Axonal degeneration and inflammation in acute optic neuritis

Aims: To investigate whether plasma biomarkers for axonal injury and inflammation are related to loss and recovery of visual function in acute optic neuritis (ON).Methods: Eighteen patients with ON and 14 controls were investigated in a longitudinal, prospective study. Plasma phosphorylated neurofilament heavy chain ( NfH(SMI35); a surrogate marker of axonal injury), nitric oxide metabolites (NOx), and citrulline ( surrogate markers of inflammation) were measured.Results: Patients with ON had higher median plasma NfH(SMI35) values than controls (0.17 versus 0.005 ng/ml; p< 0.05) and higher NOx values (49 versus 35.5 mu M; p< 0.001). Plasma NfH(SMI35) values correlated inversely with visual acuity at presentation ( R = -0.67; p = 0.01). NfH(SMI35) was higher in patients with poor recovery of visual acuity than in those with good recovery (0.25 ng/ml versus 0.09 ng/ml; p< 0.05). Three of four patients with high NfH(SMI35) and high NOx values experienced a poor recovery as opposed to only one of five with high NOx but normal NfH(SMI35) values.Conclusions: NfH(SMI35), a surrogate marker for axonal damage, is a prognostic indicator and should be considered in the design of neuroprotective treatment strategies

Treatment response in relation to inflammatory and axonal surrogate marker in multiple sclerosis

BACKGROUND: This study aimed to investigate if treatment response could retrospectively be related to inflammatory or axonal pathology as measured by plasma surrogate markers. METHODS: In this 1-year observational study 30 multiple sclerosis (MS) patients with relapsing-remitting disease were treated with intramuscular IFNbeta-1a or subcutaneous IFNbeta-1b. Responders and nonresponders were defined according to clinical and magnetic resonance imaging criteria. The control group consisted of 14 healthy subjects. Plasma levels of surrogate markers for inflammation (nitric oxide metabolites (NOx)), astrocytic activation (S100B) and axonal damage (NfH(SM135)) were measured using standard assays. RESULTS: There were 11 nonresponders and 19 responders to IFNbeta treatment. Median S100B levels were elevated in a higher proportion of treatment responders (63%, 42.9 pg/mL) compared to nonresponders (18%, 11.7 pg/mL, P < 0.05, Fisher's exact test) and controls (0%, 2 pg/mL, P < 0.001). Levels of NOx were found to be more frequently elevated in nonresponders (72%, 39 microM) compared to healthy controls (0%, 37 microM, P < 0.05). Levels of NfH(SM135) were more frequently elevated in responders (58%, 300 pg/mL, P < 0.001) and nonresponders (72%, 500 pg/mL, P < 0.001) compared to controls (0%, 4.5 pg/mL). CONCLUSION: Patients with relapsing-remitting MS who had surrogate marker supported evidence for astrocytic activation responded more frequently to treatment with IFNbeta

zfishbook: connecting you to a world of zebrafish revertible mutants

zfishbook is an internet-based openly accessible database of revertible protein trap gene-breaking transposon (GBT) insertional mutants in the zebrafish, Danio rerio. In these lines, a monomeric red fluorescent protein (mRFP) is encoded by an artificial 3′ exon, resulting in a translational fusion to endogenous loci. The natural transparency of the zebrafish embryo and larvae greatly facilitates the expression annotation of tagged loci using new capillary-based SCORE imaging methods. Molecular annotation of each line is facilitated by cloning methods such as 5′-Rapid Amplification of cDNA Ends (RACE) and inverse polymerase chain reaction (PCR). zfishbook (http://zfishbook.org) represents a central hub for molecular, expression and mutational information about GBT lines from the International Zebrafish Protein Trap Consortium (IZPTC) that includes researchers from around the globe. zfishbook is open to community-wide contributions including expression and functional annotation. zfishbook also represents a central location for information on how to obtain these lines from diverse members of the IZPTC and integration within other zebrafish community databases including Zebrafish Information Network (ZFIN), Ensembl and National Center for Biotechnology Information

Factors associated with mortality in HIV-infected people in rural and urban South Africa

PKBackground: Factors associated with mortality in HIV-infected people in sub-Saharan Africa are widely reported. However rural urban disparities and their association with all-cause mortality remain unclear. Furthermore, commonly used classical Cox regression ignores unmeasured variables and frailty. Objective: To incorporate frailty in assessing factors associated with mortality in HIV-infected people in rural and urban South Africa. Design: Using data from a prospective cohort following 6,690 HIV-infected participants from Soweto (urban) and Mpumalanga (rural) enrolled from 2003 to 2010; covariates of mortality were assessed by the integrated nested Laplace approximation method. Results: We enrolled 2,221 (33%) rural and 4,469 (67%) urban participants of whom 1,555 (70%) and 3,480 (78%) were females respectively. Median age (IQR) was 36.4 (31.0 44.1) in rural and 32.7 (28.2 38.1) in the urban participants. The mortality rate per 100 person-years was 11 (9.7 12.5) and 4 (3.6 4.5) in the rural and urban participants, respectively. Compared to those not on HAART, rural participants had a reduced risk of mortality if on HAART for 6 12 (HR: 0.20, 95% CI: 0.10 0.39) and 12 months (HR: 0.10, 95% CI: 0.05 0.18). Relative to those not on HAART, urban participants had a lower risk if on HAART 12 months (HR: 0.35, 95% CI: 0.27 0.46). The frailty variance was significant and 1 in rural participants indicating more heterogeneity. Similarly it was significant but B1 in the urban participants indicating less heterogeneity. Conclusion: The frailty model findings suggest an elevated risk of mortality in rural participants relative to the urban participants potentially due to unmeasured variables that could be biological, socio economic, or healthcare related. Use of robust methods that optimise data and account for unmeasured variables could be helpful in assessing the effect of unknown risk factors thus improving patient management and care in South Africa and elsewhere

The Prognostic Value of Brain Extracellular Fluid Nitric Oxide Metabolites After Traumatic Brain Injury.

BACKGROUND: Nitric oxide (NO) is a compound with both protective and damaging effects on neurons. Quantification of NO metabolites in humans is limited by sample contamination with blood. In vivo cerebral microdialysis may offer an alternative approach as sampling of extracellular fluid (ECF) adjacent to neurons becomes possible. We investigate the prognostic value of brain ECF NO metabolites in patients with traumatic brain injury (TBI). METHODS: A prospective case cohort of 195 ECF samples collected from 11 cases over 4 days following TBI was collected. Nitrate and nitrite concentrations ([NO( x )]) were quantified using a vanadium-based colorimetric assay. RESULTS: Early ECF [NO( x )] (<48 h post TBI) were significantly higher in non-survivors (median 59.2 μmol/l, n = 7) compared to survivors (23.3 μmol/l, n = 4) (P = 0.04). Late (48-96 h) ECF [NO( x )] remained higher in non-survivors (47.9 μmol/l) compared to survivors (23.0 μmol/l) but this was not significant (P = 0.29). Receiver operator characteristic analysis shows an optimized cutoff level for ECF [NO( x )] of 26.5 μmol/l measured <48 h post TBI for predicting non-survival (sensitivity 100%, specificity 75%). CONCLUSION: Early ECF NO( x ) concentrations are of prognostic value after TBI. ECF NO( x ) may be a useful biomarker for treatment trials targeted at nitric oxide metabolism

Hyperextended Scalar-Tensor Gravity

We study a general Scalar-Tensor Theory with an arbitrary coupling funtion $\omega (\phi )$ but also an arbitrary dependence of the ``gravitational constant'' $G(\phi )$ in the cases in which either one of them, or both, do not admit an analytical inverse, as in the hyperextended inflationary scenario. We present the full set of field equations and study their cosmological behavior. We show that different scalar-tensor theories can be grouped in classes with the same solution for the scalar field.Comment: latex file, To appear in Physical Review

Aktuelle Therapiestudien für die Indikation zystischer Nierenerkrankungen

Zusammenfassung: Familiäre zystische Nierenerkrankungen bilden eine heterogene Gruppe von seltenen Erkrankungen. Basierend auf molekularbiologischen Erkenntnissen wurden bereits zugelassene Medikamente kürzlich neu für die Indikationen autosomal-dominante polyzystische Nierenerkrankung (ADPKD) und tuberöse Sklerose geprüft. Da bei der ADPKD die Nierenfunktion über Jahrzehnte stabil ist, wird die Therapieeffizienz mittels Nierengröße als Surrogatmarker der Krankheitslast bestimmt. Tolvaptan, ein Aquaretikum, verminderte in einer 3-jährigen Studie mit 1445ADPKD-Patienten das Größenwachstum der Nieren, den Nierenfunktionsverlust und die Nierenschmerzen. Die langwirksamen Somatostatine Octreotid und Lanreotid verminderten moderat die Leber- und die Nierengröße von Patienten mit ADPKD und polyzystischer Lebererkrankung. Die mTOR-Inhibitoren Sirolimus und Everolimus waren für die Indikation ADPKD nutzlos, während sie mit tuberöser Sklerose assoziierte renale Angiomyolipome schrumpfen ließen. Die Gesundheitsbehörden werden noch 2013 über die Zulassung von Tolvaptan für die Indikation ADPKD und über Everolimus für die Indikation tuberöse Sklerose entscheide

Scalable Bayesian Functional Connectivity Inference for Multi-Electrode Array Recordings

Multi-electrode arrays (MEAs) can record extracellular action potentials (also known as 'spikes') from hundreds or thousands of neurons simultaneously. Inference of a functional network from a spike train is a fundamental and formidable computational task in neuroscience. With the advancement of MEA technology, it has become increasingly crucial to develop statistical tools for analyzing multiple neuronal activity as a network. In this paper, we propose a scalable Bayesian framework for inference of functional networks from MEA data. Our framework makes use of the hierarchical structure of networks of neurons. We split the large scale recordings into smaller local networks for network inference, which not only eases the computational burden from Bayesian sampling but also provides useful insights on regional connections in organoids and brains. We speed up the expensive Bayesian sampling process by using parallel computing. Experiments on both synthetic datasets and large-scale real-world MEA recordings show the effectiveness and efficiency of the scalable Bayesian framework. Inference of networks from controlled experiments exposing neural cultures to cadmium presents distinguishable results and further confirms the utility of our framework.Comment: in BIOKDD 202

Reduced NK-Cell Activity in Patients with Metastatic Colon Cancer

Natural killer cells (NK-cells) are believed to play an essential role in the immune surveillance against tumors and infectious diseases. The role of NK-cells in colon cancer remains obscure, since increased as well as decreased percentages and/or activity of NK-cells in comparison to control patients have been reported. Percentage and cytolytic activity of NKcells in the peripheral blood were analyzed in 42 patients with colon cancer before surgery and one year thereafter in comparison to control patients with non-malignant diseases. Patients without distant metastasis at the time of diagnosis displayed a significantly increased percentage of NK-cells as well as sustained NK-cell activity in the peripheral blood prior to surgery when compared to control patients. In contrast, patients with metastatic disease at the time of diagnosis displayed significantly decreased NK-cell activity in the peripheral blood when compared to control patients. One year after surgery, patients who remained free of metastasis still displayed sustained NK-cell activity, whereas patients who developed metastasis presented with profoundly decreased levels of NK-cell activity. Further analysis of these patients revealed that patients who developed metastasis within the first year after surgery already displayed reduced NK-cell activity prior to curative colorectal surgery. These observations indicate that metastatic spread of colorectal cancer is associated with decreased NK-cell activity. It remains speculative whether decreased NK-cell activity precedes the development of metastasis and thus may help to identify patients with a high risk of rapid tumor progression following curative colorectal surgery