Spontaneous Production of Interleukin-5 and Its Heterogeneous Effect on Eosinophils in an Adult T-Cell Leukemia Patient

ABSTRACTWe examined the functional heterogeneity of eosinophils from an adult T-cell leukemia (ATL) patient with eosinophilia. A 63-year-old man was admitted to our hospital because of lymphadenopathy. The leukocyte count was 10 400 /mm3, with 36.0% eosinophils and 3.0% abnormal lymphocytes. The diagnosis of ATL was based on the presence in serum of anti- human T-cell lymphotrophic virus-1 antibody and on histologic demonstration of ATL cells. The mononuclear cells spontaneously produced eosinophil-related cytokines (granulocyte-macrophage colony stimulating factor, 5600pg/mL; interleukin (IL)-5, 375pg/mL). Peripheral eosinophils were fractionated into normodense eosinophils (NE) and hypodense eosinophils (HE) by a Percoll density gradient method, and these cells were compared in terms of several heterogeneous functions. The NE were more chemotactically attracted to IL-5 than the HE. More apoptotic cells appeared among the NE than among the HE and this difference was correlated with the positive rate of Fas antigen on eosinophils. Survival of the HE was longer than that of the NE. Survival of the HE was prolonged by IL-5 stimulation, but survival of the NE was not. These data suggest that functionally heterogeneous eosinophils were present in this ATL patient with eosinophilia and that IL-5 enhanced this heterogeneity. The response of eosinophils to IL-5 may have contributed to the patho- genesis of eosinophilia in this patient

Brain Metastasis from Gastrointestinal Stromal Tumor: A Case Report and Review of the Literature

Metastasis of gastrointestinal stromal tumor (GIST) into the central nervous system is extremely rare. We report a patient with synchronous GIST and brain metastasis. At disease onset, there was left hemiplegia and ptosis of the right eyelids. Resection cytology of the brain tumor was reported as metastasis of GIST. After positron emission tomography examination, another tumor in the small bowel was discovered, which suggested a small bowel GIST associated with intracranial metastasis. Immunohistochemical analysis of the intestinal tumor specimen obtained by double balloon endoscopy showed a pattern similar to the brain tumor, with the tumors subsequently identified as intracranial metastases of jejunal GIST. After surgical resection of one brain tumor, the patient underwent whole brain radiation therapy followed by treatment with imatinib mesylate (Gleevec; Novartis Pharma, Basel, Switzerland). Mutational analysis of the original intestinal tumor revealed there were no gene alterations in KIT or PDGFRα. Since the results indicated the treatment had no apparent effect on either of the tumors, and because ileus developed due to an intestinal primary tumor, the patient underwent surgical resection of the intestinal lesion. However, the patient's condition gradually worsen and she subsequently died 4 months after the initial treatment

Lubiprostone Decreases the Small Bowel Transit Time by Capsule Endoscopy: An Exploratory, Randomised, Double-Blind, Placebo-Controlled 3-Way Crossover Study

The aim of this study was to investigate the usefulness of lubiprostone for bowel preparation and as a propulsive agent in small bowel endoscopy. Six healthy male volunteers participated in this randomized, 3-way crossover study. The subjects received a 24 μg tablet of lubiprostone 60 minutes prior to the capsule ingestion for capsule endoscopy (CE) and a placebo tablet 30 minutes before the capsule ingestion (L-P regimen), a placebo tablet 60 minutes prior to CE and a 24 μg tablet of lubiprostone 30 minutes prior to CE (P-L regimen), or a placebo tablet 60 minutes prior to r CE and a placebo tablet again 30 minutes prior to CE (P-P regimen). The quality of the capsule endoscopic images and the amount of water in the small bowel were assessed on 5-point scale. The median SBTT was 178.5 (117–407) minutes in the P-P regimen, 122.5 (27–282) minutes in the L-P regimen, and 110.5 (11–331) minutes in the P-L regimen (P=0.042). This study showed that the use of lubiprostone significantly decreased the SBTT. We also confirmed that lubiprostone was effective for inducing water secretion into the small bowel during CE

A novel underuse model shows that inactivity but not ovariectomy determines the deteriorated material properties and geometry of cortical bone in the tibia of adult rats

Our goal in this study was to determine to what extent the physiologic consequences of ovariectomy (OVX) in bones are exacerbated by a lack of daily activity such as walking. We forced 14-week-old female rats to be inactive for 15 weeks with a unique experimental system that prevents standing and walking while allowing other movements. Tibiae, femora, and 4th lumbar vertebrae were analyzed by peripheral quantitative computed tomography (pQCT), microfocused X-ray computed tomography (micro-CT), histology, histomorphometry, Raman spectroscopy, and the three-point bending test. Contrary to our expectation, the exacerbation was very much limited to the cancellous bone parameters. Parameters of femur and tibia cortical bone were affected by the forced inactivity but not by OVX: (1) cross-sectional moment of inertia was significantly smaller in Sham-Inactive rat bones than that of their walking counterparts; (2) the number of sclerostin-positive osteocytes per unit cross-sectional area was larger in Sham-Inactive rat bones than in Sham-Walking rat bones; and (3) material properties such as ultimate stress of inactive rat tibia was lower than that of their walking counterparts. Of note, the additive effect of inactivity and OVX was seen only in a few parameters, such as the cancellous bone mineral density of the lumbar vertebrae and the structural parameters of cancellous bone in the lumbar vertebrae/tibiae. It is concluded that the lack of daily activity is detrimental to the strength and quality of cortical bone in the femur and tibia of rats, while lack of estrogen is not. Our inactive rat model, with the older rats, will aid the study of postmenopausal osteoporosis, the etiology of which may be both hormonal and mechanical

Chiasmata Promote Monopolar Attachment of Sister Chromatids and Their Co-Segregation toward the Proper Pole during Meiosis I

The chiasma is a structure that forms between a pair of homologous chromosomes by crossover recombination and physically links the homologous chromosomes during meiosis. Chiasmata are essential for the attachment of the homologous chromosomes to opposite spindle poles (bipolar attachment) and their subsequent segregation to the opposite poles during meiosis I. However, the overall function of chiasmata during meiosis is not fully understood. Here, we show that chiasmata also play a crucial role in the attachment of sister chromatids to the same spindle pole and in their co-segregation during meiosis I in fission yeast. Analysis of cells lacking chiasmata and the cohesin protector Sgo1 showed that loss of chiasmata causes frequent bipolar attachment of sister chromatids during anaphase. Furthermore, high time-resolution analysis of centromere dynamics in various types of chiasmate and achiasmate cells, including those lacking the DNA replication checkpoint factor Mrc1 or the meiotic centromere protein Moa1, showed the following three outcomes: (i) during the pre-anaphase stage, the bipolar attachment of sister chromatids occurs irrespective of chiasma formation; (ii) the chiasma contributes to the elimination of the pre-anaphase bipolar attachment; and (iii) when the bipolar attachment remains during anaphase, the chiasmata generate a bias toward the proper pole during poleward chromosome pulling that results in appropriate chromosome segregation. Based on these results, we propose that chiasmata play a pivotal role in the selection of proper attachments and provide a backup mechanism that promotes correct chromosome segregation when improper attachments remain during anaphase I

Molecular analysis of the BCR-ABL1 kinase domain in chronic-phase chronic myelogenous leukemia treated with tyrosine kinase inhibitors in practice: Study by the Nagasaki CML Study Group

An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment

The Contribution of SAA1 Polymorphisms to Familial Mediterranean Fever Susceptibility in the Japanese Population

Background/Aims: Familial Mediterranean Fever (FMF) has traditionally been considered to be an autosomal-recessive disease, however, it has been observed that substantial numbers of patients with FMF possess only 1 demonstrable MEFV mutation. The clinical profile of familial Mediterranean fever (FMF) may be influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors. Methodology/Principal Findings: In view of the inflammatory nature of FMF, we investigated whether serum amyloid A (SAA) and interleukin-1 beta (IL-1β) gene polymorphisms may affect the susceptibility of Japanese patients with FMF. The genotypes of the -13C/T SNP in the 5′-flanking region of the SAA1 gene and the two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined in 83 Japanese patients with FMF and 200 healthy controls. The same samples were genotyped for IL-1β-511 (C/T) and IL-1 receptor antagonist (IL-1Ra) variable number of tandem repeat (VNTR) polymorphisms. There were no significant differences between FMF patients and healthy subjects in the genotypic distribution of IL-1β -511 (C/T), IL-1Ra VNTR and SAA2 polymorphisms. The frequencies of SAA1.1 allele were significantly lower (21.7% versus 34.0%), and inversely the frequencies of SAA1.3 allele were higher (48.8% versus 37.5%) in FMF patients compared with healthy subjects. The frequency of -13T alleles, associated with the SAA1.3 allele in the Japanese population, was significantly higher (56.0% versus 41.0%, p = 0.001) in FMF patients compared with healthy subjects. Conclusions/Significance: Our data indicate that SAA1 gene polymorphisms, consisting of -13T/C SNP in the 5′-flanking region and SNPs within exon 3 (2995C/T and 3010C/T polymorphisms) of SAA1 gene, are associated with susceptibility to FMF in the Japanese population

Association between serum ferritin concentrations and depressive symptoms in Japanese municipal employees

It remains unclear whether levels of body iron store are related to milder forms of depression, which are more common among apparently healthy people. We examined the association between serum ferritin concentrations and depressive symptoms among 312 men and 216 women working in two municipal offices in Japan. Depressive symptoms were assessed by using the Center for Epidemiologic Studies Depression (CESD) scale. In men, increased prevalence of depressive symptoms (defined by using a cutoff value of ≥19) was significantly associated with decreased levels of serum ferritin. In age- and study-site-adjusted models, ORs (95% CIs) for depressive symptoms for men in first, second, third, and fourth quartiles of serum ferritin concentrations were 2.83 (1.01–7.94), 1.74 (0.87–3.49), 1.33 (0.71–2.47), and 1.00 (reference), respectively (p for trend=0.02). In multivariate-adjusted model, ORs (95% CIs) in first, second, third, and fourth quartiles of serum ferritin concentrations were 2.88 (0.93–8.91), 1.91 (0.90–4.05), 1.28 (0.66–2.49), and 1.00 (reference), respectively (p for trend=0.03). No significant association was detected in women. Our finding that men with lower levels of serum ferritin concentrations had a higher prevalence of depressive symptoms suggests that adverse psychological effects may be implicated in iron deficiency among middle-age Japanese workers

Association between serum ferritin concentrations and depressive symptoms in Japanese municipal employees (Journal of Psychiatry Research)

It remains unclear whether levels of body iron store are related to milder forms of depression, which are more common among apparently healthy people. We examined the association between serum ferritin concentrations and depressive symptoms among 312 men and 216 women working in two municipal officesin Japan. Depressive symptoms were assessed by using the Center for Epidemiologic Studies Depression (CESD) scale. In men, increased prevalence of depressive symptoms (defined by using a cutoff value of ≥19) was significantly associated with decreased levels of serum ferritin. In age- and study-site-adjusted models, ORs(95% CIs) for depressive symptoms for men in first, second, third, and fourth quartiles of serum ferritin concentrations were 2.83 (1.01–7.94), 1.74 (0.87–3.49), 1.33 (0.71–2.47), and 1.00 (reference), respectively (p for trend=0.02). In multivariate-adjusted model, ORs (95% CIs) in first, second, third, and fourth quartiles of serum ferritin concentrations were 2.88 (0.93–8.91), 1.91 (0.90–4.05), 1.28 (0.66–2.49), and 1.00 (reference), respectively (p for trend=0.03). No significant association was detected in women. Our findingthat men with lower levels of serum ferritin concentrations had a higher prevalence of depressive symptoms suggests that adverse psychological effects may be implicated in iron deficiency among middle-age Japanese workers