Microvascular cerebral blood volume changes in aging APPswe/PS1dE9 AD mouse model: a voxel-wise approach

Vascular disorders can either be cause or consequence in the pathophysiology of Alzheimer’s disease (AD). To comprehensively characterize the occurrence of vascular impairment in a double transgenic mouse model for AD (APP_swe/PS1_dE9) during aging, we developed a new method to obtain microvascular relative cerebral blood volume (rCBV_micro) maps from gradient echo MR imaging by histogram evaluation and we applied a voxel-wise approach to detect rCBV_micro changes. With this methodology the development of cerebral microvascular impairments can be described in vivo with 0.16 mm isotropic resolution for the whole mouse brain. At 8 months, impaired rCBV_micro appeared in some cortical regions and in the thalamus, which spreads over several sub-cortical areas and the hippocampus at 13 months. With a ROI-based approach, we further showed that hippocampal rCBV_micro in 13-month-old wild-type and APP_swe/PS1_dE9 mice correlates well with capillary density measured with immunohistochemical staining. However, no differences in capillary density were detected between genotypes. The rCBV_micro values showed no significant correlation with amyloid-β (Aβ) plaque deposition, Aβ at blood vessel walls and biochemically measured levels of Aβ_1-40, Aβ_1-42 oligomers and fibrillar forms. These results suggest that rCBV_micro reduction is caused by an impaired vasoactivity of capillaries and arterioles, which is not directly correlated with the amount of Aβ deposition in parenchyma nor blood vessel walls.     

A lowered salt intake does not compromise iodine status in Cape Town,South Africa,where salt iodization is mandatory

ObjectiveUniversal salt iodization is an effective strategy to optimize population-level iodine. At the same time as salt-lowering initiatives are encouraged globally, there is concern about compromised iodine intakes. This study investigated whether salt intakes at recommended levels resulted in a suboptimal iodine status in a country where salt is the vehicle for iodine fortification.MethodsThree 24-h urine samples were collected for the assessment of urinary sodium and one sample was taken for urinary iodine concentrations (UICs) in a convenience sample of 262 adult men and women in Cape Town, South Africa. Median UIC was compared across categories of sodium excretion equivalent to salt intakes lower than 5, 5 to 9, and greater than or equal to 9 g/d.ResultsThe median UIC was 120 μg/L (interquartile range 75.3–196.3), indicating iodine sufficiency. Less one-fourth (23.2%) of subjects had urinary sodium excretion values within the desirable range (salt <5 g/d), 50.7% had high values (5–9 g/d), and 22.8% had very high values (≥9 g/d). No association between urinary iodine and mean 3 × 24-h urinary sodium concentration was found (r = 0.087, P = 0.198) and UIC status did not differ according to urinary sodium categories (P = 0.804).ConclusionIn a country with mandatory universal salt iodization, consumers with salt intakes within the recommended range (<5 g/d) are iodine replete, and median UIC does not differ across categories of salt intake. This indicates that much of the dietary salt is provided from non-iodinated sources, presumably added to processed foods.     

Performance of a clinical decision support system and of clinical pharmacists in preventing drug–drug interactions on a geriatric ward

Background Drug–drug interactions (DDIs) can lead to adverse drug events and compromise patient safety. Two common approaches to reduce these interactions in hospital practice are the use of clinical decision support systems and interventions by clinical pharmacists. Objective To compare the performance of both approaches with the main objective of learning from one approach to improve the other. Setting Acute geriatric ward in a university hospital. Methods Prospective single-centre, cohort study of patients admitted to the geriatric ward. An independent pharmacist compared the clinical decision support alerts with the DDIs identified by clinical pharmacists and evaluated their interventions. Contextual factors used by the clinical pharmacists for evaluation of the clinical relevance were analysed. Adverse drug events related to DDIs were investigated and the causality was evaluated by a clinical pharmacologist based on validated criteria. Main outcome measure Number of alerts, interventions and the acceptance rates. Results Fifty patients followed by the clinical pharmacists, were included. The clinical pharmacists identified 240 DDIs (median of 3.5 per patient) and advised a therapy change for 16 of which 13 (81.2 %) were accepted and three (18.8 %) were not. The decision support system generated only six alerts of which none were accepted by the physicians. Thirty-seven adverse drug events were identified for 29 patients that could be related to 55 DDIs. For two interactions the causality was evaluated as certain, for 31 as likely, for ten as possible and for 12 as unlikely. Mainly intermediate level interactions were related to adverse drug events. Contextual factors taken into account by the clinical pharmacists for evaluation of the interactions were blood pressure, international normalised ratio, heart rate, potassium level and glycemia. Additionally, the clinical pharmacists looked at individual administration intervals and drug sequence to determine the clinical relevance of the interactions. Conclusion Clinical pharmacists performed better than the decision support system mainly because the system screened only for high level DDIs and because of the low specificity of the alerts. This specificity can be increased by including contextual factors into the logic and by defining appropriate screening intervals that take into account the sequence in which the drugs are given.     

Imaging mass spectrometry of intraspecies metabolic exchange revealed the cannibalistic factors of Bacillus subtilis

During bacterial cannibalism, a differentiated subpopulation harvests nutrients from their genetically identical siblings to allow continued growth in nutrient-limited conditions. Hypothesis-driven imaging mass spectrometry (IMS) was used to identify metabolites active in a Bacillus subtilis cannibalism system in which sporulating cells lyse nonsporulating siblings. Two candidate molecules with sequences matching the products of skfA and sdpC, genes for the proposed cannibalistic factors sporulation killing factor (SKF) and sporulation delaying protein (SDP), respectively, were identified and the structures of the final products elucidated. SKF is a cyclic 26-amino acid (aa) peptide that is posttranslationally modified with one disulfide and one cysteine thioether bridged to the α-position of a methionine, a posttranslational modification not previously described in biology. SDP is a 42-residue peptide with one disulfide bridge. In spot test assays on solid medium, overproduced SKF and SDP enact a cannibalistic killing effect with SDP having higher potency. However, only purified SDP affected B. subtilis cells in liquid media in fluorescence microscopy and growth assays. Specifically, SDP treatment delayed growth in a concentration-dependent manner, caused increases in cell permeability, and ultimately caused cell lysis accompanied by the production of membrane tubules and spheres. Similarly, SDP but not SKF was able to inhibit the growth of the pathogens Staphylococcus aureus and Staphylococcus epidermidis with comparable IC₅₀ to vancomycin. This investigation, with the identification of SKF and SDP structures, highlights the strength of IMS in investigations of metabolic exchange of microbial colonies and also demonstrates IMS as a promising approach to discover novel biologically active molecules.     

Protein tyrosine phosphatases in glioma biology

Gliomas are a diverse group of brain tumors of glial origin. Most are characterized by diffuse infiltrative growth in the surrounding brain. In combination with their refractive nature to chemotherapy this makes it almost impossible to cure patients using combinations of conventional therapeutic strategies. The drastically increased knowledge about the molecular underpinnings of gliomas during the last decade has elicited high expectations for a more rational and effective therapy for these tumors. Most studies on the molecular pathways involved in glioma biology thus far had a strong focus on growth factor receptor protein tyrosine kinase (PTK) and phosphatidylinositol phosphatase signaling pathways. Except for the tumor suppressor PTEN, much less attention has been paid to the PTK counterparts, the protein tyrosine phosphatase (PTP) superfamily, in gliomas. PTPs are instrumental in the reversible phosphorylation of tyrosine residues and have emerged as important regulators of signaling pathways that are linked to various developmental and disease-related processes. Here, we provide an overview of the current knowledge on PTP involvement in gliomagenesis. So far, the data point to the potential implication of receptor-type (RPTPδ, DEP1, RPTPμ, RPTPζ) and intracellular (PTP1B, TCPTP, SHP2, PTPN13) classical PTPs, dual-specific PTPs (MKP-1, VHP, PRL-3, KAP, PTEN) and the CDC25B and CDC25C PTPs in glioma biology. Like PTKs, these PTPs may represent promising targets for the development of novel diagnostic and therapeutic strategies in the treatment of high-grade gliomas.