Clinical trial of FK 506 immunosuppression in adult cardiac transplantation

The new immunosuppressive agent FK 506 was used as primary immunotherapy in conjunction with low-dose steroids and azathioprine in 72 patients subsequent to orthotopic cardiac transplantation. Overall patient survival at a mean follow-up of 360 days was 92%. The number of episodes of cardiac rejection (grade 3A or greater) within 90 days of transplantation was 0.95 per patient. The actuarial freedom from rejection at 90 days was 41%. Achievement of this level of immunosuppression is comparable with that of cyclosporine-based triple-drug therapy with OKT3 immunoprophylaxis. Thirty percent of patients were tapered off all steroids, and the average steroid dose in the group who received steroids was 8.6 mg of prednisone per day. The incidence of infection reflected the diminished necessity for steroids: seven major infections (10%) and 11 minor infections (16%). Renal dysfunction occurred during the perioperative period in most patients in this trial. However, the incidence of hypertension was 54% compared with 70% during the cyclosporine era. Ten adults underwent successful rescue therapy with FK 506 after cardiac rejection refractory to conventional immunotherapy. Side effects of FK 506 were notably few, and the results of the trial are encouraging for the future of the cardiac transplant recipient. © 1992

Pressure dependence of the roton spectrum in liquid helium

We suggest consistency checks on neutron scattering data on liquid helium under pressure. The theoretically calculated static structure function S(k|P) leads to pressure dependence of the roton gap, momentum, and curvature in general agreement with experiment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44951/1/10909_2004_Article_BF00654621.pd

Modification of plant cell walls with hydroxycinnamic acids by BAHD acyltransferases

In the last decade it has become clear that enzymes in the "BAHD" family of acyl-CoA transferases play important roles in the addition of phenolic acids to form ester-linked moieties on cell wall polymers. We focus here on the addition of two such phenolics-the hydroxycinnamates, ferulate and p-coumarate-to two cell wall polymers, glucuronoarabinoxylan and to lignin. The resulting ester-linked feruloyl and p-coumaroyl moities are key features of the cell walls of grasses and other commelinid monocots. The capacity of ferulate to participate in radical oxidative coupling means that its addition to glucuronoarabinoxylan or to lignin has profound implications for the properties of the cell wall - allowing respectively oxidative crosslinking to glucuronoarabinoxylan chains or introducing ester bonds into lignin polymers. A subclade of similar to 10 BAHD genes in grasses is now known to (1) contain genes strongly implicated in addition of p-coumarate or ferulate to glucuronoarabinoxylan (2) encode enzymes that add p-coumarate or ferulate to lignin precursors. Here, we review the evidence for functions of these genes and the biotechnological applications of manipulating them, discuss our understanding of mechanisms involved, and highlight outstanding questions for future research

The wear of fixed and mobile bearing unicompartmental knee replacements

Unicompartmental knee replacements (UKR) are an option for surgical intervention for the treatment of single-compartment osteoarthritis. The aim of this study was to compare the wear of a low-conformity fixed-bearing UKR with a conforming mobile bearing UKR under two kinematic conditions, to investigate the effect of implant design and kinematics on wear performance in a physiological knee wear simulator. Under both sets of kinematic conditions, the relatively low-conforming fixed UKR showed lower wear, compared with the more conforming anterior-posterior sliding mobile bearing. However, it should be noted that differences in materials between the two designs also contribute to the relative wear performance of the bearings. The combined wear of the medial and lateral bearings of the fixed-bearing UKR as a ‘total knee’ were significantly reduced compared with a fixed-bearing total knee replacement studied under the same kinematic condition

The neuroblast and angioblast chemotaxic factor SDF-1 (CXCL12) expression is briefly up regulated by reactive astrocytes in brain following neonatal hypoxic-ischemic injury

BACKGROUND: Stromal cell-derived factor 1 (SDF-1 or CXCL12) is chemotaxic for CXCR4 expressing bone marrow-derived cells. It functions in brain embryonic development and in response to ischemic injury in helping guide neuroblast migration and vasculogenesis. In experimental adult stroke models SDF-1 is expressed perivascularly in the injured region up to 30 days after the injury, suggesting it could be a therapeutic target for tissue repair strategies. We hypothesized that SDF-1 would be expressed in similar temporal and spatial patterns following hypoxic-ischemic (HI) injury in neonatal brain. RESULTS: Twenty-five 7-day-old C57BL/J mice underwent HI injury. SDF-1 expression was up regulated up to 7 days after the injury but not at the later time points. The chief sites of SDF-1 up regulation were astrocytes, their foot processes along blood vessels and endothelial cells. CONCLUSION: The localization of SDF-1 along blood vessels in the HI injury zone suggests that these perivascular areas are where chemotaxic signaling for cellular recruitment originates and that reactive astrocytes are major mediators of this process. The associated endothelium is likely to be the site for vascular attachment and diapedesis of CXCR4 receptor expressing cells to enter the injured tissue. Here we show that, relative to adults, neonates have a significantly smaller window of opportunity for SDF-1 based vascular chemotaxic recruitment of bone marrow-derived cells. Therefore, without modification, following neonatal HI injury there is only a narrow period of time for endogenous SDF-1 mediated chemotaxis and recruitment of reparative cells, including exogenously administered stem/progenitor cells

Perioperative donor bone marrow infusion augments chimerism in heart and lung transplant recipients

Background.: We and others have demonstrated that a low level of donor cell chimerism was present for years after transplantation in tissues and peripheral blood of heart and lung recipients; it was associated, in the latter, with a lower incidence of chronic rejection. To augment this phenomenon, we initiated a trial combining simultaneous infusion of donor bone marrow with heart or lung allotransplantation. Methods.: Between September 1993 and January 1995, 15 nonconditioned patients received either heart (n = 10) or lung (n = 5) allografts concurrently with an infusion of unmodified donor bone marrow (3.0 × 108 cells/kg), and were maintained on an immunosuppressive regimen consisting of tacrolimus and steroids. Results.: There was no complication associated with the infusion of donor bone marrow. Chimerism was detectable in 73% of bone marrow-augmented patients up to the last sample tested. Of the 5 control recipients who did not receive bone marrow infusion, only 1 had detectable chimerism by flow on postoperative day 15, which dwindled to an undetectable level by postoperative day 36. None of the patients had evidence of donor-specific immune modulation by mixed lymphocyte reaction. Conclusions.: The combined infusion of donor bone marrow and heart or lung transplantation, without preconditioning of the recipient, is safe and is associated with an augmentation of donor cell chimerism. © 1995 The Society of Thoracic Surgeons

A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression

The decade from 1982 through 1992 witnessed tremendous growth in pediatric cardiac transplantation. At Children's Hospital of Pittsburgh 66 cardiac transplants were performed during this period (age range 7 hours to 18 years). The cause of cardiomyopathy was congenital (n = 30), cardiomyopathy (n = 29), myocarditis (n = 2), doxorubicin toxicity (n = 2), ischemic (n = 1), valvular (n = 1), and cardiac angiosarcoma (n = 1). Nine children (14 %) required mechanical circulatory support before transplantation: extracorporeal membrane oxygenation (n = 8) and Novacor left ventricular assist system (n = 1) (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.). The mean follow-up time was 2 years (range 4 months to 8 years). The overall survival in the group was 67 %. In children with congenital heart disease (>6 months of age) the perioperative (30 day) mortality was 66 % before mid-1988 (n = 10) and 0 % since mid-1988 (n = 11). The late mortality (>30 days) in children with cardiomyopathy transplanted prior to mid-1988 was 66 % (n = 14) and 7 % since mid-1988 (n = 15). Since mid-1988 1- and 3-year survival was 82 % in children with congenital heart disease and 90 % in children with cardiomyopathy. Twenty-six children have had FK 506 as their primary immunosuppressive therapy since November 1989. Survival in this group was 82 % at 1 and 3 years. The actuarial freedom from grade 3A rejection in the FK group was 60 % at 3 and 6 months after transplantation versus 20 % and 12 %, respectively, in the 15 children operated on before the advent of FK 506, who were treated with cyclosporine-based triple-drug therapy (p < 0.001, Mantel-Cox and Breslow). Twenty of 24 children (83 %) in the FK 506 group are receiving no steroids. The prevalence of posttransplantation hypertension was 4 % in the FK 506 group versus 70 % in the cyclosporine group (p < 0.001, Fisher). Renal toxicity in children treated with FK 506 has been mild. Additionally, eight children have been switched to FK 506 because of refractory rejection and drug toxicity. FK 506 has not produced hirsutism, gingival hyperplasia, or abnormal facial bone growth. The absence of these debilitating side effects, together with the observed immune advantage and steroid-sparing effects of FK 506, hold tremendous promise for the young patient facing cardiac transplantation and a future wedded to immunosuppression

Renewing Criminalized and Hegemonic Cultural Landscapes

The Mafia's long historical pedigree in Mezzogiorno, Southern Italy, has empowered the Mafioso as a notorious, uncontested, and hegemonic figure. The counter-cultural resistance against the mafiosi culture began to be institutionalized in the early 1990s. Today, Libera Terra is the largest civil society organization in the country that uses the lands confiscated from the Mafia as a space of cultural repertoire to realize its ideals. Deploying labor force through volunteer participation, producing biological fruits and vegetables, and providing information to the students on the fields are the principal cultural practices of this struggle. The confiscated lands make the Italian experience of anti-Mafia resistance a unique example by connecting the land with the ideals of cultural change. The sociocultural resistance of Libera Terra conveys a political message through these practices and utters that the Mafia is not invincible. This study draws the complex panorama of the Mafia and anti-Mafia movement that uses the ‘confiscated lands’ as cultural and public spaces for resistance and socio-cultural change. In doing so, this article sheds new light on the relationship between rural criminology and crime prevention policies in Southern Italy by demonstrating how community development practice of Libera Terra changes the meaning of landscape through iconographic symbolism and ethnographic performance

Psychological outcomes in advanced cancer patients after receiving genomic tumor profiling results

Background: Comprehensive tumor genomic profiling (CGP) offers hope for personalized treatment for cancer patients when other treatment options have been exhausted. However, receipt of nonactionable or ambiguous results could be an ongoing source of distress. We investigated patterns of hope, anxiety, depression, and CGP-specific anxiety in advanced cancer patients after receiving CGP results and 2–3months later. Method: Participants were enrolled in a longitudinal psychosocial substudy, embedded in the Molecular Screening and Therapeutics Program, and had advanced solid cancers of any histological type with sufficient and accessible tissue for CGP. At T0 (before receiving CGP results), 1,431 participants completed sociodemographic, disease and psychosocial measures. At T1 (1–4 weeks after receiving CGP results) and T2 (2–3 months post-T1), 374 participants completed psychological outcome measures. Predictors of outcomes at T2 were identified using multinomial logistic regression. Results: Approximately 75% of participants did not experience significant hopelessness or distress at T1 and T2.Hope decreased by T2, yet general anxiety and CGP-specific anxiety also decreased. Receiving actionable results did not impact psychological outcomes at T2. At T2, lower hope, and higher anxiety, depression and CGP-specific anxiety were associated with lower self-efficacy. Psychological and demo-graphic factors (age, socioeconomic status, language, medical occupation, urban living, family history of cancer) independently predicted one or more psychological trajectories. Worse health status and perceived susceptibility to cancer progression predicted hope and anxiety trajectories. Conclusion: Further research on interventions to best support patients undergoing CGP with high anxiety, hopelessness, fear of cancer progression, and poorer health is urgently needed