Stimulation of Na⁺/H⁺ Exchanger Isoform 1 Promotes Microglial Migration

Regulation of microglial migration is not well understood. In this study, we proposed that Na+/H+ exchanger isoform 1 (NHE-1) is important in microglial migration. NHE-1 protein was co-localized with cytoskeletal protein ezrin in lamellipodia of microglia and maintained its more alkaline intracellular pH (pHi). Chemoattractant bradykinin (BK) stimulated microglial migration by increasing lamellipodial area and protrusion rate, but reducing lamellipodial persistence time. Interestingly, blocking NHE-1 activity with its potent inhibitor HOE 642 not only acidified microglia, abolished the BK-triggered dynamic changes of lamellipodia, but also reduced microglial motility and microchemotaxis in response to BK. In addition, NHE-1 activation resulted in intracellular Na+ loading as well as intracellular Ca2+ elevation mediated by stimulating reverse mode operation of Na+/Ca2+ exchange (NCXrev). Taken together, our study shows that NHE-1 protein is abundantly expressed in microglial lamellipodia and maintains alkaline pHi in response to BK stimulation. In addition, NHE-1 and NCXrev play a concerted role in BK-induced microglial migration via Na+ and Ca2+ signaling. © 2013 Shi et al

Technical aspects of boron neutron capture therapy at the BNL Medical Research Reactor

The Brookhaven Medical Research Reactor, BMRR, is a 3 MW heterogeneous, tank-type, light water cooled and moderated, graphite reflected reactor, which was designed for biomedical studies. Early BNL work in Boron Neutron Capture Therapy (BNCT) used a beam of thermal neutrons for experimental treatment of brain tumors. Research elsewhere and at BNL indicated that higher energy neutrons would be required to treat deep seated brain tumors. Epithermal neutrons would be thermalized as they penetrated the brain and peak thermal neutron flux densities would occur at the depth of brain tumors. One of the two BMRR thermal port shutters was modified in 1988 to include plates of aluminum and aluminum oxide to provide an epithermal port. Lithium carbonate in polyethylene was added in 1991 around the bismuth port to reduce the neutron flux density coming from outside the port. To enhance the epithermal neutron flux density, the two vertical thimbles A-3 (core edge) and E-3 (in core) were replaced with fuel elements. There are now four fuel elements of 190 grams each and 28 fuel elements of 140 grams each for a total of 4.68 kg of {sup 235}U in the core. The authors have proposed replacing the epithermal shutter with a fission converter plate shutter. It is estimated that the new shutter would increase the epithermal neutron flux density by a factor of seven and the epithermal/fast neutron ratio by a factor of two. The modifications made to the BMRR in the past few years permit BNCT for brain tumors without the need to reflect scalp and bone flaps. Radiation workers are monitored via a TLD badge and a self-reading dosimeter during each experiment. An early concern was raised about whether workers would be subject to a significant dose rate from working with patients who have been irradiated. The gamma ray doses for the representative key personnel involved in the care of the first 12 patients receiving BNCT are listed. These workers did not receive unusually high exposures

Psychosocial implications of tubal ligation in a rural health district: A phenomenological study

<p>Abstract</p> <p>Background</p> <p>Tubal ligation is the most popular family planning method worldwide. While its benefits, such as effectiveness in protecting against pregnancies, minimal need for long-term follow-up and low side-effects profile are well documented, it has many reported complications. However, to date, these complications have not been described by residents in Congo. Therefore, the study aimed at exploring the experience of women who had undergone tubal ligation, focusing on perceptions of physical, psychological and contextual experiences of participants.</p> <p>Methods</p> <p>This qualitative study used a semi-structured questionnaire in a phenomenological paradigm to collect data. Fifteen participants were purposefully selected among sterilized women who had a ligation procedure performed, were aged between 30 and 40 years, and were living within the catchment area of the district hospital. Data were collected by two registered nurses, tape-recorded, and transcribed verbatim. Reading and re-reading cut and paste techniques, and integration were used to establish codes, categories, themes, and description.</p> <p>Results</p> <p>Diverse and sometimes opposite changes in somatic symptoms, psychological symptoms, productivity, ecological relationships, doctor-client relationships, ethical issues, and change of life style were the major problem domains.</p> <p>Conclusions</p> <p>Clients reported conflicting experiences in several areas of their lives after tubal sterilization. Management, including awareness of the particular features of the client, is needed to decrease the likelihood of psychosocial morbidity and/or to select clients in need of sterilization.</p

Application of isothermal titration calorimetry in evaluation of protein–nanoparticle interactions

Nanoparticles (NPs) offer a number of advantages over small organic molecules for controlling protein behaviour inside the cell. Protein binding to the surface of NPs depends on their surface characteristics, composition and method of preparation (Mandal et al. in J Hazard Mater 248–249:238–245, 2013). It is important to understand the binding affinities, stoichiometries and thermodynamical parameters of NP–protein interactions in order to see which interaction will have toxic and hazardous consequences and thus to prevent it. On the other side, because proteins are on the brink of stability, they may experience interactions with some types of NPs that are strong enough to cause denaturation or significantly change their conformations with concomitant loss of their biological function. Structural changes in the protein may cause exposure of new antigenic sites, “cryptic” peptide epitopes, potentially triggering an immune response which can promote autoimmune disease (Treuel et al. in ACS Nano 8(1):503–513, 2014). Mechanistic details of protein structural changes at NP surface have still remained elusive. Understanding the formation and persistence of the protein corona is critical issue; however, there are no many analytical methods which could provide detailed information about the NP–protein interaction characteristics and about protein structural changes caused by interactions with nanoparticles. The article reviews recent studies in NP–protein interactions research and application of isothermal titration calorimetry (ITC) in this research. The study of protein structural changes upon adsorption on nanoparticle surface and application of ITC in these studies is emphasized. The data illustrate that ITC is a versatile tool for evaluation of interactions between NPs and proteins. When coupled with other analytical methods, it is important analytical tool for monitoring conformational changes in proteins

A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression

Introduction: We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression. Methods: Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis. Results: A variant within a DNase hypersensitive site 5′ of TREM2, rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10−3 and 4.6 × 10−2, respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10−2 and 3.5 × 10−3, Bonferroni-corrected P = 6.7 × 10−2 and 7.1 × 10−3, respectively). Discussion: Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome-wide association study meta-analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD

Sustained Na⁺/H⁺ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation

Hypoxia ischemia (HI)-related brain injury is the major cause of long-term morbidity in neonates. One characteristic hallmark of neonatal HI is the development of reactive astrogliosis in the hippocampus. However, the impact of reactive astrogliosis in hippocampal damage after neonatal HI is not fully understood. In the current study, we investigated the role of Na +/H+ exchanger isoform 1 (NHE1) protein in mouse reactive hippocampal astrocyte function in an in vitro ischemia model (oxygen/glucose deprivation and reoxygenation, OGD/REOX). 2 h OGD significantly increased NHE1 protein expression and NHE1-mediated H+ efflux in hippocampal astrocytes. NHE1 activity remained stimulated during 1-5 h REOX and returned to the basal level at 24 h REOX. NHE1 activation in hippocampal astrocytes resulted in intracellular Na+ and Ca2+ overload. The latter was mediated by reversal of Na+/Ca2+ exchange. Hippocampal astrocytes also exhibited a robust release of gliotransmitters (glutamate and pro-inflammatory cytokines IL-6 and TNFα) during 1-24 h REOX. Interestingly, inhibition of NHE1 activity with its potent inhibitor HOE 642 not only reduced Na+ overload but also gliotransmitter release from hippocampal astrocytes. The noncompetitive excitatory amino acid transporter inhibitor TBOA showed a similar effect on blocking the glutamate release. Taken together, we concluded that NHE1 plays an essential role in maintaining H + homeostasis in hippocampal astrocytes. Over-stimulation of NHE1 activity following in vitro ischemia disrupts Na+ and Ca2+ homeostasis, which reduces Na+-dependent glutamate uptake and promotes release of glutamate and cytokines from reactive astrocytes. Therefore, blocking sustained NHE1 activation in reactive astrocytes may provide neuroprotection following HI. © 2014 Cengiz et al

A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression

INTRODUCTION: We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression. METHODS: Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis. RESULTS: A variant within a DNase hypersensitive site 5' of TREM2, rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10-3 and 4.6 × 10-2, respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10-2 and 3.5 × 10-3, Bonferroni-corrected P = 6.7 × 10-2 and 7.1 × 10-3, respectively). DISCUSSION: Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome-wide association study meta-analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD