Extracellular acidification decreases the basal motility of cultured mouse microglia via the rearrangement of the actin cytoskeleton

The present study was undertaken to examine the effect of extracellular pH (pH(0)) on the locomotor function of murine microglial cells in vitro. We have found that basal motility of microglia, as measured by a computer-assisted video assay, decreased in an acidic, but not in an alkaline environment. Extracellular acidification affected the architecture of F-actin cytoskeleton, inducing bundling of actin and the formation of stress fibers. The change in intracellular pH (pH(i)) resulting from the change in pH(0) seems to be a prerequisite for the motility decrease since other means to decrease pH(i), namely Na(+)-free solution (in the absence of HCO(-)(3)) and nigericin-containing solution, mimicked the extracellular acidification. In contrast to its pronounced effect on basal motility of microglial cells, the motility increase, as induced by the chemoattractant complement 5a (C5a), was not affected by the acidic environment. The relationship of pH(0) to the locomotor function was also studied in a long-term microchemotaxis assay where microglia migrated within a pH gradient. Intracellular acidification induced by lowering pH(0) to 6.0 or removal of Na(+) from the assay medium decreased basal microglial cell migration. The C5a-induced chemotactic migration was moderately decreased by the acidic environment. In conclusion, our results suggest that acidification of the microglial extracellular milieu leads to a decrease in pH(i) and thereby reduces the basal microglial motility and C5a-induced chemotaxis via a rearrangement of the cytoskeleton. We would therefore like to speculate that changes in pH(i) constitute an important control mechanism in regulating the locomotor function of microglia in culture and probably also in the intact tissue.     

Investigation of the aluminium biokinetics in humans: a 26Al tracer study.

Despite the well-known toxicity of aluminium in chronic renal failure, a solid database on its biokinetics has been difficult to establish. A highly sensitive method using (26)Al as tracer and accelerator mass spectrometry (AMS) for detection was used. No perturbing background and saturation effects were taken into account using a delta function input of aluminium in time. Aluminium absorption, distribution, speciation and excretion in six healthy volunteers and in two patients with chronic renal failure were investigated following administration of a single oral or i.v. dose of (26)Al. Serial samples of blood and urine were taken. In a speciation study, the time dependence of the binding of (26)Al to low-molecular weight molecules in serum was investigated. The measured data were compared and interpreted with simulations in an open compartmental model. Fractional absorption, distribution, excretion and time constants for the aluminium transport were determined. Typical intestinal absorption rates for AlCl(3) were found to be in the range of 10(-3). The ultrafiltrable percentage of aluminium in serum of one volunteer was estimated to be 5.6+/-0.8%. Differences between healthy volunteers and patients with chronic renal failure were deduced. The employed method using (26)Al and ams has proven to be highly sensitive for investigations of aluminium biokinetics at the ultra-trace element level. With the model, the measured values of (26)Al in serum and urine were used to precisely determine absorption, speciation, distribution, retention and excretion of aluminium in humans.     

Concomitant MDS with isolated 5q deletion and MGUS: case report and review of molecular aspects

Patients with monoclonal gammopathy of undetermined significance (MGUS) have a higher risk for the development of concomitant primary cancers such as multiple myeloma (MM) and myelodysplastic syndrome (MDS). We report the case of patient initially suffering from MGUS of the IgG lambda subtype for more than 10 yr, which evolved to MM and MDS with deletion (5q) with severe pancytopenia. Due to pancytopenia, he received dose‐reduced treatment with lenalidomide and dexamethasone. He achieved an ongoing transfusion independency after about 1 month of treatment. Bone marrow taken 14 months after start of treatment showed a complete cytogenetic response of the del(5q) clone and a plasma cell infiltration below 5%. In contrast to the development of MM in MGUS patients, the subsequent occurrence of MDS after diagnosis of MGUS is infrequent. Moreover, the biological association of MDS with MGUS is not sufficiently understood, but the non‐treatment‐related occurrence supports the pathogenetic role of pre‐existing alterations of stem cells. Here, we summarize data on concomitant MDS and MGUS/MM with particular emphasis on molecular aspects.     

Myelodysplasien

Myelodysplastic syndromes (MDS) are hematopoetic disorders mainly of elderly patients. Although allogeneic stem cell transplantation is the only curative therapy in MDS. However, due to age and frequently coexisting morbidities only a minority is eligible for this approach. The demethylating agent 5-azacitidine is a highly effective drug, which has been approved for MDS patients with an increased medullary blast count. In low-risk MDS patients with isolated deletion 5q lenalidomide has demonstrated its high efficacy. However, it has not yet been approved in Germany in this indication. Most patients will depend on regular transfusions of packed red blood cells with the risk of development of iron overload. Recently, new high throughput technologies have identified various molecular alterations in patients with MDS and other myeloid malignancies. Some of them might be included in upcoming classification systems, while others might be of use in optimizing risk stratification scores. Identification of molecular defects might result in the advent of specific and targeted drugs leading to a more effective treatment in MDS in the future.     

What is the evidence base for public involvement in health‐care policy?: results of a systematic scoping review

Background

Public involvement in health‐care policy has been advocated as a means to enhance health system responsiveness, yet evidence for its impact has been difficult to ascertain.

Objectives

To review the peer‐reviewed empirical evidence on outcomes of public involvement in health‐care policy.

Methods

We systematically searched PsychINFO and PubMed from November 2000 to April 2010 for empirical studies that reported on original research only; studies in languages other than English, German or French were excluded. Data were extracted using a standardized evidence table with a priori determined headings.

Main results

Nineteen studies were identified as eligible for inclusion in our review. We found that sound empirical evidence of the outcomes of public involvement activities in health care remains underdeveloped. The concept and the indicators used to examine and determine outcomes remain poorly specified and inconsistent, as does the reporting of the evidence. There was some evidence for the developmental role of public involvement, such as enhancing awareness, understanding and competencies among lay participants. Evidence for instrumental benefits of public involvement initiatives was less well documented.

Conclusions

Despite the growing body of work on public involvement in health‐care policy, evidence of its impact remains scarce; thus, firm conclusions about involvement activities that are appropriate and effective for policy development are difficult to draw. However, focus on outcomes risks missing the normative argument that involving the public in the health‐care policy process may be seen to be of intrinsic value.