Group 2 innate lymphoid cells support hematopoietic recovery under stress conditions

The cell-cycle status of hematopoietic stem and progenitor cells (HSPCs) becomes activated following chemotherapy-induced stress, promoting bone marrow (BM) regeneration; however, the underlying molecular mechanism remains elusive. Here we show that BM-resident group 2 innate lymphoid cells (ILC2s) support the recovery of HSPCs from 5-fluorouracil (5-FU)–induced stress by secreting granulocyte-macrophage colony-stimulating factor (GM-CSF). Mechanistically, IL-33 released from chemo-sensitive B cell progenitors activates MyD88-mediated secretion of GM-CSF in ILC2, suggesting the existence of a B cell–ILC2 axis for maintaining hematopoietic homeostasis. GM-CSF knockout mice treated with 5-FU showed severe loss of myeloid lineage cells, causing lethality, which was rescued by transferring BM ILC2s from wild-type mice. Further, the adoptive transfer of ILC2s to 5-FU–treated mice accelerates hematopoietic recovery, while the reduction of ILC2s results in the opposite effect. Thus, ILC2s may function by “sensing” the damaged BM spaces and subsequently support hematopoietic recovery under stress conditions.     

Plasminogen activator inhibitor 1--insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence

Cellular senescence is widely believed to play a key role in tumor suppression, but the molecular pathways that regulate senescence are only incompletely understood. By using a secretome proteomics approach, we identified insulin-like growth factor binding protein 3 (IGFBP3) as a secreted mediator of breast cancer senescence upon chemotherapeutic drug treatment. The senescence-inducing activity of IGFBP3 is inhibited by tissue-type plasminogen activator-mediated proteolysis, which is counteracted by plasminogen activator inhibitor 1 (PAI-1), another secreted mediator of senescence. We demonstrate that IGFBP3 is a critical downstream target of PAI-1-induced senescence. These results suggest a role for an extracellular cascade of secreted proteins in the regulation of cellular senescence.     

LecT-hepa, a glyco-marker derived from multiple lectins, as a predictor of liver fibrosis in chronic hepatitis C patients

Assessment of liver fibrosis in patients with chronic hepatitis C (CHC) is critical for predicting disease progression and determining future antiviral therapy. LecT-Hepa, a new glyco-marker derived from fibrosis-related glyco-alteration of serum alpha 1-acid glycoprotein, was used to differentiate cirrhosis from chronic hepatitis in a single-center study. Herein, we aimed to validate this new glyco-marker for estimating liver fibrosis in a multicenter study. Overall, 183 CHC patients were recruited from 5 liver centers. The parameters Aspergillus oryzae lectin (AOL) / Dature stramonium lectin (DSA) and Maackia amurensis lectin (MAL)/DSA were measured using a bedside clinical chemistry analyzer in order to calculate LecT-Hepa levels. The data were compared with those of seven other noninvasive biochemical markers and tests (hyaluronic acid, tissue inhibitor of metalloproteases-1, platelet count, aspartate aminotransferase-to-platelet ratio index [APRI], Forns index, Fib-4 index, and Zeng's score) for assessing liver fibrosis using the receiver-operating characteristic curve. LecT-Hepa correlated well with the fibrosis stage as determined by liver biopsy. The area under the curve (AUC), sensitivity, and specificity of LecT-Hepa were 0.802, 59.6%, and 89.9%, respectively, for significant fibrosis; 0.882, 83.3%, and 80.0%, respectively, for severe fibrosis; and 0.929, 84.6%, and 88.5%, respectively, for cirrhosis. AUC scores of LecT-Hepa at each fibrosis stage were greater than those of the seven aforementioned noninvasive tests and markers. Conclusion: The efficacy of LecT-Hepa, a glyco-marker developed using glycoproteomics, for estimating liver fibrosis was demonstrated in a multicenter study. LecT-Hepa given by a combination of the two glyco-parameters is a reliable method for determining the fibrosis stage and is a potential substitute for liver biopsy. (HEPATOLOGY 2012).     

NATURAL SKIN REDUCTION AND BREAST RECOVERY USING A TISSUE EXPANDER AFTER ENUCLEATION OF A GIANT BREAST TUMOUR

We report a new use of the tissue expander for reshaping a breast after resection of a giant tumour. After resection of giant fibroadenomas, two patients had expanders inserted into the tissue defect and gradually reduced in size over five months. This facilitated healing and natural skin shrinkage and resulted in a natural shape and size.     

Macroscopic anatomy of the sphenomandibular ligament related to the inferior alveolar nerve block

We performed macroscopic observations of the sphenomandibular ligaments, and measured the space that is surrounded by the mandibular ramus and the ligament by using computed tomography. The materials used in this study were 40 heads of 40 adult cadavers. The cadaver head was cut on the mid sagittal plane. The medial pterygoid muscles of the cadavers were removed to observe the ligaments. The attaching style of the sphenomandibular ligament to the mandibular ramus was classified into three types: Type I (5 in 40 samples; attached only to the mandibular lingula), Type II (12 in 40 samples; attached to the mandibular lingula and extended toward the rear part of the internal surface of the mandibular ramus), and Type III (23 in 40 samples; attached to the mandibular lingula and toward the posterior border of the mandibular ramus). There was no statistical difference in the length of the ligament among the three types. However, Type III showed the largest width, and the space was approximately eight and three times as large as those of Type I and II, respectively. This indicated that the Type III ligament covered a larger area over the mandibular foramen than Type I. These results suggest that the three-dimensional morphology of the sphenomandibular ligament, as represented by Type III, may affect the effectiveness of anesthesia.     

IV ATP Potentiates Midazolam Sedation as Assessed by Bispectral Index

In this study, by measuring bispectral index (BIS), we tested the hypothesis that intravenous adenosine 5′-triphosphate (ATP) infusion would deepen the level of midazolam-induced sedation. Ten healthy volunteers underwent 2 experiments with at least 2 weeks'' interval: immediately after intravenous bolus administration of midazolam (0.04 mg/kg), they received continuous infusion of either ATP infusion (100 μg/kg/min) or placebo (saline) for 40 minutes in a double-blind, randomized, crossover manner. Changes in BIS values and responsiveness to verbal command as well as cardiorespiratory variables were observed throughout the study periods. Administration of midazolam alone reduced BIS value from control: 97 ± 1 to 68 ± 18 at 25 minutes, which was accompanied by significant cardiopulmonary depressant effects, while maintaining responsiveness to verbal command (consciousness) throughout the study period. Coadministration of ATP with midazolam further reduced BIS value to 51 ± 13, associated with complete loss of consciousness without adverse effect on the cardiorespiratory systems. We conclude that the addition of ATP infusion to midazolam significantly enhances midazolam sedation without disturbing cardiorespiratory functions.Key Words: Midazolam sedation, ATP, Central adenosine receptorsIntravenous (IV) adenosine 5′-triphosphate (ATP) infusion has been used for various clinical indications.¹ However, when ATP is infused intravenously, it is rapidly broken down into adenosine. Thus, we assumed that ATP would act in a similar fashion to adenosine. Adenosine is an endogenous neuromodulator that is capable of inducing sedation and sleep. There is good evidence that adenosine is an endogenous sleep-promoting molecule.^2,3 Further, a low dose of adenosine infusion (80–140 μg/kg/min) in humans has been shown to stimulate cardiorespiratory systems.^4–6 Meanwhile, the bispectral index (BIS) was reported to provide a reliable measure of the hypnotic effect of midazolam, and BIS analysis can indicate the depth of midazolam sedation.^7,8 Previously, we have shown that coadministration of ATP with midazolam significantly enhanced the hypnotic effect of midazolam in humans, as assessed by subjective and objective questionnaire.⁹ In this study, we examined the effect of ATP infusion on midazolam-induced sedation by continuous measurement of BIS and responsiveness to verbal command as well as cardiorespiratory responses. Furthermore, we sought to find the potential beneficial and/or adverse effects of ATP infusion when combined with midazolam in healthy human volunteers.