Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli

Dendritic cells (DCs) are a family of leukocytes that initiate T- and B-cell immunity against pathogens. Migration of antigen-loaded DCs from sites of infection into draining lymphoid tissues is fundamental to the priming of T-cell immune responses. In humans, the major peripheral blood DC (PBDC) types, CD1c+ DCs and interleukin 3 receptor-positive (IL-3R+) plasmacytoid DCs, are significantly expanded in vivo with the use of Flt3 ligand (FL). DC-like cells can also be generated from monocyte precursors (MoDCs). A detailed comparison of the functional potential of these types of DCs (in an autologous setting) has yet to be reported. Here, we compared the functional capacity of FL-expanded CD1c+ PBDCs with autologous MoDCs in response to 3 different classes of stimuli: (1) proinflammatory mediators, (2) soluble CD40 ligand trimer (CD40L), and (3) intact bacteria (Escherichia coli). Significant differences in functional capacities were found with respect to changes in phenotype, migratory capacity, cytokine secretion, and T-cell stimulation. MoDCs required specific stimuli for the expression of functions. They responded vigorously to CD40L or E coli, expressing cytokines known to regulate interferon-gamma (IFN-gamma) in T cells (IL-12p70, IL-18, and IL-23), but required prostaglandin E2 (PGE2) during stimulation to migrate to chemokines. In contrast, PBDCs matured in response to minimal stimulation, rapidly acquired migratory function in the absence of PGE2-containing stimuli, and were low cytokine producers. Interestingly, both types of DCs were equivalent with respect to stimulation of allogeneic T-cell proliferation and presentation of peptides to cytotoxic T lymphocyte (CTL) lines. These distinct differences are of particular importance when considering the choice of DC types for clinical applications.     

Relationship between duration of arrhythmia and subsequent preventive effect of disopyramide after cardioversion in patients with symptomatic paroxysmal and persistent atrial fibrillation

OBJECTIVES: The relationship between the duration of arrhythmia and the subsequent long-term efficacy of disopyramide in preventing atrial fibrillation was investigated in patients with symptomatic paroxysmal and persistent atrial fibrillation. METHODS: A total of 60 patients (39 men, 21 women, mean age 65 +/- 11 years) were given disopyramide (300 mg/day) after electrical and pharmacological cardioversion based on American Heart Association Task Force on Practice Guidelines. The patients were divided into two types based on the duration of atrial fibrillation: conversion within 48 hr (group A, n = 35) and more than 48 hr (group B, n = 25) after the episode. Mean follow-up period was 47.1 +/- 28.7 months. RESULTS: Patient characteristics showed no statistically significant difference between groups A and B. The actuarial rates of maintenance of sinus rhythm at 1, 3, 6, 12, 18 and 24 months were 88.6%, 77.1%, 57.1%, 48.6%, 42.9% and 37.1%, respectively, in group A, and 72.0%, 44.0%, 28.0%, 16.0%, 12.0% and 8.0%, respectively, in group B. There was a significant difference in the rate at 24 months between groups A and B (p < 0.05). The periods for maintenance of sinus rhythm in groups A and B were 20.9 +/- 3.9 and 6.7 +/- 2.1 months, respectively, with a significant difference between groups A and B (p < 0.01). CONCLUSIONS: The efficacy of disopyramide in preventing the recurrence of atrial fibrillation varies with the duration of the previous episode. These results demonstrate that it is important to convert to normal sinus rhythm earlier to prevent the recurrence of atrial fibrillation in the long term.     

Anti-angiogenic activity of the methanol extract and its fractions of Ulmus davidiana var. japonica

This study aimed to elucidate anti-angiogenic activity of Ulmus davidiana var. japonica that has been widely used in folk medicine. The methanol extract (UDE) of Ulmus davidiana var. japonica concentration-dependently displayed a strong inhibition in the chick chorioallantoic membrane (CAM) angiogenesis. The n-butanol fraction of UDE and subsequent 30% MeOH subfraction were identified to be most responsible for the anti-angiogenic activity.     

Interim <Superscript>18</Superscript>F-FGD PET/CT may not predict the outcome in primary central nervous system lymphoma patients treated with sequential treatment with methotrexate and cytarabine

¹⁸F-fluoro-2-dexoy-D-glucose-positron emission tomography (PET)/computed tomography (CT) is a useful imaging technique for monitoring the treatment response in lymphoma cases. We investigated the value of interim brain PET/CT (I-PET/CT) for monitoring the response to intensive methotrexate-based chemotherapy in primary central nervous system lymphoma (PCNSL) patients with diffuse large B cell lymphoma (DLBCL). Of the 76 PCNSL patients treated with intensive methotrexate and cytarabine chemotherapy between September 2006 and December 2012, 66 patients with DLBCL were included in this study. The patient cohort of 66 individuals comprised 43 men and 23 women with a median age of 59 years (range, 17–75 years). During chemotherapy, 36 patients (54.5%) showed a negative metabolism on I-PET/CT, and 47 (71.2%) were negative on final (F) PET/CT. The baseline characteristics were similar between I-PET/CT-negative (n = 36) and I-PET/CT-positive patients (n = 30) except ECOG performance status. After a median follow-up of 27.5 months, there was no difference in the progression-free survival (PFS; P = 0.701) or overall survival (OS; P = 0.620) between the I-PET/CT-negative and I-PET/CT-positive groups. However, PFS in the F-PET/CT-negative group was significantly longer than that in the F-PET/CT-positive group (P < 0.001) without a significant difference in OS (P = 0.892). I-PET/CT may not predict the survival outcome of PCNSL patients with DLBCL treated with intensive methotrexate and cytarabine chemotherapy. Prospective trials are required to fully evaluate the role of I-PET/CT.     

Stronger associations of sagittal abdominal diameter with atherogenic lipoprotein subfractions than waist circumference in middle-aged US white and Japanese men

Both sagittal abdominal diameter (SAD) and waist circumference (WC) highly correlate with visceral adipose tissue (VAT) being linked to an atherogenic lipoprotein profile. However, it is uncertain whether SAD is a better correlate of atherogenic lipoprotein subfractions than WC. We examined relative associations of SAD vs WC with lipoprotein subfractions for US white and Japanese men, concurrently examining the associations of VAT vs subcutaneous adipose tissue with lipoprotein subfractions. A population-based sample of 260 white and 282 Japanese men aged 40 to 49 years was examined for VAT and subcutaneous adipose tissue by computed tomography; SAD and WC by a portable sliding-beam caliper and a measuring tape, respectively; and lipoprotein subfractions by nuclear magnetic resonance spectroscopy. Both SAD and WC were significantly and positively associated with large very low-density lipoprotein and total and small low-density lipoprotein particle concentrations, and inversely associated with large high-density lipoprotein particle concentration for both white and Japanese men. In body mass index–adjusted regression models, the significant associations of SAD remained for both white and Japanese men, whereas those of WC became nonsignificant for white men. When SAD and WC were simultaneously included into the body mass index–adjusted models, the associations of SAD remained significant and statistically stronger than those of WC for both white and Japanese men. Furthermore, the pattern of the associations of SAD with those lipoprotein subfractions was comparable to that of the associations of VAT. Sagittal abdominal diameter was comparable to VAT and stronger than WC in the associations with atherogenic lipoprotein subfractions for middle-aged, nondiabetic, white and Japanese men.     

Pheochromocytoma crisis after a dexamethasone suppression test for adrenal incidentaloma

A 61-year-old woman was referred to our department for evaluation of an incidental adrenal mass. An abdominal CT scan revealed a 4.1 cm right adrenal mass. The patient had been diagnosed with hypertension 7 years earlier and had taken antihypertensive medications intermittently. Her physical examination demonstrated a round face, central obesity, and mild hypertension. Serum catecholamines, renin, aldosterone, ACTH and 24-h urine-free cortisol, vanillylmandelic acid levels were within normal limits. However, serum cortisol level was markedly elevated and the circadian rhythm was disturbed. Successive low-dose and high-dose dexamethasone suppression tests were ordered for evaluation of a functioning adrenal incidentaloma. About 2 h after taking the second dose of 2 mg dexamethasone, she suddenly developed nausea and vomiting, palpitations, and anxiety with severe hypertension. On the same day, we measured serum catecholamines, which were markedly elevated. An elective laparoscopic right adrenalectomy was performed and pathologic examination confirmed the diagnosis of pheochromocytoma. One week after surgery, serum and urine catecholamine levels returned to normal. The patient has remained normotensive without any medications and clinically well. Patients with adrenal incidentalomas may have a functional mass that does not always manifest as a full symptomatic disease. During the investigation of adrenal incidentalomas, pheochromocytoma should ideally be ruled out before administering corticosteroids.     

A novel insight into aging: are there pluripotent very small embryonic-like stem cells (VSELs) in adult tissues overtime depleted in an Igf-1-dependent manner?

Tissue and organ rejuvenation and senescence/aging are closely related to the function of stem cells. Recently, we demonstrated that a population of pluripotent Oct-4+ SSEA-1+Sca-1+Lin-CD45- very small embryonic-like stem cells (VSELs) resides in the adult murine bone marrow (BM) and other murine tissues. We hypothesize that these pluripotent stem cells play an important role in tissue/organ rejuvenation, and have demonstrated that their proliferation and potentially premature depletion is negatively controlled by epigenetic changes of some imprinted genes that regulate insulin factor signaling (Igf2-H19 locus, Igf2R and RasGRF1). Since the attenuation of insulin/insulin growth factor (Ins/Igf) signaling positively correlates with longevity, we propose, based on our experimental data, that gradual decrease in the number of VSELs deposited in adult tissues, which occurs throughout life in an Ins/Igf signaling-dependent manner is an important mechanism of aging. In contrast, a decrease in Ins/Igf stimulation of VSELs that extends the half life of these cells in adult organs would have a beneficial effect on life span. Our preliminary data in long-living Igf-1-signaling-deficient mice show that these animals possess a 3-4 times higher number of VSELs deposited in adult BM, lending support to this novel hypothesis.