Simultaneous administration of adjuvant donor bone marrow in pancreas transplant recipients

Objective: The effect of donor bone marrow was evaluated for its potentially favorable effect in the authors' simultaneous pancreas/kidney transplant program. Methods: From July 1994 to January 1999, 177 pancreas transplants were performed, 151 of which were simultaneous pancreas/kidney transplants. All patients received tacrolimus, mycophenolate mofetil, and steroids for immunosuppression (azathioprine was used in the first year of the program). Fifty-three simultaneous pancreas/kidney transplant recipients received perioperative unmodified donor bone marrow, 3 to 6 x 108 cells/kg. Results: Overall actuarial survival rates at 1 and 3 years were 98% and 95% (patient), 95% and 87% (kidney), and 86% and 80% (pancreas), respectively. In the adjuvant bone marrow group, 1- and 3-year survival rates were 96% and 91% (patient), 95% and 87% (kidney), and 83% and 83% (pancreas), respectively. For 98 recipients who did not receive bone marrow, survival rates at 1 and 3 years were 100% and 98% (patient), 96% and 86% (kidney), and 87% and 79% (pancreas), respectively. No pancreas allografts were lost after 3 months in bone marrow recipients, and seven in the non-bone marrow recipients were lost to rejection at 0.7, 6.7, 8.8, 14.6, 24.1, 24.3, and 25.5 months. Twenty-two percent of bone marrow patients were steroid-free at 1 year, 45% at 2 years, and 67% at 3 years. Nineteen percent of the non-bone marrow recipients were steroid-free at 1 year, 38% at 2 years, and 45% (p = 0.02) at 3 years. The mean acute cellular rejection rate was 0.94 ± 1.1 in the bone marrow group and 1.57 ± 1.3 (p = 0.003) in the non-bone marrow group (includes borderline rejection and multiple rejections). The level of donor cell chimerism in the peripheral blood of bone marrow patients was at least two logs higher than in controls. Conclusion: In this series, which represents the largest experience with adjuvant bone marrow infusion in pancreas recipients, there was a higher steroid withdrawal rate (p = 0.02), fewer rejection episodes, and no pancreas graft loss after 3 months in bone marrow recipients compared with contemporaneous controls. All pancreas allografts lost to chronic rejection (n = 6) were in the non-bone marrow group. Donor bone marrow administered around the time of surgery may have a protective effect in pancreas transplantation

Military Law under the Charter

Mr. Corry reviews the courts\u27 approach to the military justice system as it relates to the fundamental rights of service personnel He recognizes that some sacrifice of procedural protections is necessary if the Armed Forces is to fulfill its purpose, but determines that, especially in light of the protections offered by the Canadian Charter of Rights and Freedoms, the courts have adopted an overly passive role in the supervision and review of the military judicial process

Structural Investigation of MscL Gating Using Experimental Data and Coarse Grained MD Simulations

The mechanosensitive channel of large conductance (MscL) has become a model system in which to understand mechanosensation, a process involved in osmoregulation and many other physiological functions. While a high resolution closed state structure is available, details of the open structure and the gating mechanism remain unknown. In this study we combine coarse grained simulations with restraints from EPR and FRET experiments to study the structural changes involved in gating with much greater level of conformational sampling than has previously been possible. We generated a set of plausible open pore structures that agree well with existing open pore structures and gating models. Most interestingly, we found that membrane thinning induces a kink in the upper part of TM1 that causes an outward motion of the periplasmic loop away from the pore centre. This previously unobserved structural change might present a new mechanism of tension sensing and might be related to a functional role in osmoregulation.The study was supported by a grant from the Australian Research Council. The simulations were carried out using computer time from iVEC and a Merit Allocation Scheme on the NCI National Facility at the Australian National University. ED was supported by a Jean Rogerson Postgraduate scholarship and the Beryl Henderson Memorial Grant by the Australian Federation of University Women ACT. Websites of funding agencies: http://nci.org.au/access/merit-allocationscheme/, http://www.ivec.org/ http://www.arc.gov.au/ncgp/default.htm, http://spe.publishing.uwa.edu.au/latest/scholarships/postgraduate/rogerson, http://www. afgw.org.au/what-we-do/scholarships-2/ The authors hereby confirm that the funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Results of pancreas transplantation after steroid withdrawal under tacrolimus immunosuppression

Purpose. The results of steroid withdrawal in pancreas transplant recipients under tacrolimus immunosuppression were analyzed. Methods. From July 4, 1994 until April 30, 1998, 147 pancreas transplantations were performed in 141 patients, including 126 simultaneous pancreas-kidney transplantations, 13 pancreas after kidney transplantation, and 8 pancreas transplantations alone. Baseline immunosuppression consisted of tacrolimus and steroids without antilymphocyte induction. Twenty-three patients were excluded from analysis because of early graft loss in 17 cases, retransplantation in 5 cases, and simultaneous pancreas-kidney transplantation after heart transplantation in 1 patient. Results. With a mean follow-up of 2.8±1.1 years (range 1.0 to 4.8 years), complete steroid withdrawal was achieved in 58 (47%) patients with a mean time to steroid withdrawal of 15.2±8 months (range 4 to 40 months after transplantation). Of the entire cohort of 141 patients, overall 1-, 2-, and 4-year patient survival rates were 98%, 95.5%, and 86%, respectively. Overall 1-, 2-, and 4- year graft survival rates were 83%, 80%, and 71% (pancreas) and 95%, 91%, and 84% (kidney), respectively. Of the 124 patients analyzed for steroid withdrawal, 1-, 2-, and 4-year patient survival rates were 98%, 97%, and 92%, respectively. Overall 1-, 2-, and 4-year graft survival rates were 98%, 91.5%, 83% (pancreas) and 97%, 95%, and 91% (kidney). Patient, pancreas, and kidney survival rates at 1 year were 100%, 100%, and 98% (off steroids) versus 97%, 91%, and 96% (on steroids, all NS) and at 4 years were 100%, 94%, and 95% (off steroids) versus 78%, 68%, and 85% (on steroids, P=0.01, 0.002, and NS, respectively). The cumulative risk of rejection at the time of follow-up was 76% for patients on steroids versus 74% for patients off steroids (P=NS). Seven patients originally tapered off steroids were treated for subsequent rejection episodes, which were all steroid sensitive, and two of these seven patients are currently off steroids. Thirteen patients received antilymphocyte therapy for steroid-resistant rejection, five of whom are now off steroids. Tacrolimus trough levels were 9.3±2.4 ng/ml (off steroids) and 9.7±4.3 (on steroids, P=NS). Mean fasting glucose levels were 98±34 mg/dl (off steroids) and 110±41 mg/dl (on steroids, P=NS). Mean glycosylated hemoglobin levels were 5.2±0.9% (off steroids) and 6.2±2.1% (on steroids, P=0.02), and mean serum creatinine levels were 1.4±0.8 mg/dl (off steroids) and 1.7±1.0 mg/dl (on steroids, P=0.02). Conclusion. These data show for the first time that steroid withdrawal can be safely accomplished in pancreas transplant recipients maintained on tacrolimus-based immunosuppression. Steroid withdrawal is associated with excellent patient and graft survival with no increase in the cumulative risk of rejection

Roving vehicle motion control Quarterly report, 1 Mar. - 31 May 1967

System and subsystem requirements for remote control of roving space vehicle motio

A Quantum-mechanical description of ion motion within the confining potentials of voltage gated ion channels

Voltage gated channel proteins cooperate in the transmission of membrane potentials between nerve cells. With the recent progress in atomic-scaled biological chemistry it has now become established that these channel proteins provide highly correlated atomic environments that may maintain electronic coherences even at warm temperatures. Here we demonstrate solutions of the Schr\"{o}dinger equation that represent the interaction of a single potassium ion within the surrounding carbonyl dipoles in the Berneche-Roux model of the bacterial \textit{KcsA} model channel. We show that, depending on the surrounding carbonyl derived potentials, alkali ions can become highly delocalized in the filter region of proteins at warm temperatures. We provide estimations about the temporal evolution of the kinetic energy of ions depending on their interaction with other ions, their location within the oxygen cage of the proteins filter region and depending on different oscillation frequencies of the surrounding carbonyl groups. Our results provide the first evidence that quantum mechanical properties are needed to explain a fundamental biological property such as ion-selectivity in trans-membrane ion-currents and the effect on gating kinetics and shaping of classical conductances in electrically excitable cells.Comment: 12 pages, 8 figure

Roving vehicle motion control Final report

Roving vehicle motion control for unmanned planetary and lunar exploratio

Galois covers of the open p-adic disc

This paper investigates Galois branched covers of the open $p$-adic disc and their reductions to characteristic $p$. Using the field of norms functor of Fontaine and Wintenberger, we show that the special fiber of a Galois cover is determined by arithmetic and geometric properties of the generic fiber and its characteristic zero specializations. As applications, we derive a criterion for good reduction in the abelian case, and give an arithmetic reformulation of the local Oort Conjecture concerning the liftability of cyclic covers of germs of curves.Comment: 19 pages; substantial organizational and expository changes; this is the final version corresponding to the official publication in Manuscripta Mathematica; abstract update

Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation

BACKGROUND AND OBJECTIVES: Locus heterogeneity is well established in autosomal recessive primary microcephaly (MCPH) and to date five loci have been mapped. However, the relative contributions of these loci have not been assessed and genotype-phenotype correlations have not been investigated. DESIGN: A study population of 56 consanguineous families resident in or originating from northern Pakistan was ascertained and assessed by the authors. A panel of microsatellite markers spanning each of the MCPH loci was designed, against which the families were genotyped. RESULTS: The head circumference of the 131 affected subjects ranged from 4 to 14 SD below the mean, but there was little intrafamilial variation among affecteds (± 1 SD). MCPH5 was the most prevalent, with 24/56 families consistent with linkage; 2/56 families were compatible with linkage to MCPH1, 10/56 to MCPH2, 2/56 to MCPH3, none to MCPH4, and 18/56 did not segregate with any of the loci. CONCLUSIONS: MCPH5 is the most common locus in this population. On clinical grounds alone, the phenotype of families linked to each MCPH locus could not be distinguished. We have also shown that further MCPH loci await discovery with a number of families as yet unlinked