Benefit of Intravenous Thrombolysis in Acute Ischemic Stroke Patients With High Cerebral Microbleed Burden

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) are a risk factor for intracranial hemorrhage. Whether intravenous thrombolysis (IVT) improves functional outcome in acute ischemic stroke patients with CMBs is unknown. We aimed to estimate the treatment effect of IVT in patients with acute ischemic stroke and a high burden (>10) of CMBs. METHODS: We devised a multistep algorithm to model 90-day modified Rankin Scale scores in patients with ≤10 versus >10 CMBs who do or do not receive IVT. Parameters were extracted from recently published meta-analyses and included pairwise relationships between CMBs, IVT, 3-month functional outcome, and intracranial hemorrhage. Uncertainty was quantified in probabilistic sensitivity analyses. RESULTS: In patients with >10 CMBs as compared with ≤10 CMBs, point estimates of the odds ratios for favorable outcome (modified Rankin Scale ≤2) associated with IVT were 7% to 10% lower but still >1 (range, 1.03–1.51). On the other hand, IVT in patients with >10 CMBs significantly increased the odds of mortality. The point estimates for the net treatment effect of IVT (change in the utility-weighted modified Rankin Scale score) in patients with >10 CMBs were in favor of withholding IVT in older patients with more severe strokes and longer treatment delays. However, because the general pretest probability of >10 CMBs is low (0.6%–2.7%), pretreatment magnetic resonance imaging to quantify CMB burden would be justified only if it delayed IVT by <10 minutes. CONCLUSIONS: High CMB burden modifies the treatment effect of IVT. In patients with >10 CMBs, IVT is associated with higher mortality and, in older patients with severe strokes and longer treatment delays, a net utility loss. Patients with higher-than-average pretest probability of >10 CMB might profit from magnetic resonance imaging screening if it does not increase the treatment time

Using reciprocity for relating the simulation of transcranial current stimulation to the EEG forward problem

To explore the relationship between transcranial current stimulation (tCS) and the electroencephalography (EEG) forward problem, we investigate and compare accuracy and efficiency of a reciprocal and a direct EEG forward approach for dipolar primary current sources both based on the finite element method (FEM), namely the adjoint approach (AA) and the partial integration approach in conjunction with a transfer matrix concept (PI). By analyzing numerical results, comparing to analytically derived EEG forward potentials and estimating computational complexity in spherical shell models, AA turns out to be essentially identical to PI. It is then proven that AA and PI are also algebraically identical even for general head models. This relation offers a direct link between the EEG forward problem and tCS. We then demonstrate how the quasi-analytical EEG forward solutions in sphere models can be used to validate the numerical accuracies of FEM-based tCS simulation approaches. These approaches differ with respect to the ease with which they can be employed for realistic head modeling based on MRI-derived segmentations. We show that while the accuracy of the most easy to realize approach based on regular hexahedral elements is already quite high, it can be significantly improved if a geometry-adaptation of the elements is employed in conjunction with an isoparametric FEM approach. While the latter approach does not involve any additional difficulties for the user, it reaches the high accuracies of surface-segmentation based tetrahedral FEM, which is considerably more difficult to implement and topologically less flexible in practice. Finally, in a highly realistic head volume conductor model and when compared to the regular alternative, the geometry-adapted hexahedral FEM is shown to result in significant changes in tCS current flow orientation and magnitude up to 45° and a factor of 1.66, respectively

European Stroke Organisation (ESO) guideline on screening for subclinical atrial fibrillation after stroke or transient ischaemic attack of undetermined origin

We aimed to provide practical recommendations for the screening of subclinical atrial fibrillation (AF) in patients with ischaemic stroke or transient ischaemic attack (TIA) of undetermined origin. These guidelines are based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Five relevant Population, Intervention, Comparator, Outcome questions were defined by a multidisciplinary module working group (MWG). Longer duration of cardiac rhythm monitoring increases the detection of subclinical AF, but the optimal monitoring length is yet to be defined. We advise longer monitoring to increase the rate of anticoagulation, but whether longer monitoring improves clinical outcomes needs to be addressed. AF detection does not differ from in- or out-patient ECG-monitoring with similar monitoring duration, so we consider it reasonable to initiate in-hospital monitoring as soon as possible and continue with outpatient monitoring for more than 48 h. Although insertable loop recorders (ILR) increase AF detection based on their longer monitoring duration, comparison with non-implantable ECG devices for similar monitoring time is lacking. We suggest the use of implantable devices, if feasible, for AF detection instead of non-implantable devices to increase the detection of subclinical AF. There is weak evidence of a useful role for blood, ECG and brain imaging biomarkers for the identification of patients at high risk of AF. In patients with patent foramen ovale, we found insufficient evidence from RCT, but prolonged cardiac monitoring in patients >55 years is advisable for subclinical AF detection. To conclude, in adult patients with ischaemic stroke or TIA of undetermined origin, we recommend longer duration of cardiac rhythm monitoring of more than 48 h and if feasible with IRL to increase the detection of subclinical AF

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

Human resources for health and burden of disease: an econometric approach

<p>Abstract</p> <p>Background</p> <p>The effect of health workers on health has been proven to be important for various health outcomes (e.g. mortality, coverage of immunisation or skilled birth attendants). The study aim of this paper is to assess the relationship between health workers and disability-adjusted life years (DALYs), which represents a much broader concept of health outcome, including not only mortality but also morbidity.</p> <p>Methods</p> <p>Cross-country multiple regression analyses were undertaken, with DALYs and DALYs disaggregated according to the three different groups of diseases as the dependent variable. Aggregate health workers and disaggregate physicians, nurses, and midwives were included as independent variables, as well as a variable accounting for the skill mix of professionals. The analysis also considers controlling for the effects of income, income distribution, percentage of rural population with access to improved water source, and health expenditure.</p> <p>Results</p> <p>This study presents evidence of a statistically negative relationship between the density of health workers (especially physicians) and the DALYs. An increase of one unit in the density of health workers per 1000 will decrease, on average, the total burden of disease between 1% and 3%. However, in line with previous findings in the literature, the density of nurses and midwives could not be said to be statistically associated to DALYs.</p> <p>Conclusions</p> <p>If countries increase their health worker density, they will be able to reduce significantly their burden of disease, especially the burden associated to communicable diseases. This study represents supporting evidence of the importance of health workers for health.</p

Bilateral effects of unilateral cerebellar lesions as detected by voxel based morphometry and diffusion imaging

Over the last decades, the importance of cerebellar processing for cortical functions has been acknowledged and consensus was reached on the strict functional and structural cortico-cerebellar interrelations. From an anatomical point of view strictly contralateral interconnections link the cerebellum to the cerebral cortex mainly through the middle and superior cerebellar peduncle. Diffusion MRI (dMRI) based tractography has already been applied to address cortico-cerebellar-cortical loops in healthy subjects and to detect diffusivity alteration patterns in patients with neurodegenerative pathologies of the cerebellum. In the present study we used dMRI-based tractography to determine the degree and pattern of pathological changes of cerebellar white matter microstructure in patients with focal cerebellar lesions. Diffusion imaging and high-resolution volumes were obtained in patients with left cerebellar lesions and in normal controls. Middle cerebellar peduncles and superior cerebellar peduncles were reconstructed by multi fiber diffusion tractography. From each tract, measures of microscopic damage were assessed, and despite the presence of unilateral lesions, bilateral diffusivity differences in white matter tracts were found comparing patients with normal controls. Consistently, bilateral alterations were also evidenced in specific brain regions linked to the cerebellum and involved in higher-level functions. This could be in line with the evidence that in the presence of unilateral cerebellar lesions, different cognitive functions can be affected and they are not strictly linked to the side of the cerebellar lesion

Reproducibility of histopathological findings in experimental pathology of the mouse: a sorry tail

Reproducibility of $\textit{in vivo}$ research using the mouse as a model organism depends on many factors, including experimental design, strain or stock, experimental protocols, and methods of data evaluation. Gross and histopathology are often the endpoints of such research and there is increasing concern about the accuracy and reproducibility of diagnoses in the literature. To reproduce histopathological results, the pathology protocol, including necropsy methods and slide preparation, should be followed by interpretation of the slides by a pathologist familiar with reading mouse slides and familiar with the consensus medical nomenclature used in mouse pathology. Likewise, it is important that pathologists are consulted as reviewers of manuscripts where histopathology is a key part of the investigation. The absence of pathology expertise in planning, executing and reviewing $\textit{in vivo}$ research using mice leads to questionable pathology-based findings and conclusions from studies, even in high-impact journals. We discuss the various aspects of this problem, give some examples from the literature and suggest solutions.This work was supported in part by US National Institutes of Health grants R01 AR049288, CA089713 and R21 AR063781 (to J.P.S.) and by The Warden and Fellows of Robinson College, Cambridge (to P.N.S.)