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

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Casein kinase iδ mutations in familial migraine and advanced sleep phase.

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine

The Role of the Gouy Phase in the Coherent Phase Control of the Photoionization and Photodissociation of Vinyl Chloride

We demonstrate theoretically and experimentally that the Gouy phase of a focused laser beam may be used to control the photo-induced reactions of a polyatomic molecule. Quantum mechanical interference between one- and three-photon excitation of vinyl chloride produces a small phase lag between the dissociation and ionization channels on the axis of the molecular beam. Away from the axis, the Gouy phase introduces a much larger phase lag that agrees quantitatively with theory without any adjustable parameters.Comment: 4 pages, 4 figure

Longitudinal Sex Differences During Landing in Knee Abduction in Young Athletes

Purpose— The objective of this study was to determine if biomechanical and neuromuscular risk factors related to abnormal movement patterns increased in females, but not males, during the adolescent growth spurt. Methods— 315 subjects participated in two testing sessions approximately one year apart. Male and female subjects were classified based on their maturation status as pubertal or post-pubertal.Three trials of a drop vertical jump (DVJ) were collected. Maximum knee abduction angle and external moments were calculated during the DVJ deceleration phase using a 3D motion analysis system. Changes in knee abduction from the first to second year were compared among four subject groups (female pubertal, female post-pubertal, male pubertal and male post-pubertal). Results— There were no sex differences in peak knee abduction angle or moment during DVJ between pubertal males and females (p\u3e0.05). However, pubertal females increased peak abduction angle from the first to second year (pp=0.90) in the matched developmental stages. Following puberty, the peak abduction angle and moment were greater in females relative to males (angle: female -9.3±5.7°, male -3.6±4.6°, pp=0.017). Conclusion— This study identified, through longitudinal analyses, that knee abduction angle was significantly increased in pubertal females during rapid adolescent growth, while males showed no similar change. In addition, knee abduction motion and moments were significantly greater for subsequent year in young female athletes, following rapid adolescent growth, compared to males

Longitudinal Sex Differences During Landing in Knee Abduction in Young Athletes

Purpose— The objective of this study was to determine if biomechanical and neuromuscular risk factors related to abnormal movement patterns increased in females, but not males, during the adolescent growth spurt. Methods— 315 subjects participated in two testing sessions approximately one year apart. Male and female subjects were classified based on their maturation status as pubertal or post-pubertal.Three trials of a drop vertical jump (DVJ) were collected. Maximum knee abduction angle and external moments were calculated during the DVJ deceleration phase using a 3D motion analysis system. Changes in knee abduction from the first to second year were compared among four subject groups (female pubertal, female post-pubertal, male pubertal and male post-pubertal). Results— There were no sex differences in peak knee abduction angle or moment during DVJ between pubertal males and females (p\u3e0.05). However, pubertal females increased peak abduction angle from the first to second year (pp=0.90) in the matched developmental stages. Following puberty, the peak abduction angle and moment were greater in females relative to males (angle: female -9.3±5.7°, male -3.6±4.6°, pp=0.017). Conclusion— This study identified, through longitudinal analyses, that knee abduction angle was significantly increased in pubertal females during rapid adolescent growth, while males showed no similar change. In addition, knee abduction motion and moments were significantly greater for subsequent year in young female athletes, following rapid adolescent growth, compared to males

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