Miracle-dz/UniFAR-FTUs huggingface dataset:
Understanding the Causes of Kidney Transplant Failure: The Dominant Role of Antibody‐Mediated Rejection and Nonadherence

We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow‐up period (median 31.4 months). Failure was rare after T‐cell–mediated rejection and acute kidney injury and common after antibody‐mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody‐mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T‐cell–mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody‐mediated or mixed rejection and also underscores the major role of nonadherence.
Statins for the reduction of risk of Alzheimer's disease.

BACKGROUND : Two recent clinical reports describe an association between statin therapy and a reduction in the occurrence of Alzheimer's disease by as much as 70 %. One report is a cross-sectional analysis of discharges among three hospitals, and the other is a nested case control study drawn from ambulatory patients of general practitioners in the UK. Because neither study is a randomized trial, the association noted between statin therapy and a reduced incidence of Alzheimer's disease may have occurred because other factors, unaccounted for in the studies, may be present (so called bias) and be responsible for the observed association. However, there is an expanding body of biological and epidemiological data that makes it plausible that statin therapy may retard or prevent the pathogenesis and clinical expression of Alzheimer's disease. This review was initiated in order to find other clinical evidence that might support or refute the hypothesized benefit of statin therapy. OBJECTIVES : The purpose is to review the evidence that treatment with statins reduces the risk of Alzheimer's disease. SEARCH STRATEGY : The following data bases were searched: Specialised Register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (1966-2000/12), EMBASE (1980-2000/12), and Psych Info (1987-2000/11). Search terms included statins,lovastatin, pravastatin, simvastatin, alzheimer*, dement*, cogn*. SELECTION CRITERIA : In order to be selected, trials needed to be randomized, doubled blinded, and of sufficient duration( probably years rather than weeks or months) to ascertain the preventive potential of statin therapy. DATA COLLECTION AND ANALYSIS : Data were to be extracted independently by two reviewers and pooled where appropriate and possible. The pooled odds ratios (95% CI) or the average differences were to be estimated. MAIN RESULTS : There were no randomized trials found in the search. REVIEWER'S CONCLUSIONS : There is no good evidence to recommend statins for reducing the risk of Alzheimer's disease. There is, however, a growing body of biological, epidemiological, and limited but non-randomized clinical evidence that lowering serum cholesterol may retard the pathogenesis of Alzheimer's disease. Mounting the clinical studies to determine the potential benefit of statin therapy should be a high priority for future research agendas.
Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma.

PURPOSE Standard therapies of head and neck squamous cell carcinoma (HNSCC) often cause profound morbidity and have not significantly improved survival over the last 30 years. Preclinical studies showed that adenoviral vector delivery of the wild-type p53 gene reduced tumor growth in mouse xenograft models. Our purpose was to ascertain the safety and therapeutic potential of adenoviral (Ad)-p53 in advanced HNSCC. PATIENTS AND METHODS Patients with incurable recurrent local or regionally metastatic HNSCC received multiple intratumoral injections of Ad-p53, either with or without tumor resection. Patients were monitored for adverse events and antiadenoviral antibodies, tumors were monitored for response and p53 expression, and body fluids were analyzed for Ad-p53. RESULTS Tumors of 33 patients were injected with doses of up to 1 x 10(11) plaque-forming units (pfu). No dose-limiting toxicity or serious adverse events were noted. p53 expression was detected in tumor biopsies despite antibody responses after Ad-p53 injections. Clinical efficacy could be evaluated in 17 patients with nonresectable tumors: two patients showed objective tumor regressions of greater than 50%, six patients showed stable disease for up to 3.5 months, and nine patients showed progressive disease. One resectable patient was considered a complete pathologic response. Ad-p53 was detected in blood and urine in a dose-dependent fashion, and in sputum. CONCLUSION Patients were safely injected intratumorally with Ad-p53. Objective antitumor activity was detected in several patients. The infectious Ad-p53 in body fluids was asymptomatic, and suggests that systemic or regional treatment may be tolerable. These results suggest the further investigation of Ad-p53 as a therapeutic agent for patients with HNSCC.
Direct Evidence for Transplacental Allergen Transfer

Allergies are increasing, and despite deeper insights into the immunologic basis of these diseases, preventive measures are not yet efficient. As the induction of allergic diseases is often triggered in early childhood, perinatal or prenatal preventive strategies would be beneficial. We investigated the transfer of inhalant and nutritive allergens across the human placenta. For this purpose, the maternal side of a placental cotyledon was perfused in vitro with an allergen-containing medium, and a specific ELISA was used to detect the allergens on the fetal side. Both allergens evaluated, birch pollen major allergen Bet v1 and the milk allergen beta-lactoglobulin, could be shown to cross the placenta. The nutritive allergen beta-lactoglobulin was not only transferred across the placenta in all eight experiments, but was also detectable within the first minutes of perfusion. The peak allergen concentration on the fetal side could be increased by addition of human immunoglobulin. For the inhalant allergen Bet v1, transfer was observed in two of 10 placental experiments, and only if human immunoglobulin was added. A pulsatility wave with a frequency of 30–35 min suggested an active transfer mechanism. We conclude that allergens are actively and selectively transferred across the placenta. Therefore, controlled maternal allergen exposure might offer new ways to induce tolerance to specific allergens in the fetus.
Influence of Exclusive Enteral Nutrition Therapy on Visceral Fat in Patients with Crohn's Disease

Background:Mesenteric fat plays an important role in the pathogenesis of Crohn's disease (CD), and a higher ratio of visceral fat area (VFA) to subcutaneous fat area (SFA) is related to complicated disease status. Exclusive enteral nutrition (EEN) is an effective treatment option for patients with CD, and the aims of this study were to assess the effects of EEN on abdominal fat in patients with CD. Methods:Patient data were obtained from a prospectively maintained database. The SFA and VFA were measured in 38 patients with CD before and after 8-week EEN therapy, and the mesenteric fat index (MFI), defined as the ratio of VFA to SFA, was calculated. The correlations between MFI and CD activity index and C-reactive protein level were also evaluated. Results:The median age of the patients in our study was 29 years, and the median duration of disease was 3.05 years. Both VFA (P = 0.029) and MFI (P = 0.021) were significantly decreased in patients after EEN, but no significant change was observed in SFA (P = 0.335). MFI was significantly correlated with CD activity index (r = 0.523, P = 0.001) and C-reactive protein (r = 0.634, P < 0.0001) in patients with active CD before EEN, although no positive correlations were observed in patients after EEN treatment. Conclusions:EEN induction therapy was associated with a significant decrease in VFA in patients with CD, and MFI was significantly correlated with CD activity index and C-reactive protein in active CD. Thus, our data reveal additional beneficial therapeutic mechanisms of enteral nutrition treatment in CD.
Antinociceptive effects of intrathecal 5-HT agonists in sheep.

OBJECTIVES To examine the role of spinal 5-hydroxytryptamine (5-HT) binding sites in nociceptive processing in conscious sheep and to study the role of 5-HT agonists in mediating analgesia. STUDY DESIGN Prospective controlled study. ANIMALS Nine adult healthy female sheep (Swaledale, Swaledale-cross or Clun Forest) weighing 45-65 kg. METHODS Intrathecal (IT) catheters were implanted at the cervical (n = 5) or lumbar (n = 4) level of the spinal cord under general anaesthesia. At least 1 week later, and at 1 week intervals thereafter, the effects of intrathecal Ringer's solution (control), xylazine (100 μg), 5-HT creatinine sulphate (200, 400 and 800 μg), RU24969 (200 μg), α-Methyl-5-HT and 1-(3-Chlorophenyl)-biguanide (CPBG) on the mechanical nociceptive threshold (MT) were studied. Results were plotted as mean variable versus time curves. Areas under portions of the curves (0-30 and 0-60 minutes) were measured and expressed as mean ± standard error. Differences between values for control and drug trials were examined using the two-tailed Student's t-test. RESULTS Baseline values of MT were lower on the hind limbs than on the forelimbs. Intrathecal Ringer's solution did not alter MT in the cervical or lumbar region. Xylazine (100 μg) produced a characteristic elevation in MT between 5 and 60 + minutes. Lumbar IT injection of 5-HT (800 μg) raised the MT more than cervical injection, while cervical injection of RU24969 (200 μg) raised the MT more than lumbar administration. Cervical IT injection of α-Me-5-HT (500 μg) produced a marked and significant increase in MT while lumbar application had no effect. CPBG (500 μg) injection caused no significant effect on MT with either cervical or lumbar applications. CONCLUSIONS The activation of 5-HT1 and 5-HT2 receptors particularly at the cervical level appears to be involved in spinal nociceptive processing in the sheep. CLINICAL RELEVANCE These effects, which lasted about 60 minutes, may have an implication in the development of new analgesic strategies for animals.
KHARON1 Mediates Flagellar Targeting of a Glucose Transporter in Leishmania mexicana and Is Critical for Viability of Infectious Intracellular Amastigotes*

Background: The mechanism for selectively targeting membrane proteins to the flagellum of kinetoplastid parasites is unknown. Results: We have identified a novel protein, KHARON1, which is important for the flagellar targeting of a glucose transporter. Conclusion: KHARON1 is the first protein identified in Kinetoplastida that targets a membrane protein to the flagellum. Significance: KHARON1 may be part of a new flagellar targeting pathway. The LmxGT1 glucose transporter is selectively targeted to the flagellum of the kinetoplastid parasite Leishmania mexicana, but the mechanism for targeting this and other flagella-specific membrane proteins among the Kinetoplastida is unknown. To address the mechanism of flagellar targeting, we employed in vivo cross-linking, tandem affinity purification, and mass spectrometry to identify a novel protein, KHARON1 (KH1), which is important for the flagellar trafficking of LmxGT1. Kh1 null mutant parasites are strongly impaired in flagellar targeting of LmxGT1, and trafficking of the permease was arrested in the flagellar pocket. Immunolocalization revealed that KH1 is located at the base of the flagellum, within the flagellar pocket, where it associates with the proximal segment of the flagellar axoneme. We propose that KH1 mediates transit of LmxGT1 from the flagellar pocket into the flagellar membrane via interaction with the proximal portion of the flagellar axoneme. KH1 represents the first component involved in flagellar trafficking of integral membrane proteins among parasitic protozoa. Of considerable interest, Kh1 null mutants are strongly compromised for growth as amastigotes within host macrophages. Thus, KH1 is also important for the disease causing stage of the parasite life cycle.
MR arthrography of the hip: improved imaging of the acetabular labrum with histologic correlation in cadavers.

OBJECTIVE The objective of this study was to correlate findings on conventional MR imaging and MR arthrography of the hip with pathologic findings in cadavers with abnormal labra to determine (1) the efficacy of MR imaging in assessing labral degeneration, (2) whether delineation of the labrum from the joint capsule is possible, and (3) if the conspicuity of surface abnormalities of the labrum is improved by administering intraarticular contrast material. MATERIALS AND METHODS Twelve cadaveric hip joints were obtained from elderly cadavers. Each hip was examined using fat-suppressed three-dimensional spoiled GRASS (gradient-recalled acquisition in the steady state) (SPGR) imaging and T1-weighted spin-echo imaging before and after intraarticular injection of contrast material. Thirty-six labral sections (three from each hip joint) were evaluated histologically to determine the labral-capsular relationship, the presence of degeneration, and the configuration of the labral base. These findings were correlated with the results of a blinded MR evaluation of these sections. RESULTS Delineation of the labrum from the adjacent joint capsule was possible on SPGR and T1-weighted MR arthrographic images (34 of 36 and 33 of 36 specimens, respectively), but was not consistently possible on standard SPGR and T1-weighted MR images (7 of 36 and 4 of 36 specimens, respectively). The sensitivities and specificities of the various MR sequences in evaluating labral degeneration varied from 50% to 67%, and from 25% to 94%. Increased signal at the base was common in both the normal (n = 12) and the abnormal (n = 24) labrum. CONCLUSION Conspicuity of the acetabular labral complex is enhanced with the intraarticular administration of contrast material. Although MR arthrography did not improve our specificity for diagnosing labral degeneration, the detection of surface abnormalities, particularly those near the base, was significantly improved.
The impact of information on maternal attitudes towards universal neonatal hearing screening

Abstract In order to improve the acceptability of universal newborn hearing screening (UNHS) among parents, several authors have proposed that information about hearing screening be provided to them. The purpose of the present study was to test the hypothesis that mothers who are informed about their baby’s hearing test are more likely to have a positive attitude towards hearing screening than are mothers who are not informed. Information given to mothers was assessed by three items concerning their involvement in their baby’s hearing test. Subjects were 90 mothers who were interviewed during their stay at the maternity unit alter delivery. Mothers’ attitudes towards the screening were assessed through their answer to the following question: ‘Should UNHS be performed despite the possibility that parents become worried by false-positive test results? ’ Mothers who answered ‘Yes’ were categorized as advocates of UNHS, whereas those who answered ‘No’ or ‘Undecided’ were categorized as sceptics. The great majority of mothers (84%) turned out to be advocates. In keeping with the hypothesis, among advocates a significantly higher proportion of mothers were well-informed about the hearing test (78%, versus 50%; p = 0.016), were present at the hearing test (51 %versus 14%; p<0.01) or knew the result of the hearing test (71 % versus 29%; p<0.01). These findings support the view that providing information about the hearing test will positively affect parental altitude towards UNHS.
"Bystander" recruitment of systemic memory T cells delays the immune response to respiratory virus infection

The concept of heterologous T cell immunity postulates that nonspecific memory T cells recruited and reactivated in the context of an unrelated virus infection may contribute to protective antiviral immunity. Pulmonary infection with respiratory syncytial virus (RSV) of mice immune to lymphocytic choriomeningitis virus (LCMV) leads to substantial recruitment of systemic LCMV‐specific memory CD8 T cells to the lung. Using a sensitive TCR‐transgenic model, we show that such "bystander" recruitment to the RSV‐infected lung could induce a single round of cell division among LCMV‐specific T cells. However, it did not change their activation status as assessed by expression of surface markers, the extent or kinetics of IFN‐γ production and cytolytic effector function. Moreover,recruitment of LCMV‐specific bystander T cells not only failed to enhance immunity to RSV, but significantly delayed virus elimination and slightly enhanced RSV‐induced weight loss in non‐transgenic BALB/c mice. This correlated with a delay in the recruitment of RSV‐specific T cells to the lung. These data show that bystander recruitment of heterologous T cells is not necessarily accompanied by bystander activation. More importantly, bystander recruitment of systemic memory T cells can impair antiviral immunity, presumably by interference with the recruitment of specific T cells.
The datafied child: The dataveillance of children and implications for their rights

Children are becoming the objects of a multitude of monitoring devices that generate detailed data about them, and critical data researchers and privacy advocates are only just beginning to direct attention to these practices. In this article, we provide an overview and critique of these varied forms of datafication and dataveillance of children, from in utero through to the school years. Our approach is informed by recent calls for research on children’s rights in the digital age that examines the conditions that give rise to children’s needs and guide provision of resources necessary for development to their full potential, the array of specific harms they may encounter and the significance of and particular opportunities to participate in matters that affect their wellbeing and enable them to play an active part in society. There remains little evidence that specific instruments to safeguard children’s rights in relation to dataveillance have been developed or implemented, and further attention needs to be paid to these issues.
Implications of polygenic risk for personalised colorectal cancer screening.

BACKGROUND We modelled the utility of applying a personalised screening approach for colorectal cancer (CRC) when compared with standard age-based screening. In this personalised screening approach, eligibility is determined by absolute risk which is calculated from age and polygenic risk score (PRS), where the PRS is relative risk attributable to common genetic variation. In contrast, eligibility in age-based screening is determined only by age. DESIGN We calculated absolute risks of CRC from UK population age structure, incidence and mortality rate data, and a PRS distribution which we derived for the 37 known CRC susceptibility variants. We compared the number of CRC cases potentially detectable by personalised and age-based screening. Using Genome-Wide Complex Trait Analysis to calculate the heritability attributable to common variation, we repeated the analysis assuming all common CRC risk variants were known. RESULTS Based on the known CRC variants, individuals with a PRS in the top 1% have a 2.9-fold increased CRC risk over the population median. Compared with age-based screening (aged 60: 10-year absolute risk 1.96% in men, 1.19% in women, as per the UK NHS National Bowel Screening Programme), personalised screening of individuals aged 55-69 at the same risk would lead to 16% fewer men and 17% fewer women being eligible for screening with 10% and 8%, respectively, fewer screen-detected cases. If all susceptibility variants were known, individuals with a PRS in the top 1% would have an estimated 7.7-fold increased risk. Personalised screening would then result in 26% fewer men and women being eligible for screening with 7% and 5% fewer screen-detected cases. CONCLUSION Personalised screening using PRS has the potential to optimise population screening for CRC and to define those likely to maximally benefit from chemoprevention. There are however significant technical and operational details to be addressed before any such programme is introduced.
Heightened stress responsivity and emotional reactivity during pubertal maturation: Implications for psychopathology

Abstract This commentary reviews and reflects on the studies of this special section: studies that collectively provide compelling evidence for meaningful changes in stress- and emotionally reactive psychophysiological systems with the transition from middle childhood into adolescence. The observed changes were complex and often overlaid upon ontogenetic differences in basal levels of activation of these systems. Maturational increases in responsiveness to stressors were stressor dependent and differentially expressed across autonomic and hormonal measures. Pubertal status increased the impact of some affective valence manipulations, although not significantly influencing others, including negative affect-related potentiation of startle/reflexes. Such ontogenetic increases in stressor and affect sensitivity may have implications for developmental psychopathology. Developmental increases in stressor reactivity may normally aid youth in responding adaptively to the challenges of adolescence, but may result in stress dysregulation among at-risk adolescents, increasing further their vulnerability for psychopathology. Pubertal-related increases in sensitivity to emotionally laden stimuli may exacerbate individual predispositions for exaggerated affective processing, perhaps contributing to the emergence of psychological disorders in these youth. Together, these studies, with their innovative use of autonomic, reflexive, and hormonal measures to index age- and pubertal-related changes in reactivity to stressors and affective stimuli, provide promising directions for future research. Some of these, along with a few cautionary notes, are outlined.