Accumulating evidence supports a major role of B cells in multiple sclerosis (MS) pathogenesis. How B cells are recruited to the CNS is incompletely understood. Our objective was to study B-cell ...chemokine concentrations in MS, their relationship with disease activity, and how treatment with methylprednisolone and natalizumab affected the concentration in CSF.
Using a cross-sectional design, CSF and blood samples were obtained from cohorts of patients with clinically isolated syndromes (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), or secondary progressive MS (SPMS), and noninflammatory neurologic disease control subjects. Some patients with RRMS were studied before and after treatment with methylprednisolone or natalizumab.
In CSF, concentrations of CXCL13, but not CXCL12, were higher in patients with CIS, RRMS, SPMS, and PPMS than in controls. CSF concentrations of CXCL13 correlated with the CSF B-cell count, with markers of immune activation, and with disease activity in patients with CIS and RRMS. CSF concentrations of CXCL13 decreased after treatment with high-dose methylprednisolone and natalizumab. High CSF concentrations of CXCL13 correlated with low expression of messenger RNA encoding the immunoregulatory cytokines interleukin 10 and transforming growth factor beta1, but not with the expression of T-helper type 1 (Th1) and Th17 factors.
The chemokine CXCL13 may play a major role in recruitment of B cells and T-cell subsets expressing the chemokine receptor CXCR5 to the CNS in multiple sclerosis (MS), and may be a useful biomarker for treatment effects in MS. Furthermore, CXCL13 or its receptor CXCR5 should be considered as therapeutic targets in MS.
Expression of
HOX transcript antisense intergenic
RNA (
HOTAIR
)—a long non-coding RNA—has been examined in a variety of human cancers, and overexpression of
HOTAIR
is correlated with poor survival ...among breast, colon, and liver cancer patients. In this retrospective study, we examine
HOTAIR
expression in 164 primary breast tumors, from patients who do not receive adjuvant treatment, in a design that is paired with respect to the traditional prognostic markers. We show that
HOTAIR
expression differs between patients with or without a metastatic endpoint, respectively. Survival analysis shows that high
HOTAIR
expression in primary tumors is significantly associated with worse prognosis independent of prognostic markers (
P
= 0.012, hazard ratio (HR) 1.747). This association is even stronger when looking only at estrogen receptor (ER)-positive tumor samples (
P
= 0.0086, HR 1.985). In ER-negative tumor samples, we are not able to detect a prognostic value of
HOTAIR
expression, probably due to the limited sample size. These results are successfully validated in an independent dataset with similar associations (
P
= 0.018, HR 1.825). In conclusion, our findings suggest that
HOTAIR
expression may serve as an independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients.
There are few detailed data on cognition in patients undergoing dialysis. We evaluated the frequency of and risk factors for poor cognitive performance using detailed neurocognitive testing.
In this ...cross-sectional cohort study, 314 hemodialysis patients from 6 Boston-area hemodialysis units underwent detailed cognitive assessment. The neuropsychological battery assessed a broad range of functions, with established age-, sex-, and education-matched normative scores. Principal component analysis was used to derive composite scores for memory and executive function domains. Risk factors for each domain were evaluated using linear regression adjusting for age, sex, race, and education status. Analyses were repeated in those with Mini-Mental State Examination (MMSE) score ≥ 24.
Compared with population norms, patients on dialysis had significantly poorer executive function but not memory performance, a finding that persisted in the subgroup with MMSE score ≥ 24. In adjusted analyses, vascular risk factors and vascular disease were associated with lower executive function (p < 0.01).
There is a high frequency of poor cognitive performance in hemodialysis patients, primarily affecting executive function. Risk factors for worse executive function include vascular risk factors as well as vascular disease. Normal performance on the MMSE does not preclude impaired cognitive function, because individuals with MMSE score ≥ 24 also have a high frequency of poor cognitive performance.
In this study, the density distributions of large nuclei are typically modeled with a Woods–Saxon distribution characterized by a radius R0 and skin depth a. Deformation parameters β are then ...introduced to describe non-spherical nuclei using an expansion in spherical harmonics R0(1+β2Y20+β4Y40). But when a nucleus is non-spherical, the R0 and a inferred from electron scattering experiments that integrate over all nuclear orientations cannot be used directly as the parameters in the Woods–Saxon distribution. In addition, the β2 values typically derived from the reduced electric quadrupole transition probability B(E2)↑ are not directly related to the β2 values used in the spherical harmonic expansion. B(E2)↑ is more accurately related to the intrinsic quadrupole moment Q0 than to β2. One can however calculate Q0 for a given β2 and then derive B(E2)↑ from Q0. In this paper we calculate and tabulate the R0, a , and β2 values that when used in a Woods–Saxon distribution, will give results consistent with electron scattering data. We then present calculations of the second and third harmonic participant eccentricity (ε2 and ε3) with the new and old parameters. We demonstrate that ε3 is particularly sensitive to a and argue that using the incorrect value of a has important implications for the extraction of viscosity to entropy ratio (η/s) from the QGP created in Heavy Ion collisions.
Suppression of anoikis after detachment of cancer cells from the extracellular matrix is a key step during metastasis. Here we show that, after detachment, mouse embryonic fibroblasts (MEFs) ...transformed by K-Ras(V12) or ETV6-NTRK3 (EN) activate a transcriptional response overrepresented by genes related to bioenergetic stress and the AMP-activated protein kinase (AMPK) energy-sensing pathway. Accordingly, AMPK is activated in both transformed and non-transformed cells after detachment, and AMPK deficiency restores anoikis to transformed MEFs. However, AMPK activation represses the mTOR complex-1 (mTORC1) pathway only in transformed cells, suggesting a key role for AMPK-mediated mTORC1 inhibition in the suppression of anoikis. Consistent with this, AMPK-/- MEFs transformed by EN or K-Ras show sustained mTORC1 activation after detachment and fail to suppress anoikis. Transformed TSC1-/- MEFs, which are incapable of suppressing mTORC1, also undergo anoikis after detachment, which is reversed by mTORC1 inhibitors. Furthermore, transformed AMPK-/- and TSC1-/- MEFs both have higher total protein synthesis rates than wild-type controls, and translation inhibition using cycloheximide partially restores their anoikis resistance, indicating a mechanism whereby mTORC1 inhibition suppresses anoikis. Finally, breast carcinoma cell lines show similar detachment-induced AMPK/mTORC1 activation and restoration of anoikis by AMPK inhibition. Our data implicate AMPK-mediated mTORC1 inhibition and suppression of protein synthesis as a means for bioenergetic conservation during detachment, thus promoting anoikis resistance.
This paper examines the role of grant size in research funding. There is an increasing focus in a number of countries on larger grant forms, such as centers of excellence, and in some cases also ...increases in the size of individual project grants. Among the rationales for this are economies of scale in research and redistribution of resources towards top researchers in order to increases scientific productivity and pathbreaking research. However, there may potentially also be negative impacts of increasing funding size, and there is limited empirical evidence on the actual consequences of increases in size. In this paper we critically examine the rationales behind increases in funding size and the empirical evidence on the impacts of size in research funding. Our goal here is to present a more coherent view of the potential impacts of these initiatives, both positive and negative, that can help inform funding design.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
In Denmark, organ donation‐rates are below the average in the western countries. We investigated the donor potential and identified barriers toward organ donation in a Danish university ...hospital.
Methods
All patients who died in Aalborg University Hospital in 2012 were retrospectively identified. Patients with a CT‐ or MRI‐proven deadly brain‐lesion were eligible for inclusion.
Results
Eighty‐five patients with deadly brain‐lesions were included, and of these 47 patients died in the intensive care unit (ICU). Older age and diagnosis of brain‐hemorrhage and infarction were associated with admission to general ward (GW). In 62.4% of the patients the potential of becoming a donor was not identified. No donations occurred from patients dying from intracerebral hemorrhage or brain‐infarction although they represented 44.7% of the potential donors.
Discussion
This study reveals a huge, unrecognized donation potential at our hospital. About 30% was lost because they were never admitted to the ICU. After primary admission to the ICU, 15.3% of the potential donors were lost because they were transferred to the GW. In patients who died in the ICU 17.6% of the patients were not evaluated as potential donors. The relatives refused donation in 17.6% of cases.
Conclusion
It would be possible to raise the donation rate considerably if patients with donation potential are intubated and admitted to the ICU. When active treatment is considered withdrawn, possibility of organ donation should be evaluated, and the next of kin be approached by experienced staff.
Background and purpose
To assess long‐term treatment effectiveness of disease‐modifying therapy (DMT) initiated early in disease course versus later treatment start.
Methods
We included all Danish ...patients with multiple sclerosis (MS) treated with DMT through two nationwide population‐based MS registries. Patients were categorized as early treated if treatment started within 2 years after the first MS symptom (n = 2316) and later treated if treatment started between 2 and 8 years after clinical onset (n = 1479). We compared time from treatment start to progression to an Expanded Disability Status Scale (EDSS) score of 6 and mortality between cohorts as hazard ratio (HR) using a Cox proportional hazards model with adjustment for stabilized inverse probability of treatment weights. Several sensitivity analyses were conducted.
Results
The median follow‐up time of 3795 patients was 7.0 (range 0.6–19.5) years for the EDSS score of 6 outcome and 10.4 (range 1.2–20.1) years for the mortality outcome. Patients with later treatment start showed a 42% increased hazard rate of reaching an EDSS score of 6 compared with the early‐treated patients HR, 1.42; 95% confidence interval (CI), 1.18–1.70; P < 0.001. When stratified by sex, the increased hazard among later‐treated women persisted (HR, 1.53; 95% CI, 1.22–1.93; P < 0.001), whereas the HR was lower in men (1.25; 95% CI, 0.93–1.69; P = 0.15). Mortality was increased by 38% in later starters (HR, 1.38; 95% CI, 0.96–1.99; P = 0.08).
Conclusions
Patients who started treatment with DMT later reached an EDSS score of 6 more quickly compared with patients who started early and the delay showed a tendency to shorten time to death. Our results support the use of early treatment.
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