Glucocorticoid-induced apoptotic pathways in eosinophils: comparison with glucocorticoid-sensitive leukemia cells

Glucocorticoids are known to promote apoptosis of eosinophils, normal and neoplastic lymphoid cells, and blastic cells in some patients with acute myeloid leukemia. We investigated the biochemical signal transduction pathways, in particular, the generation of reactive oxygen species (ROS) and activation of caspases in dexamethasone (DEX)-induced apoptosis of eosinophils, and we compared them with those in DEX-sensitive myeloid and lymphoid leukemia cell lines. The GC-receptor antagonist completely abolished DEX-induced apoptosis of eosinophils and leukemia cells. Among inhibitors related to the ROS system, diphenylene iodonium (DPI), a nicotinamide adenine dinucleotide diphosphate (NADPH) oxidase inhibitor, strongly inhibited both spontaneous and DEX-induced apoptosis of eosinophils at concentrations as low as 0.2 to 2 mumol/L, while promoting apoptosis of leukemia cells in a dose-dependent manner. Apocynin, another NADPH oxidase inhibitor, and antioxidants did not affect the apoptosis of eosinophils or leukemia cells. DEX treatment did not change intracellular production of O2- and H2O2, and it decreased the extracellular release of O2- in both cells. These results suggest little or no involvement of ROS generation in DEX-induced apoptosis of both cells. Although among peptide-based caspase inhibitors, only z-VAD-FMK, a broad caspase inhibitor, partially inhibited the apoptosis of eosinophils and leukemia cells, DEX treatment increased the activities of caspases 2-, 3-, 6-, and 8-like proteases assessed by colorimetry in both cells, suggesting the involvement of a similar caspase activation pathway in DEX-induced apoptosis in both cells. DPI markedly reduced caspase 3-like activity in eosinophils, while augmenting the activity in leukemia cells, indicating that DPI acts upstream of caspase 3 activation opposingly in both cells. Thus, the action of DPI in eosinophils seems peculiar in respect to apoptosis induction, and DPI appears to exert an influence on unknown targets rather than those involved in NADPH oxidase inhibition.     

The contribution of quasi-joint stiffness of the ankle joint to gait in patients with hemiparesis

Background

The role of ankle joint stiffness during gait in patients with hemiparesis has not been clarified. The purpose of this study was to determine the contribution of quasi-joint stiffness of the ankle joint to spatiotemporal and kinetic parameters regarding gait in patients with hemiparesis due to brain tumor or stroke and healthy individuals.

Methods

Spatiotemporal and kinetic parameters regarding gait in twelve patients with hemiparesis due to brain tumor or stroke and nine healthy individuals were measured with a 3-dimensional motion analysis system. Quasi-joint stiffness was calculated from the slope of the linear regression of the moment–angle curve of the ankle joint during the second rocker.

Findings

There was no significant difference in quasi-joint stiffness among both sides of patients and the right side of controls. Quasi-joint stiffness on the paretic side of patients with hemiparesis positively correlated with maximal ankle power (r = 0.73, P < 0.01) and gait speed (r = 0.66, P < 0.05). In contrast, quasi-joint stiffness in controls negatively correlated with maximal ankle power (r = − 0.73, P < 0.05) and gait speed (r = − 0.76, P < 0.05).

Interpretation

Our findings suggested that ankle power during gait might be generated by increasing quasi-joint stiffness in patients with hemiparesis. In contrast, healthy individuals might decrease quasi-joint stiffness to avoid deceleration of forward tilt of the tibia. Our findings might be useful for selecting treatment for increased ankle stiffness due to contracture and spasticity in patients with hemiparesis.     

Phase I/II study of humanized anti-CD33 antibody conjugated with calicheamicin, gemtuzumab ozogamicin, in relapsed or refractory acute myeloid leukemia: final results of Japanese multicenter cooperative study

The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of gemtuzumab ozogamicin (GO) in patients with relapsed and/or refractory CD33-positive acute myeloid leukemia (AML). Patients received 2-h infusions of GO twice with an interval of approximately 14 days. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria Version 2.0. Samples for pharmacokinetics were taken on day 1 and day 8 of the first treatment cycle. The dose was increased stepwise and, in each cohort, patients were treated at the same dose. Forty patients, median age 58 years (range 28–68) were treated; 20 and 20 patients were enrolled to the phase I and II parts, respectively. In the phase I part, dose-limiting toxicities (DLTs) were hepatotoxicities, and the recommended dose was established as 9 mg/m² given as two intravenous infusions separated by approximately 14 days. The pharmacokinetic study revealed that C _max and AUC were equivalent to those of non-Japanese patients. In the phase II part, complete remission was observed in 5 patients, and one patient had complete remission without platelet recovery. Four of these 6 in remission and one in the phase I are long-term survivors (alive for at least 44 months). GO is safe and effective as a single agent among Japanese CD33-positive AML patients. Remission lasted longer in a subset of patients than in non-Japanese patients in earlier studies. Further studies of this agent are warranted to establish standard therapy. S. Furusawa: deceased.     

Changes in arrhythmogenic properties and five‐year prognosis after carbon‐ion radiotherapy in patients with mediastinum cancer

Introduction

Carbon‐ion irradiation of rabbit hearts has improved left ventricular conduction abnormalities through upregulation of gap junctions. However, to date, there has been no investigation on the effect of carbon‐ion irradiation on electrophysiological properties in human. We investigated this effect in patients with mediastinum extra‐cardiac cancer treated with carbon‐ion radiotherapy that included irradiating the heart.

Methods and Results

In April–December 2009, eight patients were prospectively enrolled (including two male, aged 72.5 ± 13.0 years). They were treated with 44–72 Gray equivalent (GyE), with their hearts exposed to 1.3–19.1 GyE. High‐resolution ambulatory electrocardiography was performed before and after radiotherapy to investigate arrhythmic events, late potentials (LPs), and heart rate variability. Five patients had pre‐existing premature ventricular contraction (PVC)/atrial contraction (PAC) or paroxysmal atrial fibrillation (PAF)/AF; after irradiation, this improved in four patients with PVC/PAF/AF and did not deteriorate in one patient with PAC. Ventricular LP findings did not deteriorate and improved in one patient. In eight cases with available atrial LP findings, there was no deterioration, and two patients showed improvements. The low frequency/high frequency ratio of heart rate variability improved or did not deteriorate in the six patients who received radiation exposure to the bilateral stellate ganglions. During the five‐year follow‐up for the prognosis, six of the eight patients died because of cancer; there was no history of hospitalization for cardiac events.

Conclusion

Although this preliminary study has several limitations, carbon‐ion beam irradiation to the heart is not immediately cardiotoxic and demonstrates consistent signals of arrhythmia reduction.

     

Development of the autofluorescence endoscope imaging system

It is a well known fact that light emitted at a specific wavelength induces fluorescence in the human body. This kind of fluorescence is called autofluorescence. The application of autofluorescence diagnosis, on the other hand, is a more complicated system designed to detect faint autofluorescence inherent in tissues/cells. We have adopted this autofluorescence diagnosis method and developed a new autofluorescence endoscope imaging system called the SAFE-1000. Normal mucosa emitting autofluorescence appears green on the monitor, while abnormal mucosa shows a dark image caused by the lack of autofluorescence.     

hst-1 transforming protein: expression in silkworm cells and characterization as a novel heparin-binding growth factor

A protein encoded by an hst-1 transforming gene was expressed in silkworm-derived BmN cells and secreted into the culture medium using a recombinant baculovirus vector. The strong affinity for heparin of the secreted protein made it possible to purify the hst-1 protein to homogeneity in a two-step procedure. The purified hst-1 protein has a molecular weight of 18,000 and stimulates both DNA synthesis in NIH3T3 cells and human umbilical vein endothelial cell proliferation. In addition, morphological changes and anchorage-independent growth of NIH3T3 cells are induced by this product. These results show that the hst-1 transforming protein is a novel heparin-binding growth factor as predicted by nucleotide sequence analysis.     

Overeruption without root exposure of third molars and periodontal health in the mandible

Bone formation is seen around the third molar even when the tooth is exposed to the oral environment due to overeruption. To determine if overeruption of the third molar with or without root exposure is related to the status of the exposure of other teeth in the mandible, using orthopantomographs, 424 third molars were studied in 371 patients who were over 41 years of age. The rate of overeruption and root exposure in third molars was measured, and its relationship to the number of teeth lost and the rate of root exposure in other teeth in the mandible was analyzed. Tooth loss in the group of third molars with overeruption without root exposure was greater than in that without overeruption or root exposure in men, whereas the relationship was not seen in women. We found that root exposures of other teeth in the group of third molars with overeruption without root exposure were significantly smaller than in those with root exposure in both genders. Third molars with overeruption without root exposure, in which bone formation was easy to observe for radiographic diagnosis, were correlated with periodontal health in the mandible, suggesting a component of precision determination for predicting resistance to periodontitis.     

Macrophage activity of regional lymph nodes of cancer patients and its relation to stages of cancer

Macrophage activity of regional lymph nodes from patients with uterine cervical cancer and patients with gastric cancer was studied. Enhanced spreading of macrophages was observed in an early stage of these cancer patients, but the rate was decreased in advanced stage. In metastatic nodes, enhanced spreading was observed in many cases. Cytostatic activity of macrophages was elevated in stage II of uterine cervical cancer and in stage I of gastric cancer. Significant relation between the rate of spreading and the cytostatic activity was observed in these patients. The reasons for change of the macrophage activity in relation to tumor burden were discussed.     

Muscle spindle distribution in the levator veli palatini muscle in the rat.

We previously reported that the levator veli palatini muscle (LVP) in the rat is innervated by the glossopharyngeal nerve. The LVP positioned between the mouth and nasopharynx, has important roles in respiration, swallowing, and speech. Muscle spindles, structures scattered through skeletal muscles, appear to function like miniature strain gauges, sensing the degree of tension in the muscle. Muscle spindles were demonstrated in the rat's LVP in our neurophysiologic and histologic studies. We think the stretch of LVP modulates the rapid movements of the LVP by the proprioceptive component of the muscle spindle. Our results infer it is important to protect the innervation and the muscle spindles of the LVP from damage during any surgical dissection of the soft palate musculature.