab mafodotin monotherapy administered via the GSK expanded access compassionate care programme. One-hundred and six RRMM patients were treated with belantamab mafodotin between July 2019 and March 2021. The median age was 69.4 years. Patients were heavily pretreated with a median of six (range 2–11) prior therapy lines. Major adverse effects included ocular toxicity (keratopathy 68.4%, grade ≥3: 40.5%; blurred vision 36.8%, grade ≥3: 6.3%), thrombocytopenia (27.4%, grade ≥3: 17.9%) and infections (11.3%, grade ≥3: 7.5%). Median follow-up time was 11.9 [95% confidence interval (CI) 10.0–13.8] months. Overall response rate was 45.5%. Median progression-free survival was 4.7 (95% CI 3.5–5.9) months in the entire cohort and 8.8 (95% CI 6.6–10.9) months among responders. Median overall survival was 14.5 (95% CI 9.5–19.6) months, and not reached for responders. To conclude, in a real-world setting, belantamab mafodotin monotherapy showed efficacy comparable with the prospective clinical trials, with a tolerable toxicity profile.