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

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

Stable divisorial gonality is in NP

Divisorial gonality and stable divisorial gonality are graph parameters, which have an origin in algebraic geometry. Divisorial gonality of a connected graph $G$ can be defined with help of a chip firing game on $G$. The stable divisorial gonality of $G$ is the minimum divisorial gonality over all subdivisions of edges of $G$. In this paper we prove that deciding whether a given connected graph has stable divisorial gonality at most a given integer $k$ belongs to the class NP. Combined with the result that (stable) divisorial gonality is NP-hard by Gijswijt, we obtain that stable divisorial gonality is NP-complete. The proof consist of a partial certificate that can be verified by solving an Integer Linear Programming instance. As a corollary, we have that the number of subdivisions needed for minimum stable divisorial gonality of a graph with $n$ vertices is bounded by $2^{p(n)}$ for a polynomial $p$

A kinetic study of cation transport in erythrocytes from uremic patients

A kinetic study of cation transport from uremic patients. We previously described in red blood cells (RBCs) from uremic patients on dialysis a reduction in sodium (Na) efflux through the Na, potassium (K) cotransport system (Na,K CoT) while Na efflux through the Na,K pump was normal. We then examined Na efflux in fresh cells and in cells loaded to obtain one level of intracellular sodium (Nai) concentration at about 25 mmol/liter cell. In the present study we used similar cation flux methodology to examine the kinetics of cation efflux through the Na,K pump and Na,K CoT in uremic patients on dialysis. RBCs were Na-loaded to attain five different levels of Nat concentration over a range of 5 to 50 mmol/liter cells using the ionophore nystatin. At each level of Na-loading, the Nai achieved was similar in RBCs from controls and patients. Ouabain–sensitive Na efflux through the Na,K pump showed no difference in rate between normals and dialysis patients. When the kinetic parameters of this transport pathway were considered, the apparent affinity (K0.5) for sodium was not significantly different between controls and patients (18.4 ± 2.3 vs. 20.0 ± 2.6 mmol/liter cell) and the maximal velocity of efflux (Vmax) was also not different between controls and patients (9.6 ± 0.7 vs. 8.5 ± 1.2 mmol/liter cell/hr). Comparison of Nai-activated Na versus K efflux rates through the Na,K CoT in normal subjects demonstrated similar saturation kinetics, (K0.5 15.8 ± 3.3 vs. 12.2 ± 2.8 mmol/liter cell, Vmax0.81 ± 0.1 vs. 0.78 ± 0.1 mmol/liter cell/hr) consistent with the known stoichiometric ratio of 1 Na:l K:2 C1 described for this mechanism. In dialysis patients Nai-activated, Na,K CoT-mediated Na efflux was markedly reduced. Analysis of the kinetic parameters of Na1-activated Na efflux showed that the reduced RBC Na,K CoT is due to reduction in Vmax and not to a change in K0.5 Maximum furosemide–sensitive K efflux rate was also reduced in dialysis patients. However, instead of exhibiting the anticipated saturation kinetics observed for Na, the K efflux rates were high at low levels of Nai and remained unchanged with increasing Nai concentrations. Ouabain- and furosemide-resistant Na and K effluxes were not significantly different between normals and dialysis patients. We conclude that Na efflux through RBC Na,K pump is intact over a wide range of Nai concentrations in dialysis patients. On the other hand, the furosemide–sensitive co-efflux of Na and K, which in normal RBCs displayed a typical 1 Na to 1 K transport characteristic, was quantitatively and qualitatively altered in dialysis patients. The maximum efflux rate of both Na and K was reduced and in addition, the usual stoichiometric ratio for Na and K exit through this furosemide–sensitive pathway was no longer observed

Analytical Techniques to Support Hospital Case Mix Planning

This article introduces analytical techniques and a decision support tool to support capacity assessment and case mix planning (CMP) approaches previously created for hospitals. First, an optimization model is proposed to analyse the impact of making a change to an existing case mix. This model identifies how other patient types should be altered proportionately to the changing levels of hospital resource availability. Then we propose multi-objective decision-making techniques to compare and critique competing case mix solutions obtained. The proposed techniques are embedded seamlessly within an Excel Visual Basic for Applications (VBA) personal decision support tool (PDST), for performing informative quantitative assessments of hospital capacity. The PDST reports informative metrics of difference and reports the impact of case mix modifications on the other types of patient present. The techniques developed in this article provide a bridge between theory and practice that is currently missing and provides further situational awareness around hospital capacity.Comment: 20 pages, 11 tables, 6 figure

Developing A Personal Decision Support Tool for Hospital Capacity Assessment and Querying

This article showcases a personal decision support tool (PDST) called HOPLITE, for performing insightful and actionable quantitative assessments of hospital capacity, to support hospital planners and health care managers. The tool is user-friendly and intuitive, automates tasks, provides instant reporting, and is extensible. It has been developed as an Excel Visual Basic for Applications (VBA) due to its perceived ease of deployment, ease of use, Office's vast installed userbase, and extensive legacy in business. The methodology developed in this article bridges the gap between mathematical theory and practice, which our inference suggests, has restricted the uptake and or development of advanced hospital planning tools and software. To the best of our knowledge, no personal decision support tool (PDST) has yet been created and installed within any existing hospital IT systems, to perform the aforementioned tasks. This article demonstrates that the development of a PDST for hospitals is viable and that optimization methods can be embedded quite simply at no cost. The results of extensive development and testing indicate that HOPLITE can automate many nuanced tasks. Furthermore, there are few limitations and only minor scalability issues with the application of free to use optimization software. The functionality that HOPLITE provides may make it easier to calibrate hospitals strategically and/or tactically to demands. It may give hospitals more control over their case-mix and their resources, helping them to operate more proactively and more efficiently.Comment: 33 pages, 11 tables, 17 figure

Counting Arithmetical Structures on Paths and Cycles

Let G be a finite, connected graph. An arithmetical structure on G is a pair of positive integer vectors d, r such that (diag (d) - A) r=0 , where A is the adjacency matrix of G. We investigate the combinatorics of arithmetical structures on path and cycle graphs, as well as the associated critical groups (the torsion part of the cokernels of the matrices (diag (d) - A)). For paths, we prove that arithmetical structures are enumerated by the Catalan numbers, and we obtain refined enumeration results related to ballot sequences. For cycles, we prove that arithmetical structures are enumerated by the binomial coefficients ((2n-1)/(n-1)) , and we obtain refined enumeration results related to multisets. In addition, we determine the critical groups for all arithmetical structures on paths and cycles

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

Counting Arithmetical Structures on Paths and Cycles

Let G be a finite, connected graph. An arithmetical structure on G is a pair of positive integer vectors d, r such that (diag (d) - A) r=0 , where A is the adjacency matrix of G. We investigate the combinatorics of arithmetical structures on path and cycle graphs, as well as the associated critical groups (the torsion part of the cokernels of the matrices (diag (d) - A)). For paths, we prove that arithmetical structures are enumerated by the Catalan numbers, and we obtain refined enumeration results related to ballot sequences. For cycles, we prove that arithmetical structures are enumerated by the binomial coefficients ((2n-1)/(n-1)) , and we obtain refined enumeration results related to multisets. In addition, we determine the critical groups for all arithmetical structures on paths and cycles