Stem cells and the aging hematopoietic system Beerman, Isabel; Maloney, William J; Weissmann, Irving L ...
Current opinion in immunology,
08/2010, Letnik:
22, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Advancing age is accompanied by a number of clinically significant conditions arising in the hematopoietic system that include: diminution and decreased competence of the adaptive immune system, ...elevated incidence of certain autoimmune diseases, increased hematological malignancies, and elevated incidence of age-associated anemia. As with most tissues, the aged hematopoietic system also exhibits a reduced capacity to regenerate and return to normal homeostasis after injury or stress. Evidence suggests age-dependent functional alterations within the hematopoietic stem cell compartment significantly contribute to many of these pathophysiologies. Recent developments have shed light on how aging of the hematopoietic stem cell compartment contributes to hematopoietic decline through diverse mechanisms.
Thiazolidinediones (TZDs) enhanced body weight (BW) partially by increased adipogenesis and hyperphagia. Neuronal PPARγ knockout mice on high-fat diet (HFD) are leaner because of enhanced leptin ...response, although it could be secondary to their leanness. Thus, it still is an open question how TZDs may alter energy balance. Multiple factors regulate food intake (FI) and energy expenditure (EE), including anorexigenic hormones as insulin and leptin. Nonetheless, elevated hypothalamic AMPK activity increases FI and TZDs increase AMPK activity in muscle cells. Thus, the aim of the present study was to investigate whether Pioglitazone (PIO) treatment alters hypothalamic insulin and leptin action/signaling, AMPK phosphorylation, and whether these alterations may be implicated in the regulation of FI and EE.
Swiss mice on HFD (2 months) received PIO (25 mg kg(-1) per day-gavage) or vehicle for 14 days. AMPK and AdipoR1 were inhibited via Intracerebroventricular injections using Compound C (CompC) and small interference RNA (siRNA), respectively. Western blot, real-time PCR and CLAMS were done.
PIO treatment increased BW, adiposity, FI, NPY mRNA and decreased POMC mRNA expression and EE in HFD mice. Despite higher adiposity, PIO treatment improved insulin sensitivity, glucose tolerance, decreased insulin and increased adiponectin serum levels. This result was associated with, improved insulin and leptin action/signaling, decreased α2AMPK(Ser491) phosphorylation and elevated Acetyl-CoA carboxylase and AMPK(Thr172) phosphorylation in hypothalamus. The inhibition of hypothalamic AMPK with CompC was associated with decreased adiposity, FI, NPY mRNA and EE in PIO-treated mice. The reduced expression of hypothalamic AdipoR1 with siRNA concomitantly with PIO treatment reverted PIO induced obesity development, suggesting that adiponectin may be involved in this effect.
These results demonstrated that PIO, despite improving insulin/leptin action in hypothalamus, increases FI and decreases EE, partially, by activating hypothalamic adiponectin/AdipoR1/AMPK axis. Suggesting a novel mechanism in the hypothalamus by which TZDs increase BW.
To investigate whether the Cdc2-like kinase 2 (CLK2) is expressed in hypothalamic neurons and if it is, whether the hypothalamic CLK2 has a role in the regulation of energy balance.
Swiss mice on ...chow or high-fat diet (HFD) and db/db mice on chow diet were used to address the role of CLK2 in the hypothalamus.
Hypothalamic CLK2
phosphorylation, which induces CLK2 activity, is regulated in vivo by refeeding, insulin and leptin, in a PI3K (phosphoinositide 3-kinase)-dependent manner. The reduction of CLK2 expression in the hypothalamus, by chronic pharmacological inhibition with TG003 or by chronic knockdown with small interfering RNA was sufficient to abolish the anorexigenic effect of insulin and leptin, to increase body weight, fat mass, food intake and to decrease energy expenditure in mice on chow. In contrast, CLK2
phosphorylation in the hypothalamus in response to insulin, leptin or refeeding was impaired in mice on HFD or in db/db mice. Chronic CLK2 inhibition in the hypothalamus was associated with a slight increase in the fasting blood glucose levels, reduction in PEPCK (phosphoenolpyruvate carboxykinase) expression in the liver and enhanced glucose production from pyruvate, suggesting a regulation of hepatic glucose production. Further, overexpressing CLK2 in the mediobasal hypothalami of mice on HFD or in db/db mice by adenovirus partially reversed the obese phenotype.
Thus, our results suggest that protein CLK2 integrates some important hypothalamic pathways, and may be a promising molecule for new therapeutic approaches for obesity and diabetes.
Henoch-Schönlein purpura (HSP) is a fairly common disease in children and adolescents. There are only limited data available for adults.
A retrospective analysis was conducted to study renal ...manifestations in patients with HSP treated in our institution between 1982 and 2007. We divided our adult cohort according to age - under or over 60 years - to examine differences in elderly patients.
HSP was identified in 2.2% of patients referred to us for kidney biopsy. Purpuric lesions and renal involvement were found in all patients. An important triggering factor for the development of HSP in our series was chronic alcohol intake. Forty percent of our patients fulfilled the WHO criteria for alcoholics. Renal involvement was particularly prominent in patients over 60 years of age. At disease onset, estimated glomerular filtration rate (eGFR) was 63% lower in the elderly. Within a median follow-up of 8 years, renal function was significantly better in younger adults than in the elderly. 32% of the elderly have shown Modification of Diet in Renal Disease (MDRD) < 20 ml/min/1.73 m2 in contrast to only 7% in patients < 60 years. Furthermore, significantly more elderly patients reached end-stage renal failure.
The data indicate that renal manifestation of HSP in the elderly is severe and its outcome relatively poor, and worsens when compared to patients < 60 years.
Accelerated radioactive beams from REX-ISOLDE Kester, O; Sieber, T; Emhofer, S ...
Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms,
05/2003, Letnik:
204
Journal Article, Conference Proceeding
Recenzirano
In 2001 the linear accelerator of the
Radioactive beam
EXperiment (REX-ISOLDE) delivered for the first time accelerated radioactive ion beams, at a beam energy of 2 MeV/u. REX-ISOLDE uses the method ...of charge-state breeding, in order to enhance the charge state of the ions before injection into the LINAC. Radioactive singly-charged ions from the on-line mass separator ISOLDE are first accumulated in a Penning trap, then charge bred to an
A/
q<4.5 in an electron beam ion source (EBIS) and finally accelerated in a LINAC from 5 keV/u to energies between 0.8 and 2.2 MeV/u. Dedicated measurements with REXTRAP, the transfer line and the EBIS have been carried out in conjunction with the first commissioning of the accelerator. Thus the properties of the different elements could be determined for further optimization of the system. In two test beam times in 2001 stable and radioactive Na isotopes (
23Na–
26Na) have been accelerated and transmitted to a preliminary target station. There
58Ni- and
9Be- and
2H-targets have been used to study exited states via Coulomb excitation and neutron transfer reactions. One MINIBALL triple cluster detector was used together with a double sided silicon strip detector to detect scattered particles in coincidence with γ-rays. The aim was to study the operation of the detector under realistic conditions with γ-background from the β-decay of the radioactive ions and from the cavities. Recently for efficient detection eight tripple Ge-detectors of MINIBALL and a double sided silicon strip detector have been installed. We will present the first results obtained in the commissioning experiments and will give an overview of realistic beam parameters for future experiments to be started in the spring 2002.
Asbestos exposure is the major known risk factor for mesothelioma, but several case reports have suggested a link between radiation therapy and subsequent development of malignant mesothelioma. This ...report explores a possible association between radiation therapy for Hodgkin's disease and mesothelioma.
Four cases of malignant mesothelioma were observed following Hodgkin's disease at the Mesothelioma Clinic of the Dana-Farber Cancer Institute. A fifth such patient was found after a review of the literature.
In all five cases, the mesothelioma arose in the field of prior radiotherapy. No history of asbestos exposure was elicited by careful questioning or by review of chest radiographs. Examination of lung tissue in one patient showed 250 ferruginous bodies per gram of lung tissue, consistent with no significant prior exposure. The mean interval between radiation treatment for Hodgkin's disease and development of mesothelioma was 15 years, which emphasizes the need for continued follow-up and evaluation of these patients and supports a causal relationship.
Mesothelioma may need to be added to the list of second malignancies that arise following radiation therapy for Hodgkin's disease. Further support is given to a causal link between radiation exposure and mesothelioma.
A new measurement of the β-decay of 9Li has clarified the feeding to the highest accessible states in 9Be. It is found that the β-decay mainly populates the 11.8 MeV state, whose spin is determined ...as 5/2−. The extracted BGT value of 5.3(0.9) is a factor 4.4(1.0) larger than that of the mirror transition from 9C. A theoretical explanation of such a pronounced β-decay asymmetry is presently lacking.
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