Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of age on prefrontal subregions and hippocampal volumes in young and middle‐aged healthy humans

There are limited data available regarding the effects of age and sex on discrete prefrontal gray and white matter volumes or posterior and anterior hippocampal volumes in healthy humans. Volumes of the superior frontal gyrus, anterior cingulate gyrus, and orbital frontal lobe were computed manually from contiguous magnetic resonance (MR) images in 83 (39M/44F) healthy humans (age range = 16–40) and segmented into gray and white matter. Volumes of the posterior and anterior hippocampal formation were also computed with reliable separation of the anterior hippocampal formation from the amygdala. There were significant age‐by‐tissue type interactions for the superior frontal gyrus and orbital frontal lobe such that gray matter within these regions correlated significantly and inversely with age. In contrast, no significant age effects were evident within regional white matter volumes. Analysis of hippocampal volumes indicated that men had larger volumes of the anterior, but not posterior hippocampal formation compared to women even following correction for total brain size. These data highlight age effects within discrete prefrontal cortical gray matter regions in young and middle aged healthy humans and suggest that the white matter comprising these regions may be more resistant to age effects. Furthermore, understanding the potential role of sex and age in mediating prefrontal cortical and hippocampal volumes may have strong relevance for psychiatric disorders such as schizophrenia that have implicated neurodevelopmental abnormalities within frontotemporal circuits in their pathogenesis. Hum Brain Mapp 34:2129–2140, 2013. © 2012 Wiley Periodicals, Inc.
Review of Cancer – Associated Fibroblasts and Therapiesthat Interfere with Their Activity

Received 09 December 2012 Accepted 17 January 2013 Abstract Cancer-associated fibroblasts (CAFs) are a specific but heterogenous population of cells that reside in the tumor microenvironment and play a significant role in the neoplastic process. CAFs participate in tumorigenesis, provide a nurturing environment for neoplastic cells, promote malignant cell growth and invasiveness by remodeling the local extracellular matrix; they have pro-inflammatory and proangiogenic properties. CAFs also confer resistance to chemotherapy and raditation therapy. In order to achieve these activities, CAFs secrete multiple growth factors, cytokines and proteins. Communication between CAFs and malignant cells is not, however, one way; premalignant cells and tumor cells secrete their own cytokines and growth factors that increase CAF numbers and function. There has also been considerable clinical research with agents that may interfere with CAFs but it has been difficult to learn about and measure the interference with CAFs per se. This review addresses the current state of knowledge about CAFs, summarizes the clinical development to date of therapeutics that inhibit CAF growth and function and suggests strategies for future clinical trials that focus particularly on CAFs and their products.
Reading acquisition reorganizes the phonological awareness network only in alphabetic writing systems

It is unknown how experience with different types of orthographies influences the neural basis of oral language processing. In order to determine the effects of alphabetic and nonalphabetic writing systems, the current study examined the influence of learning to read on oral language in English and Chinese speakers. Children (8–12 years olds) and adults made rhyming judgments to pairs of spoken words during functional magnetic resonance imaging (fMRI). Developmental increases were seen only for English speakers in the left hemisphere phonological network (superior temporal gyrus (STG), inferior parietal lobule, and inferior frontal gyrus). The increase in the STG was more pronounced for words with conflicting orthography (e.g. pint‐mint; jazz‐has) even though access to orthography was irrelevant to the task. Moreover, higher reading skill was correlated with greater activation in the STG only for English speaking children. The effects suggest that learning to read reorganizes the phonological awareness network only for alphabetic and not logographic writing systems because of differences in the principles for mapping between orthographic and phonological representations. The reorganization of the auditory cortex may result in better phonological awareness skills in alphabetic readers. Hum Brain Mapp 34:3354–3368, 2013. © 2012 Wiley Periodicals, Inc.
Noninvasive Detection of Graft Rejection by In Vivo 19F MRI in the Early Stage

Diagnosis of transplant rejection requires tissue biopsy and entails risks. Here, we describe a new 19F MRI approach for noninvasive visualization of organ rejection via the macrophage host response. For this, we employed biochemically inert emulsified perfluorocarbons (PFCs), known to be preferentially phagocytized by monocytes and macrophages. Isografts from C57BL/6 or allografts from C57B10.A mice were heterotopically transplanted into C57BL/6 recipients. PFCs were applied intravenously followed by 1H/19F MRI at 9.4 T 24 h after injection. 1H images showed a similar position and anatomy of the graft in the abdomen for both cases. However, corresponding 19F signals were only observed in allogenic tissue. 1H/19F MRI enabled us to detect the initial immune response not later than 3 days after surgery, when conventional parameters did not reveal any signs of rejection. In allografts, the observed 19F signal strongly increased with time and correlated with the extent of rejection. In separate experiments, rapamycin was used to demonstrate the ability of 19F MRI to monitor immunosuppressive therapy. Thus, PFCs can serve as positive contrast agent for the early detection of transplant rejection by 19F MRI with high spatial resolution and an excellent degree of specificity due to lack of any 19F background.
Reduction of Immunosuppression as Initial Therapy for Posttransplantation Lymphoproliferative Disorder ★

Reduction of immunosuppression (RI) is commonly used to treat posttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients. We investigated the efficacy, safety and predictors of response to RI in adult patients with PTLD. Sixty‐seven patients were managed with RI alone and 30 patients were treated with surgical excision followed by adjuvant RI. The response rate to RI alone was 45% (complete response—37%, partial response—8%). The relapse rate in complete responders was 17%. Adjuvant RI resulted in a 27% relapse rate. The acute rejection rate following RI‐containing strategies was 32% and a second transplant was feasible without relapse of PTLD. The median survival was 44 months in patients treated with RI alone and 9.5 months in patients who remained on full immunosuppression (p = 0.07). Bulky disease, advanced stage and older age predicted lack of response to RI. Survival analysis demonstrated predictors of poor outcome—age, dyspnea, B symptoms, LDH level, hepatitis C, bone marrow and liver involvement. Patients with none or one of these factors had a 3‐year overall survival of 100% and 79%, respectively. These findings support the use of RI alone in low‐risk PTLD and suggest factors that predict response and survival.
Diffusion weighted imaging of prefrontal cortex in prodromal huntington's disease

Huntington's disease (HD) is a devastating neurodegenerative disease with no effective disease‐modifying treatments. There is considerable interest in finding reliable indicators of disease progression to judge the efficacy of novel treatments that slow or stop disease onset before debilitating signs appear. Diffusion‐weighted imaging (DWI) may provide a reliable marker of disease progression by characterizing diffusivity changes in white matter (WM) in individuals with prodromal HD. The prefrontal cortex (PFC) may play a role in HD progression due to its prominent striatal connections and documented role in executive function. This study uses DWI to characterize diffusivity in specific regions of PFC WM defined by FreeSurfer in 53 prodromal HD participants and 34 controls. Prodromal HD individuals were separated into three CAG‐Age Product (CAP) groups (16 low, 22 medium, 15 high) that indexed baseline progression. Statistically significant increases in mean diffusivity (MD) and radial diffusivity (RD) among CAP groups relative to controls were seen in inferior and lateral PFC regions. For MD and RD, differences among controls and HD participants tracked with baseline disease progression. The smallest difference was for the low group and the largest for the high group. Significant correlations between Trail Making Test B (TMTB) and mean fractional anisotropy (FA) and/or RD paralleled group differences in mean MD and/or RD in several right hemisphere regions. The gradient of effects that tracked with CAP group suggests DWI may provide markers of disease progression in future longitudinal studies as increasing diffusivity abnormalities in the lateral PFC of prodromal HD individuals. Hum Brain Mapp 35:1562–1573, 2014. © 2013 Wiley Periodicals, Inc.
Associations of Pretransplant Serum Albumin with Post‐Transplant Outcomes in Kidney Transplant Recipients

The association between pretransplant serum albumin concentration and post‐transplant outcomes in kidney transplant recipients is unclear. We hypothesized that in transplant‐waitlisted hemodialysis patients, lower serum albumin concentrations are associated with worse post‐transplant outcomes. Linking the 5‐year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, we identified 8961 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function (DGF) risks were estimated by Cox regression (hazard ratio [HR]) and logistic regression (Odds ratio [OR]), respectively. Patients were 48 ± 13 years old and included 37% women and 27% diabetics. The higher pretransplant serum albumin was associated with lower mortality, graft failure and DGF risk even after multivariate adjustment for case‐mix, malnutrition–inflammation complex and transplant related variable. Every 0.2 g/dL higher pretransplant serum albumin concentration was associated with 13% lower all‐cause mortality (HR = 0.87 [95% confidence interval: 0.82–0.93]), 17% lower cardiovascular mortality (HR = 0.83[0.74–0.93]), 7% lower combined risk of death or graft failure (HR = 0.93[0.89–0.97]) and 4% lower DGF risk (OR = 0.96[0.93–0.99]). Hence, lower pretransplant serum albumin level is associated with worse post‐transplant outcomes. Clinical trials to examine interventions to improve nutritional status in transplant‐waitlisted hemodialysis patients and their impacts on post‐transplant outcomes are indicated.
Potential Role of IGF-1 z Score to Predict Permanent Linear Growth Impairment in Children With IBD

ABSTRACT In this pilot study, we analyzed serum insulin-like growth factor 1 (IGF-1)- and IGF-binding protein-3-for-age z scores from 54 inflammatory bowel disease children with no, temporary, or permanent growth impairment. Although our findings did not reach statistical significance, patients with permanent linear growth impairment had lower IGF-1-for-age z scores (−1.76 [−2.25 to −0.43]) compared with those with no or temporary growth impairment (−0.84 [−1.49 to −0.3]) and −1.16 [−1.59 to −1.51], respectively). IGF-binding protein-3 levels were similar across the 3 groups. In the absence of significant inflammation and malnutrition, lower IGF-1-for-age z scores may help distinguish patients likely to have permanent growth impairment from those whose growth impairment is likely to be temporary.
Response to Letter About Intensity of Immunosuppressive Therapy on Outcome of Treatment for CMV Disease

We thank Hosseini-Moghaddam et al. (1) for their interest in our posthoc analysis of the influence of immunosuppressive intensity on CMV outcomes in the VICTORtrial (2–4). Although predefined end-points were used in this posthoc analysis, these were not end-points in the primary study (VICTOR-trial) and, as mentioned in the paper, the analysis was intended as a pure hypothesis generating work. The type of data collected limited the use of specific statistical methods, for example, that the CNI levels had to be dichotomized and analyzed together in groups without correction for other immunosuppressive drugs.
Quality of Life in Kidney Donors

Reports on quality of life of kidney donors include small populations with variable response rates. The aim was to evaluate quality of life in kidney donors in a large cross‐sectional study. Through the Norwegian Renal Registry we contacted all 1984 kidney donors in the period 1963–2007 with a response rate of 76%. All received the Short‐Form‐36 (SF ‐ 36) survey form and a questionnaire specifically designed for kidney donors. SF ‐ 36 scores for a subgroup (n = 1414) of kidney donors were not inferior to a general population sample, adjusted for age, gender and education. When asked to reconsider, a majority stated that they still would have consented to donate. Risk factors for having doubts were graft loss in the recipient (OR 3.1, p < 0.001), medical problems after donation (OR 3.7, p < 0.001), unrelated donor (OR 2.2, p = 0.01) and less than 12 years since donation (OR 1.8, p = 0.04). Older age at donation was associated with lower risk (OR 0.98, p = 0.03). Compared with other donors, those expressing doubts had inferior SF ‐ 36 scores. Norwegian kidney donors are mostly first‐degree relatives. They are fully reimbursed and offered life‐long follow‐up. All inhabitants are provided universal healthcare. This should be considered when extrapolating these results to other countries.
Generation and Large‐Scale Expansion of Human Inducible Regulatory T Cells That Suppress Graft‐Versus‐Host Disease

Adoptive transfer of thymus‐derived natural regulatory T cells (nTregs) effectively suppresses disease in murine models of autoimmunity and graft‐versus‐host disease (GVHD). TGFß induces Foxp3 expression and suppressive function in stimulated murine CD4+25‐ T cells, and these induced Treg (iTregs), like nTreg, suppress auto‐ and allo‐reactivity in vivo. However, while TGFß induces Foxp3 expression in stimulated human T cells, the expanded cells lack suppressor cell function. Here we show that Rapamycin (Rapa) enhances TGFß‐dependent Foxp3 expression and induces a potent suppressor function in naive (CD4+ 25–45RA+) T cells. Rapa/TGFß iTregs are anergic, express CD25 at levels higher than expanded nTregs and few cells secrete IL‐2, IFNγ or IL‐17 even after PMA and Ionomycin stimulation in vitro. Unlike other published methods of inducing Treg function, Rapa/TGFß induces suppressive function even in the presence of memory CD4+ T cells. A single apheresis unit of blood yields an average ∼240 × 109 (range ∼70–560 × 109) iTregs from CD4+25‐ T cells in ≤2 weeks of culture. Most importantly, Rapa/TGFß iTregs suppress disease in a xenogeneic model of GVHD. This study opens the door for iTreg cellular therapy for human diseases.
Efficacy and Safety of Early Cyclosporine Conversion to Sirolimus with Continued MMF—Four‐Year Results of the Postconcept Study

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function. We previously reported that conversion from cyclosporine A (CsA) to sirolimus (SRL) 3 months after transplantation significantly improved renal function at 1 year. In the Postconcept trial, 77 patients in the SRL group and 85 in the CsA group were followed for 48 months. Renal function (Cockcroft and Gault) was significantly better at month 48 (M48) in the SRL group both in the intent‐to‐treat population (ITT): 62.6 mL/min/1.73 m2 versus 57.1 mL/min/1.73 m2 (p = 0.013) and in the on‐treatment population (OT): 67.5 mL/min/1.73 m2 versus 57.4 mL/min/1.73 m2 (p = 0.002). Two biopsy proven acute rejection episodes occurred after M12 in each group. Graft and patient survival were comparable (graft survival: 97.4 vs. 100%; patient survival: 97.4 vs. 97.6%, respectively). The incidence of new‐onset diabetes was numerically increased in the SRL group (7 vs. 2). In OT, three cancers occurred in the SRL group versus nine in the CsA group and mean proteinuria was increased in the SRL group (0.42 ± 0.44 vs. 0.26 ± 0.37; p = 0.018). In summary, the renal benefits associated with conversion of CsA to SRL, at 3 months posttransplantation, in combination with MMF were maintained for 4 years posttransplantation.
Significant Potential Utility for Donor Yield Models: But Proceed With Caution

Over the past decade, there has been an astounding proliferation and availability of data in health care used to evaluate processes of care and provider performance. The lexicon of health care has evolved such that value-based purchasing, evidence-based medicine, comparative effectiveness, pay for performance and now health care reform have tangible implications for the practice of medicine. Transparency of health care information has many laudable goals including the facilitation of informed decisionmaking for both caregivers and patients, enabling evaluations of best care models, providing quality assurance and allowing for rigorous analyses of interventions in clinical practice. However, there are also concerns about the potential misuse of data and unintended consequences that may arise from public reporting of health care outcomes without well conceived strategic planning.
New Partners for Tolerogenic Dendritic Cells

Numerous studies in small animal models have demonstrated that the adoptive transfer of cells with immune regulatory potential, in particular tolerogenic dendritic cells (DC) or regulatory T cells (Treg), can promote transplant tolerance. Use of such cells as adjuvant therapy in organ transplantation may reduce dependence on immunosuppressive drugs and facilitate donor-specific, longterm graft survival. At present, immunoregulatory mechanisms, including the roles of specific cytokines that are instigated by tolerogenic cell therapy are not well understood.
Reversed hierarchy in the brain for general and specific cognitive abilities: A morphometric analysis

Intelligence is composed of a set of cognitive abilities hierarchically organized. General and specific abilities capture distinguishable, but related, facets of the intelligence construct. Here, we analyze gray matter with three morphometric indices (volume, cortical surface area, and cortical thickness) at three levels of the intelligence hierarchy (tests, first‐order factors, and a higher‐order general factor, g). A group of one hundred and four healthy young adults completed a cognitive battery and underwent high‐resolution structural MRI. Latent scores were computed for the intelligence factors and tests were also analyzed. The key finding reveals substantial variability in gray matter correlates at the test level, which is substantially reduced for the first‐order and the higher‐order factors. This supports a reversed hierarchy in the brain with respect to cognitive abilities at different psychometric levels: the greater the generality, the smaller the number of relevant gray matter clusters accounting for individual differences in intelligent performance. Hum Brain Mapp 35:3805–3818, 2014. © 2014 Wiley Periodicals, Inc.
Urinary miR‐210 as a Mediator of Acute T‐Cell Mediated Rejection in Renal Allograft Recipients

MicroRNAs (miRNAs) are small ribonucleotides regulating gene expression. Circulating miRNAs are remarkably stable in the blood. We tested whether miRNAs are also detectable in urine and may serve as new predictors of outcome in renal transplant patients with acute rejection. We profiled urinary miRNAs of stable transplant patients and transplant patients with acute rejection. The miR‐10a, miR‐10b and miR‐210 were strongly deregulated in urine of the patients with acute rejection. We confirmed these data in urine of a validation cohort of 62 patients with acute rejection, 19 control transplant patients without rejection and 13 stable transplant patients with urinary tract infection by quantitative RT‐PCR. The miR‐10b and miR‐210 were downregulated and miR‐10a upregulated in patients with acute rejection compared to controls. Only miR‐210 differed between patients with acute rejection when compared to stable transplant patients with urinary tract infection or transplant patients before/after rejection. Low miR‐210 levels were associated with higher decline in GFR 1 year after transplantation. Selected miRNAs are strongly altered in urine of the patients with acute renal allograft rejection. The miR‐210 levels identify patients with acute rejection and predict long‐term kidney function. Urinary miR‐210 may thus serve as a novel biomarker of acute kidney rejection.
CSF phosphorylated neurofilament subunit NF-H (pNF-H) levels are biomarkers of Spinal Cord Injury

Abstract Several studies showed that the phosphorylated form of the neurofilament subunit NF-H (pNF-H) are related to neuronal injuries and its detection provide information about the presence and degree of neuronal loss. Neurofilaments are three subunits, namely NF-L, NF-M and NF-H. The phosphorylated neurofilament subunit NF-H (pNF-H) is present into serum and CSF in significant amounts following neuronal injury and may be detected. The pNF-H can be a biomarker of the neuronal injuries and its detection allows the monitoring neuronal pathology and may provide diagnosis and prognosis in humans. We are interested in pNF-H as biomarker of neuronal injury in spinal cord injury and we used a pNF-H ELISA test capable of detecting the levels of phosphorylated NF-H (pNF-H) to patients with spinal cord injury. We studied the pNF-H levels in CSF in two patients with spinal cord injury (SCI) and for normal values of pNF-H we determined the CSF pNF-H level from individuals without neurological damage. The pNF-H values of CSF from the two patients with SCI were 5-10 times higher than the normal and its higher values were related to an unfavorable outcome. In conclusion, although the number of cases is very low - only two, in the context of experimental studies in animals with SCI, we can say that pNF-H is marker in SCI in humans and its increased values are consistent with an unfavorable outcome.
Specificity of Histological Markers of Long‐Term CNI Nephrotoxicity in Kidney‐Transplant Recipients Under Low‐Dose Cyclosporine Therapy

The specificity of chronic histological lesions induced by calcineurin inhibitors (CNI) is often questioned, but few studies have directly compared long‐term lesions in renal‐transplant patients who received this treatment and those who did not. We therefore conducted a retrospective study of 141 kidney‐transplant recipients treated with (n = 48) or without (n = 93) cyclosporine (CsA) to compare the histological lesions observed at 3‐month, 24‐month and 10‐year protocol biopsies. All of the chronic elementary lesions (glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, fibrointimal thickening) progressed in frequency and severity in both groups, although significantly more in the CsA group. Ten‐year biopsy results showed that 92% of patients in the CsA‐treated group and 65% in the control group had arteriolar hyalinosis lesions. When we focused on muscular arteriolar hyaline deposits more specific to CsA arteriolopathy, we observed these lesions in 68% of CsA patients and 28% of patients who had never received CsA. CsA was not the sole factor involved in the development of arteriolar hyalinosis and was independently associated with an increased risk of graft loss. In summary, we observed that histological lesions commonly attributed to CsA nephrotoxicity were not sufficiently specific to definitively diagnose CNI nephrotoxicity.