IFN-gamma-dependent transcription of MHC class II IA is impaired in macrophages from aged mice

To determine the effect of aging on IFN-gamma-induced MHC class II antigen expression, we produced bone marrow¿derived macrophages in vitro. In these conditions, we analyzed the effect of aging on the genomic expression of macrophages without the influence of other cell types that may be affected by aging. Although macrophages from young and aged mice showed an identical degree of differentiation, after incubation with IFN-gamma, the expression at the cell surface of the IA complex and the levels of IAbeta protein and mRNA were lower in aged macrophages. Moreover, the transcription of the IAbeta gene was impaired in aged macrophages. The amount of transcription factors that bound to the W and X, but not to the Y, boxes of the IAbeta promoter gene was lower in aged macrophages. Similar levels of CIITA mRNA were found after IFN-gamma treatment of both young and aged macrophages. This shows that neither the initial cascade that starts after the interaction of IFN-gamma with the receptor nor the second signals involved in the expression of CIITA are impaired in aged macrophages. These data indicate that aging is associated with low levels of MHC class II gene induction by IFN-gamma because of impaired transcription.

Iron supply for erythropoiesis in the rabbit

Marrow radioiron uptake and marrow blood flow were measured in order to evaluate iron supply for erythropoiesis. Normal, phenylhydrazine-treated and bled animals were studied. The plasma iron turnover of seven normal rabbits was 1.49 +/- 0.22 mg/dl whole blood per d, of 11 rabbits treated 4 d before with phenylhydrazine was 5.16 +/- 1.81, and of four bled animals the plasma iron turnover was 3.75 +/- 1.61. The cardiac output and the percentage of blood flow to the marrow was increased in phenylhydrazine-treated and bled animals. Marrow iron flow in phenylhydrazine-treated animals was 38.3 +/- 32.6 micrograms/min per kg as compared with control values of 7.0 +/- 1.3 (P less than 0.01). This was due to an increase in marrow flow, an increase in plasma iron, and an increase in plasmatocrit. In bled animals, in spite of an increased marrow blood flow, marrow iron flow of 7.3 +/- 2.2 was similar to that of control animals due to a lower plasma iron concentration. The calculated marrow iron extraction of 3.7 +/- 2.4% in phenylhydrazine-treated animals was not different from that of control animals of 4.3 +/- 1.1, whereas extraction was increased in bled animals to 7.9 +/- 1.3 (P less than 0.01). In additional studies of transfused animals, acutely induced anemia was associated with an increased cardiac output, but also with a relative decrease in marrow flow, which left marrow iron supply unaffected. It would appear from these studies that an important mechanism for meeting the increased iron requirement of the hyperplastic erythroid marrow is an increase in marrow blood flow.

Demonstration and partial characterization of the interferon-gamma receptor on human mononuclear phagocytes.

Radioiodinated recombinant human interferon-gamma (IFN gamma) bound to human monocytes, U937, and HL60 cells in a specific, saturable, and reversible manner. At 4 degrees C, the different cell types bound 3,000-7,000 molecules of IFN gamma, and binding was of comparable affinity (Ka = 4-12 X 10(8) M-1). No change in the receptor was observed after monocytes differentiated to macrophages or when the cell lines were pharmacologically induced to differentiate. The functional relevance of the receptor was validated by the demonstration that receptor occupancy correlated with induction of Fc receptors on U937. Binding studies using U937 permeabilized with digitonin showed that only 46% of the total receptor pool was expressed at the cell surface. The receptor appears to be a protein, since treatment of U937 with trypsin or pronase reduced 125I-IFN gamma binding by 87 and 95%, respectively. At 37 degrees C, ligand was internalized, since 32% of the cell-associated IFN gamma became resistant to trypsin stripping. Monocytes degraded 125I-IFN gamma into trichloroacetic acid-soluble counts at 37 degrees C but not at 4 degrees C, at an approximate rate of 5,000 molecules/cell per h. The receptor was partially characterized by SDS-polyacrylamide gel electrophoresis analysis of purified U937 membranes that had been incubated with 125I-IFN gamma. After cross-linking, the receptor-ligand complex migrated as a broad band that displayed an Mr of 104,000 +/- 18,000 at the top and 84,000 +/- 6,000 at the bottom. These results thereby define and partially characterize the IFN gamma receptor of human mononuclear phagocytes.

Traitements de fer: preuves de t'efficacité et bonne pratique clinique [Iron therapy: proof of efficacy and good clinical practice].

Efficacy of iron therapy, whether oral or intravenous, on biological markers of body iron stores is well recognized in medical literature, but current studies are heterogeneous, of sometimes dubious quality, and rarely address clinical outcomes. Precise practical guidelines appear available only for indications related to kidney disease. First-line intravenous use is reserved for situations comprising chronic renal failure, or patients presenting with malabsorption syndromes such as in inflammatory bowel disease. In all other situations, because of the non-negligible risk of hypersensitivity reactions, intravenous iron use is considered justified only in clinically sustained indications, for patients in whom oral administration of iron is unsatisfactory or impossible.

Trigeminal neuralgia related to megadolichobasilar artery compression: a prospective series of twenty-nine patients treated with gamma knife surgery, with more than one year of follow-up.

BACKGROUND: Trigeminal neuralgia (TN) secondary to megadolichobasilar artery (MBA) compression is considerably difficult to manage surgically. OBJECTIVE: This study aims to evaluate the safety/efficacy of Gamma Knife surgery (GKS) in this special group of patients. METHODS: Between July 1992 and November 2010, 29 patients with >1 year of follow-up presenting with MBA compression were treated with GKS at Timone University Hospital. Radiosurgery was performed using a Gamma Knife (model B, C or Perfexion). A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 9.1 mm (range: 6-18.2 mm) from the emergence. RESULTS: The median follow-up period was 46.1 months (range: 12.9-157.9 months). Initially, all patients (100%) were pain free; the average time to complete pain relief was 13.5 days (range: 0-240 days). Their actuarial probability of remaining pain free without medication at 0.5, 1 and 2 years was 93.1, 79.3 and 75.7%, respectively, and remained stable until 13 years after treatment. The actuarial probability of hypoesthesia onset at 6 months was 4.3%; at 1 year it reached 13% and remained stable until 13 years after treatment. CONCLUSIONS: GKS proved to be reasonably safe and effective on a long-term basis as a first- and/or second-line surgical treatment for TN due to MBA compression.

Iron-deficiency anemia and hematochezia: when is colonoscopy appropriate?

Background: Colonoscopy is usually proposed for the evaluation of lower gastrointestinal blood loss (hematochezia) or iron deficiency anemia (IDA). Clinical practice guidelines support this approach but formal evidence is lacking. Real clinical scenarios made available on the web would be of great help in decision-making in clinical practice as to whether colonoscopy is appropriate for a given patient. Method: A multidisciplinary multinational expert panel (EPAGE II) developed appropriateness criteria based on best published evidence (systematic reviews, clinical trials, guidelines) and experts' judgement. Using the explicit RAND Appropriateness Method (3 round of experts' votes and a panel meeting) 102 clinical scenarios were judged inappropriate, uncertain, appropriate, or necessary. Results: In IDA, colonoscopy was appropriate in patients >50 years and necessary in the presence of lower abdominal symptoms. In both men and women aged <50 years, colonoscopy was appropriate if prior sigmoidoscopy and/or gastroscopy did not explain the IDA, and necessary if lower gastrointestinal symptoms were present. In women <50 years with a potential gynecological cause, additional lower gastrointestinal symptoms rendered colonoscopy appropriate. In patients >50 years with hematochezia, colonoscopy was always appropriate and mostly necessary, except if a prior colonoscopy was normal within the previous 5 years. Under age 50 years, the presence of any risk factor for colorectal cancer (CRC) and no previous normal colonoscopy (within the last 5 years) made this procedure appropriate and necessary. Conclusion: Colonoscopy is appropriate and even necessary for many indications related to iron deficiency anemia or hematochezia, in particular in patients aged >50 years. The main factors influencing appropriateness are age, results of prior investigations (sigmoidoscopy, gastroscopy, previous colonoscopy), CRC risk and sex. EPAGE II appropriateness criteria are available on www.epage.ch

Learning form Nature to improve the heat generation of iron-oxide nanoparticles for magnetic hyperthermia applications.

The performance of magnetic nanoparticles is intimately entwined with their structure, mean size and magnetic anisotropy. Besides, ensembles offer a unique way of engineering the magnetic response by modifying the strength of the dipolar interactions between particles. Here we report on an experimental and theoretical analysis of magnetic hyperthermia, a rapidly developing technique in medical research and oncology. Experimentally, we demonstrate that single-domain cubic iron oxide particles resembling bacterial magnetosomes have superior magnetic heating efficiency compared to spherical particles of similar sizes. Monte Carlo simulations at the atomic level corroborate the larger anisotropy of the cubic particles in comparison with the spherical ones, thus evidencing the beneficial role of surface anisotropy in the improved heating power. Moreover we establish a quantitative link between the particle assembling, the interactions and the heating properties. This knowledge opens new perspectives for improved hyperthermia, an alternative to conventional cancer therapies.

Appropriateness of colonoscopy in Europe (EPAGE II). Iron-deficiency anemia and hematochezia.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for the investigation of iron-deficiency anemia (IDA) and hematochezia, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews and primary studies regarding the evaluation and management of IDA and hematochezia was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: IDA occurs in 2 %-5 % of adult men and postmenopausal women. Examination of both the upper and lower gastrointestinal tract is recommended in patients with iron deficiency. Colonoscopy for IDA yields one colorectal cancer (CRC) in every 9-13 colonoscopies. Hematochezia is a well-recognized alarm symptom and such patients are likely to be referred for colonoscopy. Colonoscopy is unanimously recommended in patients aged > or = 50. Diverticulosis, vascular ectasias, and ischemic colitis are common causes of acute lower gastrointestinal bleeding (LGIB); CRC is found in 0.2 %-11 % of the colonoscopies performed for LGIB. Most patients with scant hematochezia have an anorectal or a distal source of bleeding. The expert panel considered most clinical indications for colonoscopy as appropriate in the presence of IDA (58 %) or hematochezia (83 %). CONCLUSION: Despite the limitations of the published studies, guidelines unanimously recommend colonoscopy for the investigation of IDA and hematochezia in patients aged > or = 50 years. These indications were also considered appropriate by EPAGE II, as were indications in patients at low risk for CRC with no obvious cause of bleeding found during adequate previous investigations.

T cell receptor delta gene rearrangement and T early alpha (TEA) expression in immature alpha beta lineage thymocytes: implications for alpha beta/gamma delta lineage commitment.

Mature T cells comprise two mutually exclusive lineages expressing heterodimeric alpha beta or gamma delta antigen receptors. During development, beta, gamma, and delta genes rearrange before alpha, and mature gamma delta cells arise in the thymus prior to alpha beta cells. The mechanism underlying commitment of immature T cells to the alpha beta or gamma delta lineage is controversial. Since the delta locus is located within the alpha locus, rearrangement of alpha genes leads to deletion of delta. We have examined the rearrangement status of the delta locus immediately prior to alpha rearrangement. We find that many thymic precursors of alpha beta cells undergo VDJ delta rearrangements. Furthermore, the same cells frequently coexpress sterile T early alpha (TEA) transcripts originating 3' of C delta and 5' of the most upstream J alpha, thus implying that individual alpha beta lineage cells undergo sequential VDJ delta and VJ alpha rearrangements. Finally, VDJ delta rearrangements in immature alpha beta cells appear to be random, supporting models in which alpha beta lineage commitment is determined independently of the rearrangement status at the TCR delta locus.

Marqueurs diagnostiques de la carence en fer: lequel choisir [Diagnostic markers of iron deficiency: which should we choose?].

Iron deficiency is generally investigated when faced with anemia, or with symptoms that could be related to iron deficiency without anemia. This simple disorder is easy to treat, provided that the diagnosis is correct. Several biological tests are available, but their interpretation is oftentimes problematic. Pre-analytical factors can interfere with measurements, normal values can change depending on suppliers, and, above all, results from different markers can be contradictory in some clinical situations. The aim of this article is to evaluate how the evolution of scientific knowledge and clinical trials can contribute to a better understanding and greater reliability in the diagnosis of iron deficiency.

Peroxisome proliferator-activated receptor gamma is required in mature white and brown adipocytes for their survival in the mouse.

The peroxisome proliferator-activated receptor gamma (PPARgamma) mediates the activity of the insulin-sensitizing thiazolidinediones and plays an important role in adipocyte differentiation and fat accretion. The analysis of PPARgamma functions in mature adipocytes is precluded by lethality of PPARgamma(-/-) fetuses and tetraploid-rescued pups. Therefore we have selectively ablated PPARgamma in adipocytes of adult mice by using the tamoxifen-dependent Cre-ER(T2) recombination system. We show that mature PPARgamma-null white and brown adipocytes die within a few days and are replaced by newly formed PPARgamma-positive adipocytes, demonstrating that PPARgamma is essential for the in vivo survival of mature adipocytes, in addition to its well established requirement for their differentiation. Our data suggest that potent PPARgamma antagonists could be used to acutely reduce obesity.

Human inhalation exposure to iron oxide particles

In the past decade, many studies have been conducted to determine the health effects induced by exposure to engineered nanomaterials (NMs). Specifically for exposure via inhalation, numerous in vitro and animal in vivo inhalation toxicity studies on several types of NMs have been published. However, these results are not easily extrapolated to judge the effects of inhaling NMs in humans, and few published studies on the human response to inhalation of NMs exist. Given the emergence of more industries utilizing iron oxide nanoparticles as well as more nanomedicine applications of superparamagnetic iron oxide nanoparticles (SPIONs), this review presents an overview of the inhalation studies that have been conducted in humans on iron oxides. Both occupational exposure studies on complex iron oxide dusts and fumes, as well as human clinical studies on aerosolized, micron-size iron oxide particles are discussed. Iron oxide particles have not been described to elicit acute inhalation response nor promote lung disease after chronic exposure. The few human clinical studies comparing inhalation of fine and ultrafine metal oxide particles report no acute changes in the health parameters measured. Taken together existing evidence suggests that controlled human exposure to iron oxide nanoparticles, such as SPIONs, could be conducted safely.