Search

Background Alzheimer’s disease (AD) is the most common form of age-related neurodegenerative diseases. Cerebral deposition of Aβ peptides, especially Aβ42, is considered the major neuropathological hallmark of AD and the putative cause of AD-related neurotoxicity. Aβ peptides are produced by sequential proteolytic processing of APP, with β-secretase (BACE) being the initiating enzyme. Therefore, BACE has been considered an attractive therapeutic target in AD research and several BACE inhibitors have been tested in clinical trials, but so far, all have had negative outcomes or even led to worsening of cognitive function. AD can be triggered by Aβ years before the first symptoms appear and one reason for the failures could be that the clinical trials were initiated too late in the disease process. Another possible explanation could be that BACE inhibition alters physiological APP processing in a manner that impairs synaptic function, causing cognitive deterioration. Methods The aim of this study was to investigate if partial BACE inhibition, mimicking the putative protective effect of the Icelandic mutation in the APP gene, could reduce Aβ generation without affecting synaptic transmission. To investigate this, we used an optical electrophysiology platform, in which effects of compounds on synaptic transmission in cultured neurons can be monitored. We employed this method on primary cortical rat neuronal cultures treated with three different BACE inhibitors (BACE inhibitor IV, LY2886721, and lanabecestat) and monitored Aβ secretion into the cell media. Results We found that all three BACE inhibitors tested decreased synaptic transmission at concentrations leading to significantly reduced Aβ secretion. However, low-dose BACE inhibition, resulting in less than a 50% decrease in Aβ secretion, did not affect synaptic transmission for any of the inhibitors tested. Conclusion Our results indicate that Aβ production can be reduced by up to 50%, a level of reduction of relevance to the protective effect of the Icelandic mutation, without causing synaptic dysfunction. We therefore suggest that future clinical trials aimed at prevention of Aβ build-up in the brain should aim for a moderate CNS exposure of BACE inhibitors to avoid side effects on synaptic function.

Background: Patients with preoperative dual antiplatelet therapy prior to coronary artery bypass surgery are at risk of bleeding and blood component transfusion. We hypothesise that an optimised cardiopulmonary bypass strategy reduces postoperative blood loss and transfusions. Methods: In total, 60 patients admitted for coronary artery bypass grafting with ticagrelor and aspirin medication withdrawn ® heparin-coated circuit with low systemic heparinisation (activated clotting time ® coated open circuit, full systemic heparinisation (activated clotting time > 480 seconds) and conventional cardiotomy suction. This perfusion strategy was evaluated by the chest drain volume after 24 hours, perioperative haemoglobin and platelet loss accompanied by global coagulation assessments. Results: Patients in the study group demonstrated significantly better outcomes signified by lower blood loss 554 ± 224 versus 1,100 ± 989 mL (p 9/L (p = 0.001). Indices of rotational thromboelastometry indicated shorter clotting times within the internal and external pathways. Adenosine diphosphate activated platelet function was within normal range based on Multiplate® aggregometry, while ROTEM® platelet analyses indicated inhibited function both preoperatively and post-bypass. Platelet inhibition by aspirin was verified throughout the perioperative period. Platelet function showed no intergroup differences. Conclusion: A stringent perfusion strategy reduced blood loss and transfusions in dual antiplatelet therapy patients requiring urgent surgery.

A reduction in the global burden of malaria over the past two decades has encouraged efforts for regional malaria elimination. Despite the need to target all Plasmodium species, current focus is mainly directed towards Plasmodium falciparum, and to a lesser extent P. vivax. There is a substantial lack of data on both global and local transmission patterns of the neglected malaria parasites P. malariae and P. ovale spp. We used a species-specific real-time PCR assay targeting the Plasmodium 18s rRNA gene to evaluate temporal trends in the prevalence of all human malaria parasites over a 22-year period in a rural village in Tanzania.We tested 2897 blood samples collected in five cross-sectional surveys conducted between 1994 and 2016. Infections with P. falciparum, P. malariae, and P. ovale spp. were detected throughout the study period, while P. vivax was not detected. Between 1994 and 2010, we found a more than 90% reduction in the odds of infection with all detected species. The odds of P. falciparum infection was further reduced in 2016, while the odds of P. malariae and P. ovale spp. infection increased 2- and 6-fold, respectively, compared to 2010. In 2016, non-falciparum species occurred more often as mono-infections. The results demonstrate the persistent transmission of P. ovale spp., and to a lesser extent P. malariae despite a continued decline in P. falciparum transmission. This illustrates that the transmission patterns of the non-falciparum species do not necessarily follow those of P. falciparum, stressing the need for attention towards non-falciparum malaria in Africa. Malaria elimination will require a better understanding of the epidemiology of P. malariae and P. ovale spp. and improved tools for monitoring the transmission of all Plasmodium species, with a particular focus towards identifying asymptomatic carriers of infection and designing appropriate interventions to enhance malaria control., Author summary The reduction in the global burden of malaria has encouraged efforts for elimination. Attempts to control and monitor transmission have mainly focused on the predominant malaria parasites Plasmodium falciparum and P. vivax. However, eliminating malaria requires the elimination of all human malaria parasites and limited interest has been directed towards estimating the disease burden attributable to the neglected malaria parasites P. ovale spp. and P. malariae. The authors used molecular methods to analyse 2897 blood samples collected in five cross-sectional surveys over a period of 22 years, and described the transmission patterns of all human malaria parasites in a Tanzanian village. They demonstrate a persistent transmission of P. malariae and P. ovale spp. despite a substantial reduction in transmission of P. falciparum, highlighting the need for more attention towards non-falciparum malaria. The authors discuss the implications of these findings in the context of current efforts for regional malaria elimination.

Quantification tools for SPECT/CT are a field of ongoing research among hybrid imaging techniques. A recent multicenter study evaluating SUV SPECT software on phantoms showed that quantitative SPECT/CT is reproducible in Hybrid Viewer software. The aim of our study was to evaluate the intra- and interobserver agreement of quantitative SUV SPECT measurements in clinical settings for patients with solid renal tumors. Methods: The evaluation was part of a study that examined the role of 99mTc-sestamibi SPECT/CT in the characterization of solid kidney tumors and the differentiation of renal oncocytomas from renal cell carcinomas. Quantitative evaluation of SUV measurements was performed in Hybrid Viewer PDR, version 2.5. Forty-eight renal lesions were identified and examined twice by 2 independent readers. The agreement of the SUV measurements, concerning renal tumors and adjacent renal parenchyma, was evaluated using the intraclass correlation coefficient (ICC). Results: ICC for SUVmax measurements by the same reader was 97%-99% for solid renal tumors and 92%-98% for ipsilateral healthy renal parenchyma. ICC for SUVmax measurements between readers was 87%-89% for solid renal tumors and 72%-73% for ipsilateral healthy renal parenchyma. Estimated ICC for SUVmean measurements of solid renal tumors was 95%-98% for the same reader and 86%-89% between readers. Similar results were found for SUVpeak measurements. Conclusion: The high ICCs indicate a strong agreement among SUV measurements for patients with solid renal lesions undergoing 99mTc-sestamibi SPECT/CT, not only for measurements by the same reader but also for measurements between 2 different readers.

Many countries using sensitive screening methods for detection of carriage of methicillin-resistant Staphylococcus aureus (MRSA) have a sustained low incidence of MRSA infections. For diagnostic laboratories with high sample volumes, MRSA screening requires stability, low maintenance and high performance at a low cost. Herein we designed oligonucleotides for a new nuc targeted hydrolysis probe PCR to replace the standard in-house nuc SybrGreen PCR assay. This new, more time-efficient, PCR assay resulted in a 40% increase in daily sample capacity, with maintained high specificity and sensitivity. The assay was also able to detect Staphylococcus aureus clonal cluster 75 (CC75) lineage strains, recently re-classified as Staphylococcus argenteus, with a sensitivity considerably increased compared to our previous assay. While awaiting consensus if the CC75 lineage of S. aureus should be considered as S. argenteus, and whether methicillin-resistant S. argenteus should be included in the MRSA definition, many diagnostic laboratories need to update their MRSA assay sensitivity/specificity towards this lineage/species. The MRSA screening assay presented in this manuscript is comprised of nuc oligonucleotides separately targeting S. aureus and CC75 lineage strains/S. argenteus, thus providing high user flexibility for the detection of CC75 lineage strains/S. argenteus.

Background: The majority (70%) of cardiac arrests in Sweden are experienced in the patient’s home. In these situations, the ambulance nurses may encounter several ethical dilemmas. Aim: The aim was to investigate Swedish specialist ambulance nurses’ experiences of ethical dilemmas associated with cardiac arrest situations in adult patients’ homes. Methods: Nine interviews were conducted with specialist ambulance nurses at four different ambulance stations in the southeast region of Sweden. Data were analysed using content analysis. Ethical considerations: Ethical principles mandated by the Swedish Research Council were carefully followed during the whole process. Findings: Two main themes with six sub-themes were identified: The scene – creating a sheltered space for caring and Ethical decision-making. The results showed that ethical dilemmas might occur when trying to create a sheltered space to preserve the patients’ integrity and dignity. A dilemma could be whether or not to invite significant others to be present during the medical treatment. Ethical decision-making was dependent on good communication and ethical reasoning among all parties. In certain situations, decisions were made not to commence or to terminate care despite guidelines. The decision was guided by combining the medical/nursing perspectives and ethical competence with respect to the human being’s dignity and a will to do good for the patient. The nurses followed the voice of their heart and had the courage to be truly human. Conclusion: The ambulance nurses were guided by their ethos, including the basic motive to care for the patient, to alleviate suffering, to confirm the patient’s dignity and to serve life and health.

Background Despite the progress in the quality of multiphasic CT and MRI scans, it is still difficult to fully characterize a solid kidney lesion. Approximately 10% of all solid renal tumours turn out to be oncocytomas. In actual clinical practice, this is verified only following unnecessary surgery or a renal biopsy/ablation. The objective of our pilot study examines whether 99mTc-sestamibi SPECT/CT can play a crucial role in the characterization of solid renal neoplasms and the differentiation of oncocytomas from renal cell carcinomas. The study included 27 patients identified with 31 solid renal lesions. All patients were discussed in a multidisciplinary conference, and a decision for surgery or biopsy was taken. Prior to invasive procedures, patients underwent a SPECT/CT with 99mTc-sestamibi. Visual evaluation was performed, and any focal 99mTc-sestamibi uptake detected on SPECT in the localisation of tumour was considered as positive. Results Eleven out of 12 oncocytomas (91.6%) displayed positive uptake of 99mTc-sestamibi. Three hybrid tumours (mixed-type oncocytoma and chromophobe renal cancer) were positive on SPECT/CT. One papillary renal cell carcinoma had a slight uptake of 99mTc-sestamibi. The remaining 11 renal cell carcinomas were sestamibi negative. Conclusions Differentiation of benign renal oncocytomas from renal cell carcinomas seems very promising on 99mTc-sestamibi SPECT/CT examination. Additional supplement to visual evaluation, i.e. quantitative tools, should be sought for an accurate estimate of biological behaviour and hence a secure diagnosis.

In parallel to the increased utilization of cross-sectional imaging, the incidence of small renal masses has steadily risen in recent years. At the present time, anatomical imaging techniques are limited in their ability to differentiate benign from malignant renal masses. Moreover, renal mass biopsy has a high non-diagnostic rate, poor negative-predictive ability, and carries potential risks as well as substantial costs. As a result, benign renal masses are often unnecessarily resected for the false presumption of cancer. (99m)Tc-sestamibi single photon emission computed tomography/computed tomography (SPECT/CT) is a molecular imaging test that allows for the differentiation of benign renal oncocytomas and hybrid oncocytomic/chromophobe tumours apart from malignant renal cell carcinomas on the basis of differences in mitochondrial content as well as multidrug resistant pump expression. Herein, we review the principles of (99m)Tc-sestamibi SPECT/CT administration and image interpretation for the purpose of renal mass characterization.

We present an experimental system that allows visualization of conformational changes in membrane proteins at the single-molecule level. The target membrane protein is reconstituted in a giant liposome for independent control of the aqueous environments on the two sides of the membrane. For direct observation of conformational changes, an extra-liposomal site(s) of the target protein is bound to a glass surface, and a probe that is easily visible under a microscope, such as a micron-sized plastic bead, is attached to another site on the intra-liposomal side. A conformational change, or an angular motion in the tiny protein molecule, would manifest as a visible motion of the probe. The attachment of the protein on the glass surface also immobilizes the liposome, greatly facilitating its manipulation such as the probe injection. As a model system, we reconstituted ATP synthase (FOF1) in liposomes tens of mu m in size, attached the protein specifically to a glass surface, and demonstrated its ATP-driven rotation in the membrane through the motion of a submicron bead. (c) 2009 Elsevier B.V. All rights reserved.