Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation

Bone marrow-derived mesenchymal stem cells (MSCs) are known to interact with hematopoietic stem cells (HSCs) and immune cells, and represent potential cellular therapy to enhance allogeneic hematopoietic engraftment and prevent graft-versus-host disease (GVHD). We investigated the role of human MSCs in NOD-SCID mice repopulation by unrelated human hematopoietic cells and studied the immune interactions between human MSCs and unrelated donor blood cells in vitro. When hematopoietic stem cell numbers were limited, human engraftment of NOD-SCID mice was observed only after coinfusion of unrelated human MSCs, but not with coinfusion of mouse mesenchymal cell line. Unrelated human MSCs did not elicit T-cell activation in vitro and suppressed T-cell activation by Tuberculin and unrelated allogeneic lymphocytes in a dose-dependent manner. Cell-free MSC culture supernatant, mouse stromal cells and human dermal fibroblasts did not elicit this effect. These preclinical data suggest that unrelated, human bone marrow-derived, culture-expanded MSCs may improve the outcome of allogeneic transplantation by promoting hematopoietic engraftment and limiting GVHD and their therapeutic potential should be tested in clinic.     

Changing epidemiology of bacterial meningitis among adults in England and Wales 1991-2002

We examined the epidemiology of community-acquired bacterial meningitis among adults in England and Wales between 1991 and 2002. Among 3169 cases, meningococcal infection was predominant among young adults and pneumococcal meningitis among older adults. Whilst infection due to most causes decreased, the incidence of tuberculous (TB) meningitis doubled over the 12 years. The mortality rate among meningococcal and pneumococcal infections fell from 0.45/10(5) to 0.31/10(5) (P=0.0001). This study demonstrates important changes in the epidemiology of bacterial meningitis among UK adults. Improvements in clinical management, childhood vaccination programmes and the re-emergence of tuberculosis are likely to be drivers of these changes.     

The Patterns of Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Use in Patients with Atrial Fibrillation in Seven Balkan Countries: a Report from the BALKAN-AF Survey

Introduction

Data on management of atrial fibrillation (AF) in the Balkan Region are scarce. To capture the patterns in AF management in contemporary clinical practice in the Balkan countries a prospective survey was conducted between December 2014 and February 2015, and we report results pertinent to the use of non-vitamin K antagonist oral anticoagulants (NOACs).

Methods

A 14-week prospective, multicenter survey of consecutive AF patients seen by cardiologists or internal medicine specialists was conducted in Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Montenegro, Romania, and Serbia (a total of about 50 million inhabitants).

Results

Of 2712 enrolled patients, 2663 (98.2%) had complete data relevant to oral anticoagulant (OAC) use (mean age 69.1 ± 10.9 years, female 44.6%). Overall, OAC was used in 1960 patients (73.6%) of whom 338 (17.2%) received NOACs. Malignancy [odds ratio (OR), 95% confidence interval (CI) 2.06, 1.20–3.56], rhythm control (OR 1.64, 1.25–2.16), and treatment by cardiologists were independent predictors of NOAC use (OR 2.32, 1.51–3.54) [all p < 0.01)], whilst heart failure and valvular disease were negatively associated with NOAC use (both p < 0.01). Individual stroke and bleeding risk were not significantly associated with NOAC use on multivariate analysis.

Conclusions

NOACs are increasingly used in AF patients in the Balkan Region, but NOAC use is predominantly guided by factors other than evidence-based decision-making (e.g., drug availability on the market or reimbursement policy). Efforts are needed to establish an evidence-based approach to OAC selection and to facilitate the optimal use of OAC, thus improving the outcomes in AF patients in this large region.

     

Evoked potential correlates of Post-Traumatic Stress Disorder in refugees with history of exposure to torture

The presence and magnitude of information processing deviations associated with Post-Traumatic Stress Disorder (PTSD) are far from being well-characterized. In this study we assessed the auditory and visually evoked cerebral responses in a group of Iraqi refugees who were exposed to torture and developed PTSD (N = 20), Iraqi refugees who had been exposed to similar trauma but did not develop PTSD (N = 20), and non-traumatized controls matched for age, gender, and ethnicity (N = 20). We utilized two paired-stimulus paradigms in auditory and visual sensory modalities, respectively. We found significantly smaller amplitudes of both the auditory P50 and the visual N75 responses in PTSD patients compared to controls, reflecting decreased response to simple sensory input during a relatively early phase of information processing (interval 50–75 ms post stimulus). In addition, deficient suppression of the P50/N75 response to repeating stimuli at this early stage in both modalities is indicative of difficulty in filtering out irrelevant sensory input. Among associations between electrophysiological and clinical measures, a significant positive correlation was found between dissociation score and P50 S1 amplitudes (p = 0.024), as well as stronger auditory P50 gating correlated with higher quality-of-life index scores (p = 0.013). In addition, smaller amplitudes of N150 visual evoked response to S1 showed a significant association with higher avoidance scores (p = 0.015). The results of this study highlight the importance of early automatic auditory and visual evoked responses in probing the information processing and neural mechanisms underlying symptomatology in PTSD.     

Mapping repetition suppression of the P50 evoked response to the human cerebral cortex

ObjectiveThe cerebral network subserving repetition suppression (RS) of the P50 auditory evoked response as observed using paired-identical-stimulus (S1–S2) paradigms is not well-described.MethodsWe analyzed S1–S2 data from electrodes placed on the cortices of 64 epilepsy patients. We identified regions with maximal amplitude responses to S1 (i.e., stimulus registration), regions with maximal suppression of responses to S2 relative to S1 (i.e., RS), and regions with no or minimal RS 30–80 ms post stimulation.ResultsSeveral temporal, parietal and cingulate area regions were shown to have significant initial registration activity (i.e., strong P50 response to S1). Moreover, prefrontal, cingulate, and parietal lobe regions not previously proposed to be part of the P50 habituation neural circuitry were found to exhibit significant RS.ConclusionsThe data suggest that the neural network underlying the initial phases of the RS process may include regions not previously thought to be involved like the parietal and cingulate cortexes. In addition, a significant role for the frontal lobe in mediating this function is supported.SignificanceA number of regions of interest are identified through invasive recording that will allow further probing of the RS function using less invasive technology.     

A statistical methodology to improve accuracy in differentiating schizophrenia patients from healthy controls

We present a methodology to statistically discriminate among univariate and multivariate indices to improve accuracy in differentiating schizophrenia patients from healthy controls. Electroencephalogram data from 71 subjects (37 controls/34 patients) were analyzed. Data included P300 event-related response amplitudes and latencies as well as amplitudes and sensory gating indices derived from the P50, N100, and P200 auditory-evoked responses resulting in 20 indices analyzed. Receiver operator characteristic (ROC) curve analyses identified significant univariate indices; these underwent principal component analysis (PCA). Logistic regression of PCA components created a multivariate composite used in the final ROC. Eleven univariate ROCs were significant with area under the curve (AUC) >0.50. PCA of these indices resulted in a three-factor solution accounting for 76.96% of the variance. The first factor was defined primarily by P200 and P300 amplitudes, the second by P50 ratio and difference scores, and the third by P300 latency. ROC analysis using the logistic regression composite resulted in an AUC of 0.793 (0.06), p<0.001 (CI=0.685–0.901). A composite score of 0.456 had a sensitivity of 0.829 (correctly identifying schizophrenia patients) and a specificity of 0.703 (correctly identifying healthy controls). Results demonstrated the usefulness of combined statistical techniques in creating a multivariate composite that improves diagnostic accuracy.     

cpsf1 is required for definitive HSC survival in zebrafish

A comprehensive understanding of the genes and pathways regulating hematopoiesis is needed to identify genes causally related to bone marrow failure syndromes, myelodysplastic syndromes, and hematopoietic neoplasms. To identify novel genes involved in hematopoiesis, we performed an ethyl-nitrosourea mutagenesis screen in zebrafish (Danio rerio) to search for mutants with defective definitive hematopoiesis. We report the recovery and analysis of the grechetto mutant, which harbors an inactivating mutation in cleavage and polyadenylation specificity factor 1 (cpsf1), a gene ubiquitously expressed and required for 3' untranslated region processing of a subset of pre-mRNAs. grechetto mutants undergo normal primitive hematopoiesis and specify appropriate numbers of definitive HSCs at 36 hours postfertilization. However, when HSCs migrate to the caudal hematopoietic tissue at 3 days postfertilization, their numbers start decreasing as a result of apoptotic cell death. Consistent with Cpsf1 function, c-myb:EGFP(+) cells in grechetto mutants also show defective polyadenylation of snrnp70, a gene required for HSC development. By 5 days postfertilization, definitive hematopoiesis is compromised and severely decreased blood cell numbers are observed across the myeloid, erythroid, and lymphoid cell lineages. These studies show that cpsf1 is essential for HSC survival and differentiation in caudal hematopoietic tissue.     

Sensory-gating deficit of the N100 mid-latency auditory evoked potential in medicated schizophrenia patients

The clinical and neuro-cognitive correlates of the P50 and N100 auditory evoked responses gating deficits in schizophrenia have thus far eluded identification. Based on our prior results, we hypothesized that, in addition to the P50, gating of the N100 is significantly decreased in schizophrenia and that this deficit correlates with the negative symptoms dimension of schizophrenia. Amplitudes and gating measures of the P50 and N100 were compared between stable out-patients (N = 45) (mainly on atypical antipsychotics) with chronic schizophrenia and age- and gender-matched healthy controls (N = 49) and the clinical correlates examined. All subjects underwent the paired-stimulus paradigm in 3 or 4 different days. Data from day one and the mean of all days (MOAD) were examined. P50 and N100 amplitudes and gating measures were correlated with PANSS and Wisconsin Card Sorting Test data. Utilizing day one data, no amplitude or gating measures were significantly different between the groups. Utilizing MOAD data, both P50 and N100 gating were significantly decreased in schizophrenia patients. The N100 gating deficit correlated with the negative-symptoms cluster and measures of frontal lobe dysfunction. The data suggest a correlation between N100 gating deficit and the negative-cognitive deficits dimensions of schizophrenia. Data also suggest that improving the signal to noise ratio (MOAD data) increases the sensitivity for detecting gating abnormalities and assessing their clinical correlates.     

Electroencephalographic evidence of sensory gating in the occipital visual cortex

Sensory gating refers to the suppression of the neuronal response to a repeating stimulus and is considered a protection mechanism in the brain. In this study, we assessed gating of the mid-latency components of the visual evoked potentials (N75, P100, N150) in 11 healthy individuals using a paired-flash paradigm. A significant decrease of P100 and N150 amplitudes was shown; additionally, a significant increase in the latency of N75 and P100 for the second stimulus of the pair compared with the first one was also observed. Absolute power of the stimulus 2 signal at theta frequency was significantly suppressed as compared with the stimulus 1 signal. These results indicate a gating effect in the visual modality, reflected in both time-domain and frequency-domain measures.