Negative effects of GM-CSF signaling in a murine model of t(8;21)-induced leukemia

The t(8;21)(q22;q22) is common in adult acute myeloid leukemia (AML). The RUNX1-ETO fusion protein that is expressed by this translocation is poorly leukemogenic and requires additional mutations for transformation. Loss of sex chromosome (LOS) is frequently observed in t(8;21) AML. In the present study, to evaluate whether LOS cooperates with t(8;21) in leukemogenesis, we first used a retroviral transduction/transplantation model to express RUNX1-ETO in hematopoietic cells from XO mice. The low frequency of leukemia in these mice suggests that the potentially critical gene for suppression of t(8;21) leukemia in humans is not conserved on mouse sex chromosomes. The gene encoding the GM-CSF receptor α subunit (CSF2RA) is located on X and Y chromosomes in humans but on chromosome 19 in mice. GM-CSF promotes myeloid cell survival, proliferation, and differentiation. To determine whether GM-CSF signaling affects RUNX1-ETO leukemogenesis, hematopoietic stem/progenitor cells that lack GM-CSF signaling were used to express RUNX1-ETO and transplanted into lethally irradiated mice, and a high penetrance of AML was observed in recipients. Furthermore, GM-CSF reduced the replating ability of RUNX1-ETO-expressing cells. These results suggest a possible tumor-suppressor role of GM-CSF in RUNX1-ETO leukemia. Loss of the CSF2RA gene may be a critical mutation explaining the high incidence of LOS associated with the t(8;21)(q22;q22) translocation.     

Mechanized assay of plasma prekallikrein by activation with Pseudomonas aeruginosa elastase and amidolysis of chromogenic substrate.

An automated assay of plasma prekallikrein is described. Prekallikrein was converted to kallikrein with Pseudomonas aeruginosa elastase, and the hydrolytic activity of kallikrein to H-D-Pro-Phe-Arg-paranitroanilide subsequently measured.

The conversion was complete within 8 minutes and the amidolytic activity remained stable at least another 10 min at 37 ° C. This method worked in plasma deficient in Hageman factor (blood coagulation factor XII). Using anti-prekallikrein antibody and plasma deficient in prekallikrein, the amidolytic activity generated in normal plasma was identified as due to kallikrein. With plasma samples, the coefficients of variation (CV) for multiple measurements within run (n = 10) and between run (n = 10) were as low as 5.0% and 6.6%, respectively, and the minimum measurable concentration of prekallikrein in plasma was 10% of the normal level.     

Left subclavian artery stenting: an option for the treatment of the coronary-subclavian steal syndrome

Introduction

The subclavian steal syndrome is characterized by the vertebral artery flow inversion, due to a stenotic lesion in the origin of the subclavian artery. The Coronary-subclavian Steal Syndrome is a variation of the Subclavian Steal Syndrome and is characterized by inversion of flow in the Internal Thracic artery that has been used as conduct in a myocardial revascularization. Its diagnosis must be suspected in patients with difference in pulse and arterial pressure in the upper limbs, that present with angina pectoris and that have done a myocardial revascularization. Its treatment must be a surgical bypass or a transluminal angioplasty.

Objective

The objective is to show the left subclavian artery stenting as a safe and effective method to treat the coronary-subclavian steal syndrome.

Methods

Historical prospective, non-randomized trial, through revision of the hospital records of the patients treated with the stenting of the left subclavian artery, from January 2006 to September 2012.

Results

In the mentioned period, 4.291 miocardial revascularizations were performed with the use of the left mammary artery, and 16 patients were identified to have the Coronary-subclavian steal syndrome. All of them were submitted to endovascular treatment. The success rate was 100%; two patients experienced minor complications; none of them presented with major complications. Eleven of the 16 patients had ultrassonographic documentation of patent stent for at least one year; two patients lost follow up and other two died.

Conclusion

The stenting of the left subclavian artery is a good option for the treatment of the Coronary-subclavian Steal Syndrome, with high level of technical and clinical success.     

Adverse Tissue Reactions and Metal Ion Behavior After Small‐Head Metasul Hip Arthroplasty: A Long‐Term Follow‐Up Study

ObjectiveTo investigate the long‐term survivorship, incidence of adverse reactions to metal debris (ARMD), and metal ion behavior in patients who underwent small‐head Metasul metal‐on‐metal (MoM) total hip arthroplasty (THA).MethodsBetween February 1998 and September 2003, a retrospective study was performed on 43 consecutive patients (43 hips) who underwent unilateral cementless Metasul MoM THAs at our institution. Of them, 35 patients (nine males and 26 females) who were available for follow‐up more than 15 years after THA were enrolled in this study and underwent metal artifact reduction sequence magnetic resonance imaging (MARS‐MRI) to identify ARMD. The mean age at surgery of the patients was 59.7 years old (range, 31–83). Clinical and radiographic outcomes were evaluated retrospectively. Clinical examinations were conducted using the Harris Hip Score (HHS). Serum cobalt (Co) and chromium (Cr) ion levels and Co/Cr ratio were assessed at different postoperative periods of <5, 5–10, 11–14, and ≥15 years.ResultsThe mean follow‐up period for the 35 patients included was 18.1 years (range, 15–22). The mean HHS significantly improved from 44.6 ± 11.3 points preoperatively to 89.4 ± 7.9 points at the final follow‐up (P < 0.0001). ARMD was found in 20% of the patients using MARS‐MRI. No signs of stem loosening were found clinically or radiographically, whereas cup loosening and ARMD were observed in three patients (9%), for whom revision THAs were performed. The Kaplan–Meier survival rates with revision for any reason as the endpoint were 90.9% at 5 years, 84.8% at 10 years, 84.8% at 15 years (95% CI, 67.1–93.6), and 70.3% at 20 years (95% CI, 43.6–87.0). The survival rates with revision for ARMD as the endpoint were 100% at 5 years, 96.6% at 10 years, 96.6% at 15 years (95% CI, 77.2–99.7), and 80.1% at 20 years (95% CI, 45.3–95.2). Serum Co ion level peaked at 5–10 years after THA, which was significantly higher than that <5 years; however, it decreased to the initial level after 15 years. In contrast, serum Cr ion level significantly increased at 5–10 years and then remained almost constant. Significant differences in Cr ion levels (1.0 vs 2.0 μg/L, P = 0.024) and Co/Cr ratio (1.3 vs 0.9, P = 0.037) were found between non‐ARMD and ARMD patients at >11 years postoperatively.ConclusionOur results suggest that increased Cr ion levels and decreased Co/Cr ratio may be signs of ARMD in patients who underwent small‐head Metasul MoM THA.     

Volumetric tomography of fluorescent proteins through small animals in vivo

Volumetric detection and accurate quantification of fluorescent proteins in entire animals would greatly enhance our ability to monitor biological processes in vivo. Here we present a quantitative tomographic technique for visualization of superficial and deep-seated (>2-3 mm) fluorescent protein activity in vivo. We demonstrate noninvasive imaging of lung tumor progression in a murine model, as well as imaging of gene delivery using a herpes virus vector. This technology can significantly improve imaging capacity over the current state of the art and should find wide in vivo imaging applications in drug discovery, immunology, and cancer research.     

Selective adsorption of human CD4 T cells

The pathogenesis of most autoimmune diseases directly involves CD4(+) helper T cells. To remove CD4(+) T cells selectively from the circulation, we designed a new column in which an anti-CD4 monoclonal antibody was immobilized on the activated substance. Nearly 90% of CD4(+) T cells were selectively adsorbed from whole blood with a single passage through the column in vitro, resulting in depletion of the antigen-specific T cell responses. We conclude that this new column would be potentially useful for treatment of T cell-mediated autoimmune diseases.     

Use of sodium–glucose cotransporter 2 inhibitors in older patients with type 2 diabetes mellitus

Aim

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that act on the proximal renal tubules to lower blood glucose levels by inhibiting glucose reabsorption and promoting urinary glucose excretion. The present study assessed the long‐term use of SGLT2 inhibitors in older patients with diabetes.

Methods

A total of 117 older patients with type 2 diabetes who were given SGLT2 inhibitors were enrolled from April 2014 to March 2016.

Results

The mean age of the patients was 73.7 ± 10.0 years. During the follow‐up period (mean 289.3 days), there was no event associated with oral administration of SGLT2 inhibitors. These drugs significantly lowered fasting blood glucose and glycosylated hemoglobin levels at 6 months, and did not affect the creatinine level, blood urea nitrogen/creatinine ratio or estimated glomerular filtration rate during treatment. Although the treatment significantly increased hemoglobin and hematocrit levels, it did not affect the ultrasonographically determined diameter of the inferior vena cava, and no signs of intravascular collapse were observed. Changes in brain natriuretic peptide levels during the follow‐up period were assessed in 78 patients with a brain natriuretic peptide level exceeding the normal upper limit before treatment with SGLT2 inhibitors. The brain natriuretic peptide levels significantly decreased after 6 months of treatment.

Conclusions

In older Japanese patients with diabetes, treatment with SGLT2 inhibitors for 6 months exerted a favorable hypoglycemic effect, while no sign of dehydration was observed. Geriatr Gerontol Int 2018; 18: 108–114 .     

Recognition of regional hypertrophy in hypertrophic cardiomyopathy using thallium-201 emission-computed tomography: Comparison with two-dimensional echocardiography

The configuration of the hypertrophied myocardium was evaluated by thallium-201 emission-computed tomography and 2-dimensional (2-D) sector scan in 10 patients with obstructive hypertrophic cardiomyopathy (HC), 10 with nonobstructive HC with giant negative T waves and 10 with concentric left ventricular (LV) hypertrophy. Thallium-201 myocardial imaging was reconstructed into multiple 12-mm-thick slices in 3 planes. The thickness ratio of the ventricular septum and the LV posterior wall in the short-axis plane and the ratio of the ventricular septum and the apical wall in the long-axis plane were analyzed. In the patients with obstructive HC the ventricular septal wall thickness index was increased, and the ratio of septal to posterior wall thickness index (1.45 ± 0.23) was greater than that in the patients with nonobstructive HC with giant negative T waves or in those with concentric LV hypertrophy (1.03 ± 0.20 and 0.98 ± 0.11, respectively; p <0.01 for each). In the patients with nonobstructive HC with giant negative T waves, increased apical wall thickness with apical cavity obliteration was characteristic, and the ratio of ventricular septal to apical wall thickness index (0.66 ± 0.14) was less than that in the patients with obstructive HC or in those with concentric LV hypertrophy (1.46 ± 0.38 and 1.04 ± 0.09, respectively; p <0.001 for each). In contrast, technically satisfactory 2-D sector scanning (83%) demonstrated various configurations of the hypertrophied ventricularseptum, but could not detect apical hypertrophy in 4 of the 10 patients with nonobstructive HC with giant negative T waves whose LV cineangiograms demonstrated apical hypertrophy. Thus, thallium-201 emission-computed tomography is useful in evaluating the characteristics of LV hypertrophy and assists 2-D sector scan, especially in patients with apical hypertrophy in HC.     

A Rare Case of Ectopic Adrenocorticotropic Hormone Syndrome with Recurrent Olfactory Neuroblastoma

A 40-year-old woman who had a history of recurrent olfactory neuroblastoma presented with full moon face, central obesity, buffalo hump, impaired glucose tolerance and bilateral cervical lymph node swelling. Laboratory tests showed morbidly elevated levels of adrenocorticotropic hormone (ACTH) and cortisol, which were not suppressed by high-dose (8 mg) dexamethasone. Biopsies of the enlarged cervical lymph nodes revealed ACTH-positive metastatic olfactory neuroblastoma, and ectopic ACTH syndrome was diagnosed. Metyrapone was used to suppress cortisol production and resulted in decreased levels of ACTH and cortisol. Bilateral cervical tumor resection further reduced the ACTH and cortisol levels, accompanied by a reduction in the metyrapone dosage. Cushing''s syndrome was alleviated through ACTH-producing tumor removal.     

Evaluation and clinical use of early washout ratio of thallium-201 in normal and ischemic myocardium after dipyridamole-induced vasodilation using ring-type emission computed tomography

Using newly developed ring-type emission computed tomography (SPECT), we investigated the washout ratio (WR) of T1-201 in the myocardium quantitatively with fast dynamic scanning after infusion of dipyridamole (0.57 mg/kg), and assessed the feasibility of early WR as a marker to detect coronary artery disease. Twenty-three patients with and 8 patients without coronary artery disease had serial SPECT images obtained every 5 min for 45 min and at 180 min after dipyridamole and subsequent T1-201 injection. The best appropriate transaxial slice was selected for WR analysis. Most appropriate diagnostic time was 25 min after infusion of T1-201 (WR-25). Normal WR-25 was 7.1 +/- 4.0%, 5.9 +/- 3.1% and 7.1 +/- 2.3% at the septum, anterior and lateral wall, respectively. Sensitivity, specificity and accuracy to identify coronary stenosis greater than 50% with a usage of abnormal WR-25, defined as WR-25 less than (mean of normals--1SD) in each region of inferest of the left ventricle (LV), were 96%, 100% and 97%, respectively. These results were better than those achieved by visual analysis (sensitivity 78%, specificity 100%, accuracy 84%). In patients with single as well as multivessel disease, the regional accuracy in assessing stenosis of more than 50% in the left anterior descending artery (LAD) and left circumflex artery (LCX) by WR-25 was 94% and 83%, respectively, which was significantly better than using visual methods (LAD 72% and LCX 50%; p less than 0.05). Thus, evaluation of early washout ratios (WR-25) after dipyridamole injection is a valuable method to increase sensitivity in assessing regional myocardial perfusion abnormality and is helpful in detection of ischemic heart disease, even with multivessel disease.