The factors controlling stem cell recirculation. i. Migration of hemopoietic stem cells in adrenalectomized mice

The influence of bilateral adrenalectomy on hemopoietic stem cell (CFU) migration in mice has been studied. Formation of endogenous spleen colonies in lethally irradiated, leg-shielded mice was sharply increased by prior adrenalectomy, and this increase was not dependent on the volume of shielded bone marrow. Adrenalectomy was shown to increase endogenous spleen colony formation in sublethally irradiated mice as well. However, it had no affect on formation of spleen colonies in lethally irradiated mice injected with syngeneic bone marrow. The CFU content of murine bone marrow decreased acutely after removal of the adrenals, and this decrease was accompanied by a concomitant increase in the peripheral blood and splenic CFU. Thus, adrenalectomy appeared to have no affect on the splenic plating efficiency or proliferative rate of hemopoietic stem cells, but it did result in increased migration of stem cells from the bone marrow to the blood, and thence to the spleen. It is concluded that the adrenal steroids may be of physiologic importance in the regulation of ehmopoietic stem cell migration.     

Vorwärmung entsprechend der „S3 Leitlinie Vermeidung von unbeabsichtigter perioperativer Hypothermie 2014“

Background

Inadvertent perioperative hypothermia, which is defined as a core body temperature of less than 36.0?°C, can have serious consequences in surgery patients. These include cardiac complications, increased blood loss, wound infections and postoperative shivering; therefore, the scientific evidence that inadvertent perioperative hypothermia should be avoided is undisputed and several national guidelines have been published summarizing the scientific evidence and recommending specific procedures. The German AWMF guidelines were the first to emphasize the importance of prewarming for surgery patients to avoid inadvertant perioperative hypothermia; however, in contrast to intraoperative warming, prewarming is so far not sufficiently implemented in clinical practice in many hospitals. Furthermore, a recent study has questioned the effectiveness of prewarming.

Objective

The aim of this retrospective investigation was to evaluate the hypothermia rates that can be achieved when prewarming in the anesthesia induction room is introduced into the clinical practice and performed in addition to intraoperative warming.

Material and methods

The ethics committee of the Medical Faculty of the Martin Luther University Halle Wittenberg gave approval for data storage and retrospective data analysis from the anesthesia database. According to the existing local standard operating procedure, prewarming with forced air was performed in addition to intraoperative warming in the anesthesia induction room in 3899 patients receiving general anesthesia with a duration of 30?min or longer from January 2015 to December 2016. The results were compared with a control group of 3887 patients from July 2012 to August 2014 who received intraoperative warming but were not subjected to prewarming. Tracheal intubation was carried out in all patients and temperature measurements after the induction of anesthesia were performed using esophageal, urinary catheter or intra-arterial temperature probes.

Results

The mean duration of prewarming was 25?min in the treatment group. Patients subjected to prewarming showed an intraoperative hypothermia rate of 15.8% and a postoperative hypothermia rate of 5.1%. Patients without prewarming showed an intraoperative hypothermia rate of 30.4% and a postoperative hypothermia rate of 12.4%. This means a 52% reduction of the intraoperative hypothermia rate and a 41% reduction of the postoperative hypothermia rate for patients who received prewarmimg (p < 0.0001). Multivariate logistic regression revealed that the lack of prewarming was independently associated with intraoperative hypothermia with an odds ratio of 2.5 (95% confidence interval CI 2.250–2.841; p < 0.0001) and postoperative hypothermia with an odds ratio of 2.8 (95% CI 2.316–3.277; p < 0.0001).

Conclusion

Prewarming, as recommended in the AWMF guidelines, resulted in a significant and clinically relevant reduction in the incidence of inadvertent perioperative hypothermia; therefore, prewarming can still be regarded as an effective method to avoid perioperative hypothermia. Hypothermia rates of 15.8% intraoperatively and 5.1% postoperatively can be achieved in clinical practice, when prewarming is performed in addition to intraoperative warming in the anesthesia induction room directly before the start of surgical procedures.

     

Biochemical and pharmacological characterization of AZD1981, an orally available selective DP2 antagonist in clinical development for asthma

Background and Purpose

The discovery of DP₂ as a second receptor for PGD₂ has prompted the search for antagonists as potential novel therapies based on the associations between PGD₂ and disease. Here we describe the biochemical and pharmacological properties of 4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid (AZD1981), a novel DP₂ receptor antagonist.

Experimental Approach

Binding to DP₂, functional receptor pharmacology and selectivity were studied in both human and animal systems.

Key Results

AZD1981 displaced radio-labelled PGD₂ from human recombinant DP₂ with high potency (pIC₅₀ = 8.4). Binding was reversible, non-competitive and highly selective against a panel of more than 340 other enzymes and receptors, including DP₁ (>1000-fold selective). AZD1981 inhibited DP₂-mediated shape change and CD11b up-regulation in human eosinophils, shape change in basophils and chemotaxis of human eosinophils and Th2 cells with similar potency. AZD1981 exhibited good cross-species binding activity against mouse, rat, guinea pig, rabbit and dog DP₂. Evaluation in mouse, rat or rabbit cell systems was not possible as they did not respond to DP₂ agonists. Agonist responses were seen in guinea pig and dog, and AZD1981 blocked DP₂-mediated eosinophil shape change. Such responses were more robust in the guinea pig, where AZD1981 also blocked DP₂-dependent eosinophil emigration from bone marrow.

Conclusions and Implications

AZD1981 is a DP₂ antagonist that blocks functional responses in eosinophils, Th2 cells and basophils. It exhibited similar potency irrespective of the cell type, DP₂ agonist or species used. This selective orally active agent is currently under clinical evaluation as a potential therapeutic agent in respiratory diseases including asthma.     

Die Entwicklung der gesetzlichen Unfallversicherung in den neuen Bundesländern aus ärztlicher Sicht

In the five eastern federal districts of Germany the condition for organizing treatment forms of the Social Insurance for Occupational Accidents were different. In 1990 qualification of traumatologic surgeons demonstrated intensive standards and similary positions as western Germany. On the other hand we have miserable buildings for patients and poor equipments. After two years the development of statutory accident insurance is respectable. The present situation reflects very good co-operation between western and eastern institutions, to remove some insufficencies and to establish a sure territorical system for medical treatment.     

Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction

Thrombopoietin (TPO), the ligand for c-mpl, stimulates proliferation of committed megakaryocytic progenitors and induces maturation of megakaryocytes. To better understand factors regulating TPO levels, we measured blood levels of TPO in patients with impaired platelet production due to aplastic anemia (AA) and with platelet destructive disorders, including idiopathic thrombocytopenic purpura (ITP), posttransfusion purpura (PTP), drug purpura (DP), and X-linked thrombocytopenia (XLTP). The TPO receptor capture enzyme immunoassay (EIA) used had a detection limit of integral of approximately-150 to 200 pg/mL. TPO was undetectable in 88 of 89 normal individuals. Eighteen of 19 patients with AA and a mean platelet count (MPC) of 18,000/microliters (2,000 to 61,000/microliters) had markedly elevated TPO levels (mean, 1,467 pg/mL; range, 597 to 3,834 pg/mL). Eight AA patients who responded to immunosuppressive therapy with their MPC increasing to 140,000/microliters (92,000 to 175,000/microliters) had substantial decreases in TPO (mean, 440 pg/mL; range, 193 to 771 pg/mL). Initial TPO levels did not differ significantly between responders and nonresponders. In contrast, all 21 patients with ITP and an MPC of 16,000/microliters (1,000 to 51,000 /microliters) had undetectable TPO levels, as did 6 patients with acute PTP or DP and 2 patients with XLTP. Megakaryocyte mass, reflected in the rate of platelet production, appears to be the major determinant of TPO levels in thrombocytopenic patients rather than circulating platelet levels per se. Measurement of serum TPO may be useful in differentiating thrombocytopenias due to peripheral destruction from those due to thrombopoietic failure.