Miracle-dz/UniFAR-FTUs huggingface dataset:
Allografts Stimulate Cross‐Reactive Virus‐Specific Memory CD8 T Cells with Private Specificity

Viral infections have been associated with the rejection of transplanted allografts in humans and mice, and the induction of tolerance to allogeneic tissues in mice is abrogated by an ongoing viral infection and inhibited in virus‐immune mice. One proposed mechanism for this ‘heterologous immunity’ is the induction of alloreactive T cell responses that cross‐react with virus‐derived antigens. These cross‐reactive CD8 T cells are generated during acute viral infection and survive into memory, but their ability to partake in the immune response to allografts in vivo is not known. We show here that cross‐reactive, virus‐specific memory CD8 T cells from mice infected with LCMV proliferated in response to allografts. CD8 T cells specific to several LCMV epitopes proliferated in response to alloantigens, with the magnitude and hierarchy of epitope‐specific responses varying with the private specificities of the host memory T cell repertoire, as shown by adoptive transfer studies. Last, we show that purified LCMV‐specific CD8 T cells rejected skin allografts in SCID mice. These findings therefore implicate a potential role for heterologous immunity in virus‐induced allograft rejection.
Phonological processing in first‐degree relatives of individuals with autism: An fMRI study

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders. Twin studies have provided heritability estimates as high as 90% for idiopathic ASD. Further evidence for the spectrum's heritability is provided by the presence of the broad autism phenotype (BAP) in unaffected first‐degree relatives. Language ability, specifically phonological processing, is proposed to be a core BAP trait. To date, however, no functional neuroimaging investigations of phonological processing in relatives of individuals with ASD have been undertaken. We conducted a functional magnetic resonance imaging (fMRI) study in parents of children with ASD utilizing a priming task probing implicit phonological processing. In our condition that placed heavier demands on phonological recoding, parents exhibited greater hemodynamic responses than controls in a network of cortical regions involved in phonological processing. Across conditions, parents exhibited enhanced priming‐induced response suppression suggesting compensatory neural processing. A nonword repetition test used in previous studies of relatives was also administered. Correlations between this measure and our functional measures also suggested compensatory processing in parents. Regions exhibiting atypical responses in parents included regions previously implicated in the spectrum's language impairments and found to exhibit structural abnormalities in a parent study. These results suggest a possible neurobiological substrate of the phonological deficits proposed to be a core BAP trait. However, these results should be considered preliminary. No previous fMRI study has investigated phonological processing in ASD, so replication is required. Furthermore, interpretation of our fMRI results is limited by the fact that the parent group failed to exhibit behavioral evidence of phonological impairments. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
De novo Thrombotic Microangiopathy in Renal Allograft Biopsies—Role of Antibody‐Mediated Rejection

The most common cause of thrombotic microangiopathy (TMA) in renal allografts is thought to be calcineurin inhibitor toxicity. Antibody‐mediated rejection (AMR) can also cause TMA, but its true impact on de novo TMA is unknown. In a retrospective review of renal allograft biopsies from January 2003 to December 2008 at our institution, we determined the prevalence of TMA in patients with C4d positive (n = 243) and C4d negative (n = 715) biopsies. Over 90% of patients received cyclosporine in both groups. De novo TMA was seen in 59 (6.1%) patients; most of them (55%) with C4d positive biopsy. Among patients with C4d positive biopsies, 13.6% had TMA, as compared to only 3.6% patients with C4d negative biopsies (p < 0.0001). Incidence of graft loss between C4d positive and C4d negative TMA groups was not significantly different, but 70% of patients with C4d positive TMA who received plasmapheresis had slightly lower graft loss rate. In biopsies with AMR‐associated TMA, glomerulitis and peritubular capillaritis were significantly more prominent. AMR is the most common cause of TMA in renal allografts in our patient population. It is important to recognize AMR‐related TMA because plasmapheresis treatment may be beneficial.
Triage of x ray films?

Glucksman found that casualty officers prescribed tetanus immunisation more appropriately if patients' immune state had been previously recorded by a triage nurse.4 Casualty officers seem to benefit from gentle reminders, especially when they are busy. I firmly believe that radiographers should be encouraged to triage accident and emergency radiographs; this has been shown to decrease the false negative error rate. '
Representation and propagation of epileptic activity in absences and generalized photoparoxysmal responses

Although functional imaging studies described networks associated with generalized epileptic activity, propagation patterns within these networks are not clear. In this study, electroencephalogram (EEG)‐based coherent source imaging dynamic imaging of coherent sources (DICS) was applied to different types of generalized epileptiform discharges, namely absence seizures (10 patients) and photoparoxysmal responses (PPR) (eight patients) to describe the representation and propagation of these discharges in the brain. The results of electrical source imaging were compared to EEG‐functional magnetic resonance imaging (fMRI) which had been obtained from the same data sets of simultaneous EEG and fMRI recordings. Similar networks were described by DICS and fMRI: (1) absence seizures were associated with thalamic involvement in all patients. Concordant results were also found for brain areas of the default mode network and the occipital cortex. (2) Both DICS and fMRI identified the occipital, parietal, and the frontal cortex in a network associated with PPR. (3) However, only when PPR preceded a generalized tonic‐clonic seizure, the thalamus was involved in the generation of PPR as shown by both imaging techniques. Partial directed coherence suggested that during absences, the thalamus acts as a pacemaker while PPR could be explained by a cortical propagation from the occipital cortex via the parietal cortex to the frontal cortex. In conclusion, the electrical source imaging is not only able to describe similar neuronal networks as revealed by fMRI, including deep sources of neuronal activity such as the thalamus, but also demonstrates interactions interactions within these networks and sheds light on pathogenetic mechanisms of absence seizures and PPR. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
Brain activity during sympathetic response in anticipation and experience of pain

Pain is a multidimensional phenomenon with sensory, affective, and autonomic components. Here, we used parametric functional magnetic resonance imaging (fMRI) to correlate regional brain activity with autonomic responses to (i) painful stimuli and to (ii) anticipation of pain. The autonomic parameters used for correlation were (i) skin blood flow (SBF) and (ii) skin conductance response (SCR). During (i) experience of pain and (ii) anticipation of pain, activity in the insular cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), posterior parietal cortex (PPC), secondary somatosensory cortex (S2), thalamus, and midbrain correlated with sympathetic outflow. A conjunction analysis revealed a common central sympathetic network for (i) pain experience and (ii) pain anticipation with similar correlations between brain activity and sympathetic parameters in the anterior insula, prefrontal cortex, thalamus, midbrain, and temporoparietal junction. Therefore, we here describe shared central neural networks involved in the central autonomic processing of the experience and anticipation of pain. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
Usefulness of MALDI-TOF/MS Identification of Low-MW Fragments in Sera for the Differential Diagnosis of Pancreatic Cancer

Objectives To identify new biomarkers of pancreatic cancer (PaCa), we performed MALDI-TOF/MS analysis of sera from 22 controls, 51 PaCa, 37 chronic pancreatitis, 24 type II diabetes mellitus (DM), 29 gastric cancer (GC), and 24 chronic gastritis (CG). Methods Sera were purified by Sep-Pak C18 before MALDI-TOF/MS Anchorchip analysis. Results Features present in at least 5% of all spectra were selected (n = 160, m/z range, 1200–5000). At univariate analysis, 2 features (m/z 2049 and 2305) correlated with PaCa, 3 (m/z 1449, 1605, and 2006) with DM. No feature characterized gastric cancer or chronic gastritis. Ten-fold cross-validation binary recursive partitioning trees were obtained for patients’ classification. The tree (CA 19-9, age, m/z 2006, 2599, 2753, and 4997), built considering only patients with diabetes, allowed a distinction between DM [area under the receiver operating characteristic curve (AUC), 0.997], chronic pancreatitis (AUC, 0.968), and PaCa (AUC, 0.980), with an overall correct classification rate of 89%. The tree including CA 19-9, 1550, and 2937 m/z features, achieved an AUC of 0.970 in distinguishing localized from advanced PaCa. MALDI-TOF-TOF analysis revealed the 1550 feature as a fragment of Apo-A1, which was determined as whole protein and demonstrated to be closely correlated with PaCa. Conclusions The findings made demonstrate a role for serum peptides identified using MALDI-TOF/MS for addressing PaCa diagnosis.
The Histology of Solitary Renal Allografts at 1 and 5 Years After Transplantation

Previous studies suggest that the majority of renal allografts are affected by progressive, severe chronic histologic injury, yet studies using current protocols are lacking. The goal of this study was to examine the prevalence and progression of histologic changes using protocol allograft biopsies at 1 and 5 years after solitary kidney transplantation in patients transplanted between 1998 and 2004. Chronic histologic changes generally were mild at both 1 and 5 years and were similar in deceased and living donor kidneys. The overall prevalence of moderate or severe fibrosis was 13% (60/447) at 1 year and 17% (60/343) at 5 years. In a subgroup of 296 patients who underwent both 1‐ and 5‐year biopsies, mild fibrosis present at 1 year progressed to more severe forms at 5 years in 23% of allografts. The prevalence of moderate or severe arteriolar hyalinosis was similar in tacrolimus and calcineurin inhibitor‐free immunosuppression. These results in the recent era of transplantation demonstrate fewer, less severe and less progressive chronic histologic changes in the first 5 years after transplantation than previously reported.
Sleep spindles predict neural and behavioral changes in motor sequence consolidation

The purpose of this study was to investigate the predictive function of sleep spindles in motor sequence consolidation. BOLD responses were acquired in 10 young healthy subjects who were trained on an explicitly known 5‐item sequence using their left nondominant hand, scanned at 9:00 pm while performing that same task and then were retested and scanned 12 h later after a night of sleep during which polysomnographic measures were recorded. An automatic algorithm was used to detect sleep spindles and to quantify their characteristics (i.e., density, amplitude, and duration). Analyses revealed significant positive correlations between gains in performance and the amplitude of spindles. Moreover, significant increases in BOLD signal were observed in several motor‐related areas, most of which were localized in the right hemisphere, particularly in the right cortico‐striatal system. Such increases in BOLD signal also correlated positively with the amplitude of spindles at several derivations. Taken together, our results show that sleep spindles predict neural and behavioral changes in overnight motor sequence consolidation. Hum Brain Mapp 34:2918–2928, 2013. © 2012 Wiley Periodicals, Inc.
Selective Targeting of Human Alloresponsive CD8+ Effector Memory T Cells Based on CD2 Expression

Costimulation blockade (CoB), specifically CD28/B7 inhibition with belatacept, is an emerging clinical replacement for calcineurin inhibitor‐based immunosuppression in allotransplantation. However, there is accumulating evidence that belatacept incompletely controls alloreactive T cells that lose CD28 expression during terminal differentiation. We have recently shown that the CD2‐specific fusion protein alefacept controls costimulation blockade‐resistant allograft rejection in nonhuman primates. Here, we have investigated the relationship between human alloreactive T cells, costimulation blockade sensitivity and CD2 expression to determine whether these findings warrant potential clinical translation. Using polychromatic flow cytometry, we found that CD8+ effector memory T cells are distinctly high CD2 and low CD28 expressors. Alloresponsive CD8+CD2hiCD28− T cells contained the highest proportion of cells with polyfunctional cytokine (IFNγ, TNF and IL‐2) and cytotoxic effector molecule (CD107a and granzyme B) expression capability. Treatment with belatacept in vitro incompletely attenuated allospecific proliferation, but alefacept inhibited belatacept‐resistant proliferation. These results suggest that highly alloreactive effector T cells exert their late stage functions without reliance on ongoing CD28/B7 costimulation. Their high CD2 expression increases their susceptibility to alefacept. These studies combined with in vivo nonhuman primate data provide a rationale for translation of an immunosuppression regimen pairing alefacept and belatacept to human renal transplantation.
Sustained attention is associated with right superior longitudinal fasciculus and superior parietal white matter microstructure in children

Sustained attention develops during childhood and has been linked to the right fronto‐parietal cortices in functional imaging studies; however, less is known about its relation to white matter (WM) characteristics. Here we investigated whether the microstructure of the WM underlying and connecting the right fronto‐parietal cortices was associated with sustained attention performance in a group of 76 typically developing children aged 7–13 years. Sustained attention was assessed using a rapid visual information processing paradigm. The two behavioral measures of interest were the sensitivity index d′ and the coefficient of variation in reaction times (RTCV). Diffusion‐weighted imaging was performed. Mean fractional anisotropy (FA) was extracted from the WM underlying right dorsolateral prefrontal (DLPFC) and parietal cortex (PC), and the right superior longitudinal fasciculus (SLF), as well as equivalent anatomical regions‐of‐interest (ROIs) in the left hemisphere and mean global WM FA. When analyzed collectively, right hemisphere ROIs FA was significantly associated with d′ independently of age. Follow‐up analyses revealed that only FA of right SLF and the superior part of the right PC contributed significantly to this association. RTCV was significantly associated with right superior PC FA, but not with right SLF FA. Observed associations remained significant after controlling for FA of equivalent left hemisphere ROIs or global mean FA. In conclusion, better sustained attention performance was associated with higher FA of WM in regions connecting right frontal and parietal cortices. Further studies are needed to clarify to which extent these associations are driven by maturational processes, stable characteristics and/or experience. Hum Brain Mapp 34:3216–3232, 2013. © 2012 Wiley Periodicals, Inc.
Memory performance and fMRI signal in presymptomatic familial Alzheimer's disease

Rare autosomal dominant mutations result in familial Alzheimer's disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late‐onset AD. Evaluation of fMRI activity in presymptomatic FAD mutation carriers versus noncarriers provides insight into preclinical changes in those who will certainly develop AD in a prescribed period of time. Adults from FAD mutation‐carrying families (nine mutation carriers, eight noncarriers) underwent fMRI scanning while performing a memory task. We examined fMRI signal differences between carriers and noncarriers, and how signal related to fMRI task performance within mutation status group, controlling for relative age and education. Mutation noncarriers had greater retrieval period activity than carriers in several AD‐relevant regions, including the left hippocampus. Better performing noncarriers showed greater encoding period activity including in the parahippocampal gyrus. Poorer performing carriers showed greater retrieval period signal, including in the frontal and temporal lobes, suggesting underlying pathological processes. Hum Brain Mapp 34:3308–3319, 2013. © 2012 Wiley Periodicals, Inc.
A Meta-Analysis of Gemcitabine Biomarkers in Patients With Pancreaticobiliary Cancers

Objectives The objective of this study was to summarize all clinical studies evaluating the prognostic role of gemcitabine (GEM) metabolic genes in pancreaticobiliary (PB) cancer patients receiving GEM therapy in the neoadjuvant, adjuvant, or palliative settings. Methods Meta-analyses were performed to calculate the pooled hazard ratios for each gene by each clinical outcome (overall survival [OS], disease-free survival [DFS], and progression-free survival) using a random-effects approach. Results The search strategy identified 16 eligible studies, composed of 632 PB patients total, with moderate quality. Compared with low expression, pooled hazard ratios for OS of hENT1, dCK, RRM1, RRM2, and DPD were 0.37 (95% confidence interval [CI], 0.28–0.47), 0.40 (95% CI, 0.20–0.80), 2.21 (95% CI, 1.12–4.36), 2.13 (95% CI, 1.00–4.52), and 1.91 (95% CI, 1.16–3.17), respectively. A similar trend was observed for each of these biomarkers in DFS and progression-free survival prognostication. Subgroup analyses for hENT1 showed a comparable survival correlation in the adjuvant and palliative settings. Conclusions High expression of hENT1 in PB cancer patients receiving GEM-based adjuvant therapy is associated with improved OS and DFS and may be the best examined prognostic marker to date. Evidence for other biomarkers is limited by a small number of publications investigating these markers.
Regional specificity of sex effects on subcortical volumes across the lifespan in healthy aging

When conceptualizing age‐specific onsets and sex‐specific characteristics of neuropsychiatric diseases in a neurobiological context, it may be crucially important to consider differential trajectories of aging. Here, we investigated effects of age, sex, and their interactions on absolute and relative volumes of subcortical structures with known involvement in psychiatric disorders, including the basal ganglia, thalamus, hippocampus, and amygdala. Structural MRI data of 76 healthy subjects (38 males, 19–70 years) from the ICBM database were analyzed. Age‐related absolute atrophy was generally found in the basal ganglia and thalamus, while in the hippocampus decline was only observed in males, and was generally absent in the amygdala. Disproportionate degeneration in the basal ganglia and thalamus, exceeding cortical decline was specific for females. When allowing higher‐order models, a quadratic model could better describe the negative relation of absolute volume and age in the basal ganglia in males, and generally in the hippocampus and amygdala. We could show that negative age‐relations are highly specific for certain subcortical structures in either gender. Importantly these findings also emphasize the significant impact of analytical strategies when deciding for correction of subcortical volumes to the whole‐brain decline. Specifically, in the basal ganglia disproportionate shrinkage in females was suggested by the relative analysis while absolute volume analysis rather stressed an accelerating decline in older males. Given strong involvement of the basal ganglia in both cognitive aging and emotional regulation, our findings may be crucial for studies investigating the onset and prevalence of dementia and depressive symptoms in male and female aging. Hum Brain Mapp 35:238–247, 2014. © 2012 Wiley Periodicals, Inc.
Response to Questions Regarding the Design and Results of the IMPACT Trial

The IMPACT study was a meticulously designed doubleblinded study, which has been scrutinized and considered robust enough in design, endpoints and outcome, by US and EU health authorities, so as to lead to global label changes in prescribing valganciclovir for kidney transplant patients. Kalil et al. state a major weakness of the IMPACT study was inadequate blinding. Active drug and placebo were indistinguishable and fully matched in terms of shape, size, color and labeling. All study investigators, site staff and sponsor, were fully blinded to the treatment allocation until after the analysis of the primary endpoint. Therefore, any conclusions regarding the lack of valid blinding are not scientifically sound. Withdrawal from treatment between groups was indeed different, however the reason for withdrawal was not due to compliance or unblinding as suggested, but due to the development of cytomegalovirus (CMV) disease after the first 100 days. Obviously patients who are being treated for CMV disease can’t continue to get blinded study drug. The suggestion to separately analyze CMV disease in patients who completed 200 days of drug simply does not make sense. Furthermore, a compliance issue did not occur. Compliance was closely monitored, with drug dispense and return logs being performed at each study visit and was comparable between arms. Similarly, the author’s conclusion that patients in the 100day group had more frequent dose adjustments is incorrect; the results show that each group was similar for renal function over time. Dose adjustments were carried out alike for all patients regardless of group, according to renal function.
Brain network of semantic integration in sentence reading: Insights from independent component analysis and graph theoretical analysis

A set of cortical and sub‐cortical brain structures has been linked with sentence‐level semantic processes. However, it remains unclear how these brain regions are organized to support the semantic integration of a word into sentential context. To look into this issue, we conducted a functional magnetic resonance imaging (fMRI) study that required participants to silently read sentences with semantically congruent or incongruent endings and analyzed the network properties of the brain with two approaches, independent component analysis (ICA) and graph theoretical analysis (GTA). The GTA suggested that the whole‐brain network is topologically stable across conditions. The ICA revealed a network comprising the supplementary motor area (SMA), left inferior frontal gyrus, left middle temporal gyrus, left caudate nucleus, and left angular gyrus, which was modulated by the incongruity of sentence ending. Furthermore, the GTA specified that the connections between the left SMA and left caudate nucleus as well as that between the left caudate nucleus and right thalamus were stronger in response to incongruent vs. congruent endings. Hum Brain Mapp 35:367–376, 2014. © 2012 Wiley Periodicals, Inc.