Miracle-dz/UniFAR-FTUs huggingface dataset:
A2/A2B to B Renal Transplantation: Past, Present, and Future Directions

One component of the new national kidney allocation system (KAS) in the United States that was implemented on December 4, 2014, was the allocation of kidneys from A2 and A2B (A, non‐A1 and AB, non‐A1B) deceased donors into blood group B candidates (A2/A2B → B). In so far as this is an important component of the new KAS that has the potential to further increase the access to transplantation for blood group B candidates on the waiting list, most of whom are minority candidates, we will review the body of evidence and historical perspectives that led to its inclusion in the new KAS. This review will also describe prospects for more widespread use of A2/A2B → B transplantation and a novel mechanism of humoral immunosuppression in B patients before and after transplantation with an A2 or A2B kidney.
Energy-Efficient and Metastability-Immune Timing-Error Detection and Instruction-Replay-Based Recovery Circuits for Dynamic-Variation Tolerance

Microprocessor clock frequency (FCLK) is traditionally determined based on maximum supply voltage (Vcc) droop and temperature specifications. Since typical usage patterns usually run at nominal Vcc and temperature, these infrequent dynamic variations severely limit FCLK. The concept of timing-error detection and correction in previous work by Ernst, D. , et al, (2003) is extended and implemented in a test-chip in 65nm CMOS in Bai, P., et al, (2004) to explore the effectiveness of resilient circuits in eliminating Vcc and temperature FCLK guardbands as well as exploiting path-activation probabilities to maximize throughput (TP).
Immune activation and IL‐12 production during acute/early HIV infection in the absence and presence of highly active, antiretroviral therapy

Suppressed IL‐12 production and maladaptive immune activation, both of which are ameliorated by successful highly active antiretroviral therapy (HAART), are thought to play important roles in the immunopathogenesis of chronic HIV infection. Despite the important effects of the immunological and virological events of early HIV infection on subsequent disease progression, IL‐12 production and immune activation in early infection remain under‐defined. To quantify IL‐12 production and immune activation during acute/early HIV infection, in the presence and absence of HAART, we performed a prospective, longitudinal study of participants in the Baltimore site of the Acute Infection and Early Disease Research Program, with cross‐sectional comparison to healthy control subjects. PBMC cytokine productive capacity and plasma immune activation markers [soluble CD8 (sCD8), sCD4, granzyme B, neopterin, β2‐microglobulin, sIL‐2R, sTNFRI, sTNFRII, and IL‐12p70] were quantified by ELISA. Notably, PBMC from patients with acute/early HIV infection exhibited in vivo IL‐12p70 production along with increased, maximal in vitro IL‐12 production. Further, despite evidence from plasma markers of generalized immune activation, no elevation in plasma levels of sCD4 was observed, suggesting relative blunting of in vivo CD4+ T cell activation from the beginning of HIV infection. Finally, despite successful virological responses to HAART, heightened in vivo CD8+ T cell activation, IL‐12 production, and IFN activity were sustained for at least 6 months during primary HIV infection. These data underscore the need for comparative mechanistic analysis of the immunobiology of early and chronic HIV infection.
Reduced T cell expansion by a superantigen as a result of impaired B cell development in mice deficient for the p85α regulatory subunit of PI3K

PI3K plays crucial roles in the immune system. Mice deficient for p85α, a major regulatory subunit of class IA PI3K, show various defects and alterations in B cells, mast cells, macrophages, and DCs, and peripheral T cells are reportedly normal, at least in vitro. In normal mice, long‐term exposure to a SAg, SEA, in vivo induced a high level of the protracted expansion of SEA‐reactive Vβ3+CD4+ T cells, whereas the same treatment induced T cell expansion in p85α‐deficient mice but to a much lesser extent than in normal mice. However, mixed bone marrow chimera mice, which have normal and p85α‐deficient T and B cells, demonstrated equal responses of both T cells following stimulation with a SEA pump. In reciprocal cotransfer experiments of T and B cells from normal and p85α‐deficient mice into Rag2‐deficient mice, followed by SEA stimulation, p85α‐deficient T cells revealed much higher proliferative capacity in the presence of normal B cells than did normal T cells with p85α‐deficient B cells. Histologically, a marked B cell reduction was observed in the follicles and MZ of the spleen, and DCs accumulated in the MZ. In addition, p85α‐deficient B cells had a low level of MHC class II expression. Collectively, these data suggested that the PI3K p85α subunit alters the SAg presentation capacity of B cells and indirectly modulates the magnitude of the T cell response, which may affect the protection against SEA‐containing bacteria.
Role of intestinal mucus and pancreatic proteases in the pathogenesis of trauma–hemorrhagic shock-induced gut barrier failure and multiple organ dysfunction syndrome

The development of the multiple organ dysfunction syndrome (MODS) is one of the leading causes of death in critically ill patients. Owing to its clinical importance, MODS, as well as acute respiratory distress syndrome and systemic inflammatory response syndrome, has been the focus of significant research to delineate its causes as well as potential therapies for it. A large body of research has focused on the role of the gut in the pathogenesis of MODS, with a special focus on the mechanisms of gut injury as well as the processes by which a localized or limited gut injury is transduced into a systemic inflammatory state. Previous studies have focused on the systemic arm of gut ischemia–reperfusion injury and have largely ignored the non-bacterial intraluminal contents of the gut. The current review will present the hypothesis that the luminal contents of the gut, including the mucus gel layer and intraluminal pancreatic proteases as well as the gut flora, are critically involved in the pathogenesis of is.
The high incidence and bioethics of findings on magnetic resonance brain imaging of normal volunteers for neuroscience research

Background: We were finding volunteers for functional magnetic resonance imaging studies with abnormalities requiring referral surprisingly frequently. The bioethics surrounding the incidental findings are not straightforward and every imaging institution will encounter this situation in their normal volunteers. Yet the implications for the individuals involved may be profound. Should all participants have review of their imaging by an expert and who should be informed? Methods: The normal volunteers that were imaged with magnetic resonance (MR) which were reviewed by a consultant neuroradiologist. All participants completed a volunteer consent form in addition to a standard departmental MR safety screening form. The volunteer screening form requires the general practitioner details to be completed and asks the participant to consider closely the possibility and implications of finding an unexpected but potentially serious abnormality before signing. Results: 525 different individuals were scanned as normal volunteers, the mean age was 35-years and 330 were males. Of these 525, 46 had definite significant abnormalities (8.8%), mean age 50-years. Conclusion: We have found a high rate of incidental abnormalities amongst individuals participating in imaging studies at our institution. It is our current practice to inform the research study participant of the findings, counsel them and inform their primary care physician. We think that it is advisable for researchers utilising MR imaging of the brain to have access to trained neuroradiologists, a protocol in place to deal with this problem and take consent in a way that allows the participant to realise the possibility of an abnormal finding.
SENSORY RECEPTORS IN THE PULMONARY VASCULAR BED

Methods are described for perfusing (in the dog):— (1) A head-thorax-preparation in which the systemic and pulmonary circulations are supplied by separate pumps, the systemic blood being oxygenated by isolated perfused lungs from another animal; (2) the entire animal by two separate pumps, the outlet connexions of which are tied into the pulmonary artery and ascending aorta; (3) the entire animal, less the lower limbs, by two separate pumps the outlet of one of which is tied into the abdominal aorta and the outlet of the other inserted into the right ventricle. In all three preparations an increase of pulmonary blood flow gives rise to a slight but definite fall in systemic arterial pressure and a rise or fall in heart rate. These effects do not appear after section of both cervical vagosympathetic nerves. An increase of pulmonary flow causes an acceleration of respiration in some preparations. Obstruction to the outflow of blood from the left auricle is more effective than a rise in pulmonary arterial pressure in producing cardiosystemic reflexes. The possible significance of these results in relation to the evocation of reflexes in consequence of left heart failure and of pulmonary embolism is discussed. The pulmonary arterial pressure may exhibit periodic variations unaccompanied by similar changes in the systemic arterial pressure. We wish to express our thanks to Dr. J. L. Berry and Miss Barbara Petrovskaia for help with some of the experiments, and to the Government Grants Committee of the Royal Society for defraying the expenses of the investigation by a grant to one of us (I. de B. D.).
High MafB expression following burn augments monocyte commitment and inhibits DC differentiation in hemopoietic progenitors

We have previously shown that perturbed bone marrow progenitor development promotes hyporesponsive monocytes following experimental burn sepsis. Clinical and experimental sepsis is associated with monocyte deactivation and depletion of mDCs. Decrease in circulating DCs is reported in burn patients who develop sepsis. In our 15% TBSA scald burn model, we demonstrate a significant reduction in the circulating MHC‐II+ population and mDCs (Gr1negCD11b+CD11c+) with a corresponding decrease in bone marrow MHC‐II+ cells and mDCs for up to 14 days following burn. We explored the underlying mechanism(s) that regulate bone marrow development of monocytes and DCs following burn injury. We found a robust bone marrow response with a significant increase in multipotential HSCs (LSK) and bipotential GMPs following burn injury. GMPs from burn mice exhibit a significant reduction in GATA‐1, which is essential for DC development, but express high levels of MafB and M‐CSFRs, both associated with monocyte production. GMPs obtained from burn mice differentiated 1.7 times more into Mφ and 1.6‐fold less into DCs compared with sham. Monocytes and DCs expressed 50% less MHC‐II in burn versus sham. Increased monocyte commitment in burn GMPs was a result of high MafB and M‐CSFR expressions. Transient silencing of MafB (siRNA) in GMP‐derived monocytes from burn mice partially restored DC differentiation deficits and increased GATA‐1 expression. We provide evidence that high MafB following burn plays an inhibitory role in monocyte‐derived DC differentiation by regulating M‐CSFR and GATA‐1 expressions.
Epigenetic mechanisms of age‐dependent KIR2DL4 expression in T cells

Killer Ig‐like receptor (KIR) expression is mostly restricted to NK cells controlling their activation. With increasing age, KIRs are expressed on T cells and contribute to age‐related diseases. We examined epigenetic mechanisms that determine the competency of T cells to transcribe KIR2DL4. Compared with Jurkat cells and CD4+CD28+ T cells from young individuals, DNA methyltransferase (DNMT) inhibition was strikingly more effective in T cells from elderly adults and the CD4+CD28− T cell line HUT78 to induce KIR2DL4 transcription. In these susceptible cells, the KIR2DL4 promoter was partially demethylated, and dimethylated H3‐Lys 4 was increased, and all other histone modifications were characteristic for an inactive promoter. In comparison, NK cells had a fully demethylated KIR2DL4 promoter and the full spectrum of histone modifications indicative of active transcription with H3 and H4 acetylation, di‐ and trimethylated H3‐Lys 4, and reduced, dimethylated H3‐Lys 9. These results suggest that an increased competency of T cells to express KIR2DL4 with aging is conferred by a selective increase in H3‐Lys 4 dimethylation and limited DNA demethylation. The partially accessible promoter is sensitive to DNMT inhibition, which is sufficient to induce full transcription without further histone acetylation and methylation.
Total Hip Arthroplasty Following Failed Internal Fixation of Acetabular Fractures

Summary Total hip arthroplasty after failed open reduction internal fixation of acetabular fractures can be challenging surgery. Recent studies reported that operative time, blood loss, and complication rates are higher than with primary total hip arthroplasty. Soft tissue scarring, heterotopic bone, fracture nonunion, and retained hardware contribute to this increased complexity of the reconstruction. Despite perioperative difficulties with total hip arthroplasty in this patient population, excellent outcome with modern cementless acetabular components can be expected.
Calcineurin Inhibitor Minimization, Conversion, Withdrawal, and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta‐Analysis

Despite their clinical efficacy, concerns about calcineurin inhibitor (CNI) toxicity make alternative regimens that reduce CNI exposure attractive for renal transplant recipients. In this systematic review and meta‐analysis, we assessed four CNI immunosuppression strategies (minimization, conversion, withdrawal, and avoidance) designed to reduce CNI exposure and assessed the impact of each on patient and allograft survival, acute rejection and renal function. We evaluated 92 comparisons from 88 randomized controlled trials and found moderate‐ to high‐strength evidence suggesting that minimization strategies result in better clinical outcomes compared with standard‐dose regimens; moderate‐strength evidence indicating that conversion to a mammalian target of rapamycin inhibitor or belatacept was associated with improved renal function but increased rejection risk; and moderate‐ to high‐strength evidence suggesting planned CNI withdrawal could result in improved renal function despite an association with increased rejection risk. The evidence base for avoidance studies was insufficient to draw meaningful conclusions. The applicability of the review is limited by the large number of studies examining cyclosporine‐based strategies and low‐risk populations. Additional research is needed with tacrolimus‐based regimens and higher risk populations. Moreover, research is necessary to clarify the effect of induction and adjunctive agents in alternative immunosuppression strategies and should include more comprehensive and consistent reporting of patient‐centered outcomes.
Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis

HIV continues to be a global health crisis with more than 34 million people infected worldwide (UNAIDS: Report on the Global AIDS Epidemic 2010, Geneva, World Health Organization). HIV enters the CNS within 2 weeks of infection and establishes a spectrum of HAND in a large percentage of infected individuals. These neurologic deficits greatly impact the quality of life of those infected with HIV. The establishment of HAND is largely attributed to monocyte transmigration, particularly that of a mature CD14+CD16+ monocyte population, which is more susceptible to HIV infection, across the BBB into the CNS parenchyma in response to chemotactic signals. To enter the CNS, junctional proteins on the monocytes must participate in homo‐ and heterotypic interactions with those present on BMVECs of the BBB as they transmigrate across the barrier. This transmigration is responsible for bringing virus into the brain and establishing chronic neuroinflammation. While there is baseline trafficking of monocytes into the CNS, the increased chemotactic signals present during HIV infection of the brain promote exuberant monocyte transmigration into the CNS. This review will discuss the mechanisms of monocyte differentiation/maturation, HIV infectivity, and transmigration into the CNS parenchyma that contribute to the establishment of cognitive impairment in HIV‐infected individuals. It will focus on markers of monocyte subpopulations, how differentiation/maturation alters HIV infectivity, and the mechanisms that promote their increased transmigration across the BBB into the CNS.
Rapamycin Interferes With Postdepletion Regulatory T Cell Homeostasis and Enhances DSA Formation Corrected by CTLA4‐Ig

Previously, we demonstrated that alemtuzumab induction with rapamycin as sole maintenance therapy is associated with an increased incidence of humoral rejection in human kidney transplant patients. To investigate the role of rapamycin in posttransplant humoral responses after T cell depletion, fully MHC mismatched hearts were transplanted into hCD52Tg mice, followed by alemtuzumab treatment with or without a short course of rapamycin. While untreated hCD52Tg recipients acutely rejected B6 hearts (n = 12), hCD52Tg recipients treated with alemtuzumab alone or in conjunction with rapamycin showed a lack of acute rejection (MST > 100). However, additional rapamycin showed a reduced beating quality over time and increased incidence of vasculopathy. Furthermore, rapamycin supplementation showed an increased serum donor‐specific antibodies (DSA) level compared to alemtuzumab alone at postoperation days 50 and 100. Surprisingly, additional rapamycin treatment significantly reduced CD4+CD25+FoxP3+ T reg cell numbers during treatment. On the contrary, ICOS+PD‐1+CD4 follicular helper T cells in the lymph nodes were significantly increased. Interestingly, CTLA4‐Ig supplementation in conjunction with rapamycin corrected rapamycin‐induced accelerated posttransplant humoral response by directly modulating Tfh cells but not Treg cells. This suggests that rapamycin after T cell depletion could affect Treg cells leading to an increase of Tfh cells and DSA production that can be reversed by CTLA4‐Ig.
Acute and chronic effects of pneumatic lumbar support on muscular strength, flexibility, and functional impairment index

This research project was designed to assess the causal influence of wearing an “air belt”; (pneumatic lumbar support) on the development of muscular strength, hip and back flexibility, and a functional impairment (pain) index. Thirty subjects were randomly selected from a pool of individuals who were diagnosed as having muscular strain/sprain of the lower back by an orthopedic‐neurologic examination. They were graded as mild, moderate, or severe. Subjects in the treatment and control groups were matched according to gender and grade of strain/sprain. Each subject was tested initially, again after I hour, 3 weeks into the program, and finally post‐tested after 6 weeks of therapy or control. Subjects in the treatment group were required to wear the air belt for 1 hour after a pretest, then for 6 hours a day, 5 days a week for the 6 weeks of rehabilitation. Gain scores were analyzed using an analysis of covariance (ANCOVA) with age and pain as the covariates, p ≤ s 0.05. Muscular strength improved 4.9% afte.
The cost of autonomy: estimates from recent advances in living donor kidney transplantation

Autonomy, an individual's right to make personal decisions regarding his/her own health, represents one of the major ethical principles of medicine. While there are many examples citing the benefits this right provides for the individual, the impact that personal healthcare decisions have on others is often neglected. Here, evidence from end-stage renal disease is reviewed to hypothesise the creation of a universal kidney donation programme that although provides unparalleled benefits to its citizens, relies on the participation of a large proportion of the society. Given that this essay also addresses the public's major concerns regarding kidney donation, one of the only remaining implementation barriers is the individuals' right not to participate. Therefore, irrespective of the humane and complex emotionally laden reasons for not enrolling in such programmes, this essay provides some estimates of the significant resource and quality of life costs associated with autonomy. Assuming humans are competent to make informed personal healthcare choices, similar to recent efforts to increase awareness about the negative impact of certain lifestyle choices on global warming, citizens should also be better informed about the medical costs their autonomy has on society.
DHA‐enriched fish oil targets B cell lipid microdomains and enhances ex vivo and in vivo B cell function

DHA is a n‐3 LCPUFA in fish oil that generally suppresses T lymphocyte function. However, the effect of fish oil on B cell function remains relatively understudied. Given the important role of B cells in gut immunity and increasing human fish oil supplementation, we sought to determine whether DFO leads to enhanced B cell activation in the SMAD−/− colitis‐prone mouse model, similar to that observed with C57BL/6 mice. This study tested the hypothesis that DHA from fish oil is incorporated into the B cell membrane to alter lipid microdomain clustering and enhance B cell function. Purified, splenic B cells from DFO‐fed mice displayed increased DHA levels and diminished GM1 microdomain clustering. DFO enhanced LPS‐induced B cell secretion of IL‐6 and TNF‐α and increased CD40 expression ex vivo compared with CON. Despite increased MHCII expression in the unstimulated ex vivo B cells from DFO‐fed mice, we observed no difference in ex vivo OVA‐FITC uptake in B cells from DFO or CON mice. In vivo, DFO increased lymphoid tissue B cell populations and surface markers of activation compared with CON. Finally, we investigated whether these ex vivo and in vivo observations were consistent with systemic changes. Indeed, DFO‐fed mice had significantly higher plasma IL‐5, IL‐13, and IL‐9 (Th2‐biasing cytokines) and cecal IgA compared with CON. These results support the hypothesis and an emerging concept that fish oil enhances B cell function in vivo.
Temporal IgG Subtype Changes in Recurrent Idiopathic Membranous Nephropathy

Determination of the IgG subtypes within the immune deposits in membranous nephropathy (MN) may be helpful in the differential diagnosis. IgG4 is the predominant subtype in idiopathic MN and recurrent MN, while IgG1, IgG2, and IgG3 subtypes are more common in secondary MN and de novo disease in the allograft. The temporal change of IgG subclasses in individual patients and its correlation with clinical variables have not been studied. We reviewed all posttransplantation protocol and indication biopsies (49) in 18 patients with recurrent MN who underwent transplantation at our center between 1998 and 2013 and performed IgG subtyping (IgG1–4). We tested serum for M‐type phospholipase A2 receptor (PLA2R) autoantibodies or performed PLA2R antigen staining on the kidney biopsy. IgG4 was the (co)dominant IgG subtype in 10 of 14 biopsies at the diagnosis of recurrence regardless of PLA2R association. In 8 of 12 transplantations with serial biopsies, the (co)dominant subtype did not change over time. There was a trend toward IgG1 and IgG3 (co)dominance in biopsies >1 year from recurrence and more IgG1 (co)dominant subtyping in the setting of more‐advanced EM deposits. Treatment with rituximab did not affect the IgG subtype. In conclusion, the dominant IgG subtype did not change over time in recurrent MN.