The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Longitudinal studies of a B cell-derived signature of tolerance in renal transplant recipients.

Biomarkers of transplant tolerance would enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving immunosuppression. To this end, we examined blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling. Using a previously reported tolerant cohort as well as newly identified tolerant patients, we confirmed our previous finding that tolerance was associated with increased expression of B cell-associated genes relative to immunosuppressed patients. This was not accounted for merely by an increase in total B cell numbers, but was associated with the increased frequencies of transitional and naïve B cells. Moreover, serial measurements of gene expression demonstrated that this pattern persisted over several years, although patients receiving immunosuppression also displayed an increase in the two most dominant tolerance-related B cell genes, IGKV1D-13 and IGLL-1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to minimal immunosuppression, showed similar increases in IGKV1D-13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and that it is a useful monitoring tool in prospective trials.

Humeral fracture in arm wrestling: bone morphology as a permanent risk factor. Indications for safety measures in arm wrestling.

BACKGROUND: Arm wrestling has been recognized as a popular and potentially dangerous competition. Reports on injuries related to arm wrestling are increasing. The most important of these injuries are humeral shaft fractures. The generally accepted theory states that the shoulder joint is actively internally rotated against the opponent while the elbow is fixed in flexion resulting in enormous violent torque forces across the humeral shaft. METHODS: The reported fracture morphology seems similar so we theorized that the basis of this fracture type is the bone structure. There is no experimental model of the arm wrestling fracture other than a virtual one. We assess morphology of the humeral bone by means of the bone cutting procedures and to verify the theory that the structure of humeral bone is a basis of the arm-wrestling fracture by means of newly developed model on human bones. RESULTS: Results of the study suggest that the humeral shaft fracture morphology during arm wrestling is based on the spiral structure of the bone combined with the direction of the revolving, rotational force during the match. CONCLUSION: The safety rules of the arm-wrestling match based on results of our experimental study and the literature metaanalysis are also formulate.

Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients.

Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft health. This 1-year, randomized, controlled, open-label, exploratory study assessed two belatacept-based regimens compared to a tacrolimus (TAC)-based, steroid-avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept-mycophenolate mofetil (MMF), belatacept-sirolimus (SRL), or TAC-MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty-nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept-MMF, belatacept-SRL and TAC-MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two-thirds of patients in the belatacept groups remained on CNI- and steroid-free regimens at 12 months and the calculated glomerular filtration rate was 8-10 mL/min higher with either belatacept regimen than with TAC-MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC-based regimen.

Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.

The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.

Visual pigment density in single primate foveal cones.

The feasibility is demonstrated of microspectrophotometric studies on primate photoreceptors aligned at right angles to the test beam, rather than axially illuminated. Pigment densities, and hence absorption per unit thickness, are approximately equal in primate rods and foveal cones. These pigment densities are similar to those reported for frog rods and fish cones.

Isolation and partial characterization of the pancreatic secretory trypsin inhibitor in the rat.

Isolation in a 55% yield of the low molecular weight pancreatic secretory trypsin inhibitor was achieved by gel filtration of an acid extract of whole inactive rat pancreas juice on Sephadex G-50 at pH 2.5 followed by desalting and ion-exchange chromatography on SP Sephadex C-50 at pH 4.5. Two distinct chromatographic fractions were obtained, labeled fraction 1 and 2. Fractions 1 and 2 showed three, respectively two, distinct closely migrating cationic bands on gel electrophoresis in barbital buffer, pH 8.6. Each fraction demonstrated one band on polyacrylamide disc electrophoresis at pH 4.6. The inhibitor is homogenous on gel filtration and on the basis of its stoichiometry with active site titrated rat anionic trypsin. Its molecular weight is approx. 6024. The amino acid composition is included. Rat pancreatic secretory trypsin inhibitor is trypsin-specific and interacts on a 1:1 molar basis with rat trypsin. It is a good inhibitor of bovine trypsin but a poor inhibitor of human cationic trypsin and its binding to trypsin is reversible by acidification. Like other inhibitors of this sort, it is present in about 0.1-0.2% of the total protein content of the juice, and normally exists in its free form. A simple procedure for the production of antiserum to the inhibitor which is a poor antigen is also described.

Livers transplanted from donors after cardiac death occurring in the ICU or the operating room have excellent outcomes.

BACKGROUND: Increasing donor hospital cooperation with donation after cardiac death (DCD) requires the organ procurement organization (OPO) to use current withdrawal of life support (WLS) protocols. Hospital ICU nurses/physicians are comfortable performing the emotionally draining procedure of WLS in the ICU while OPOs are reluctant to accept these donors due to increased warm ischemia (WI). In our area, several hospitals will only allow WLS to occur in the ICU. This study compares liver outcomes from DCD donors where death occurred in the ICU (DCDICU) vs the OR (DCDOR). METHODS: From March 2003 to June 2004, 34 DCD donors were recovered by our OPO. WLS occurred in the ICU for 26 donors (76%) and in the OR for 8 donors (24%). Thirteen of 26 DCDICU and 5 of 8 DCDOR livers were transplanted. Donor demographics, warm ischemic time, cold ischemic time, distance shipped, and recipient functions were analyzed. RESULTS: Eighteen livers were transplanted both locally and at distant transplant centers. Results are outlined in the . CONCLUSIONS: Although DCDICU donors averaged approximately 4 minutes longer WI than DCDOR donors, short-term results for both groups were equivalent. These findings support using DCDICU livers. DCDICU donors have the potential to significantly improve donor hospital cooperation.

Physical restraints in the practice of medicine. Current concepts.

OBJECTIVE: This article reviews the current status of the utilization of physical restraints in the practice of medicine. Based on current data from the reference sources, appropriate guidelines for the utilization of physical restraints in the practice of medicine are presented. DATA SOURCES: A review of the current literature as referenced in the article. Only English-language references were used. STUDY DESIGN: Articles were selected based on a review of articles from Index Medicus, English-language only. Articles were reviewed by the author for validity and appropriateness. DATA EXTRACTION: The guidelines of data quality, validity, and appropriateness were applied to all articles by the author. DATA SYNTHESIS: Restraints are frequently used in the practice of medicine. As many as 85% of nursing home patients will be restrained at some time and up to 17% of hospitalized medical patients will be restrained. This treatment is not always appropriate but there are no current guidelines available for the practicing physician to assist him or her in these decisions. The current use of physical restraints is discussed. The risks of restraints are reviewed and the reasons for restraint use are cited. The question regarding the efficacy of restraints is directly addressed for each of the situations in which restraints are most commonly used. The ethical and legal considerations concerning the use of restraints are reviewed, current concepts are summarized, and guidelines for improved usage of restraints are suggested. CONCLUSIONS: Despite their extensive use, there is virtually no evidence to support the efficacy of restraints. The risks of using mechanical restraints are numerous and well documented. The detrimental psychologic impact of restraints needs to be emphasized. Restraints are inappropriately used if employed because of fear of liability should a patient fall. The proper approach to the patient at risk of falling is to address the contributing factors that place the patient at risk and, where possible, correct them. Restraints are overused in medicine. Guidelines are given to help improve the employment of this potentially harmful practice.

Pheochromocytoma of the broad ligament. Localization by computerized tomography and ultrasonography.

Computerized tomography (CT) and ultrasonography demonstrated a pheochromocytoma of the broad ligament of the uterus in a patient in whom arteriographic findings had been negative. We suggest that either or both of these techniques be used initially because, although they are not histologically specific, they are noninvasive and sensitive. An additional advantage of CT is its ability to evaluate sites of extra-adrenal pheochromocytomas above the diaphragm.

The effect of chronic corticosterone on fear learning and memory depends on dose and the testing protocol.

Chronic exposure to the stress hormone corticosterone (CORT) is known to alter plasticity within hippocampal and amygdalar circuits that mediate fear learning and memory. The purpose of this experiment was to clarify the effects of chronic CORT on Pavlovian fear conditioning, which is dependent on intact hippocampal and amygdalar activity. In particular, we assessed whether the effect of chronic CORT on fear learning and memory is influenced by two factors-the dose of CORT and the order in which rats are tested for freezing to context versus tone cues. Male Long-Evans rats received low-dose CORT (5mg/kg), high-dose CORT (40mg/kg), or vehicle injections once daily for 21days. On day 22, the rats were trained in a fear-conditioning paradigm. On days 23 and 24, the rats were tested for the retrieval of fear memories to context and tone cues in a counterbalanced way-half the rats received context testing on day 23 and then tone testing on day 24 and half the rats received tone testing on day 23 followed by context testing on day 24. Our results revealed dose-dependent effects of CORT on memory retrieval: Rats injected with high-dose CORT froze significantly more than control rats to both context and tone cues regardless of what testing day these cues were presented. However, rats injected with low-dose CORT froze significantly more than control rats to tone cues only. We also found an order effect in that the effects of CORT on freezing were greater on the second day of testing, regardless of whether that testing was to context or tones cues. This order effect may be due to a lack of extinction in the CORT rats. Overall, these results suggest a relationship between stress intensity and testing conditions that should be taken into account when assessing the effect of stress on fear memories.

Limbic but not non-limbic kindling impairs conditioned fear and promotes plasticity of NPY and its Y2 receptor.

Epileptic seizures negatively affect cognition. However, the mechanisms that contribute to cognitive impairments after seizures are largely unknown. Here, we examined the effects of long-term kindling (i.e., 99 stimulations) of limbic (basolateral amygdala, dorsal hippocampus) and non-limbic (caudate nucleus) brain sites on conditioned fear and hippocampal plasticity. We first showed that kindling had no effect on acquisition of a hippocampal-dependent trace fear-conditioning task but limbic kindling impaired the retrieval of these fear memories. To determine the relationship between memory and hippocampal neuronal activity, we examined the expression of Fos protein 90 min after memory retrieval (i.e., 4 days after the last kindling stimulation). We found that limbic kindling, but not non-limbic kindling, decreased Fos expression in the granule cell layer, hilus, CA3 pyramidal cell layer, and CA1 pyramidal cell layer. Next, to investigate a mechanism that could contribute to dampen hippocampal neuronal activity in limbic-kindled rats, we focused on the endogenous anticonvulsant neuropeptide Y (NPY), which is expressed in a subset of GABAergic interneurons and can prevent glutamate release through interactions with its Y2 receptor. We found that limbic kindling significantly decreased the number of NPY-immunoreactive cells in several hippocampal subfields despite minimal staining of the neurodegenerative marker Fluoro-Jade B. However, we also noted that limbic kindling enhanced NPY immunoreactivity throughout the mossy fiber pathway. In these same regions, we observed limbic kindling-induced de novo expression of the NPY Y2 receptor. These novel findings demonstrate the site-specific effects of kindling on cognition and NPY plasticity, and they provide evidence that altered hippocampal NPY after limbic seizures coincides with dampened neural activity and cognitive impairments.

Characterization of circulating insulin in insulin autoimmune syndrome.

We examined the forms of circulating insulin in three patients with the insulin autoimmune syndrome by a method combining gel filtration and reverse phase high performance liquid chromatography (RP-HPLC). Insulin bound to circulating antibody was dissociated by molecular sieve chromatography at acid pH. The free insulin peak eluted from a Sephadex G-50 column was subsequently chromatographed on a Bio-Gel P-30 column. In all three patients, insulin coeluted with normal human insulin. However, when the partially purified insulins, obtained by gel filtration, were applied to RP-HPLC, an abnormally migrating insulin was found in two of three patients. The insulins were more hydrophobic than normal human, porcine, or bovine insulin, but were different from each other. A third patient had only a single insulin peak on RP-HPLC which corresponded to normal insulin. In contrast, the insulin from insulin-treated diabetic patients with antibodies to exogenous insulin corresponded to either porcine or bovine and normal human insulin. The antibodies in the circulation of these patients with the autoimmune syndrome were of the immunoglobulin G type and contained kappa and lambda-chains in the same proportions as antibodies in insulin-treated patients. Autoantibodies could not be distinguished from those secondary to exogenous insulin treatment on the basis of displacement of binding by human, beef, or pork insulin. These results suggest that in certain patients with the insulin autoimmune syndrome, there may be a molecular abnormality of circulating insulin. Whether this comprises a cause for the syndrome or is a result of posttranslational processing of insulin remains to be determined.

Gastritis with valproate therapy.

We have identified ten children who developed gastritis after prolonged anticonvulsant therapy that included either valproic acid or divalproex sodium. Presenting symptoms were primarily feeding difficulties, including anorexia and refusal to eat. Vomiting was present in two thirds of the patients, with diarrhea, weight loss, and abdominal pain occurring less frequently. Occult blood in stool samples was a late development. All patients responded to therapy with H2-receptor antagonists, oral antacids, or both, with prolonged treatment often necessary to prevent relapse. Although gastrointestinal tract side effects are common with the initiation of valproate sodium therapy, feeding difficulties after long-term treatment are less common. Gastritis should be suspected in children receiving valproate therapy when feeding difficulties arise, particularly if the symptoms are persistent or recurrent.

Amino acid sequence analysis, gene construction, cloning, and expression of gelonin, a toxin derived from Gelonium multiflorum.

The plant toxin gelonin is an extremely potent inhibitor of protein synthesis, similar in action to ricin. The mature protein primary sequence was obtained using conventional sequencing techniques. Gelonin was found to be composed of 258 amino acids and contains 21 lysine residues. This toxin shares approximately 33% sequence homology with trichosanthin and ricin A chain. A 774 bp synthetic gene encoding gelonin was synthesized and expressed in E. coli. Recombinant gelonin (approximately 28 kD) expression was monitored and demonstrated by western analysis. Purification and functional activity studies demonstrated that this protein behaves identically to that of the natural product. Recombinant gelonin (RG) thus joins a growing list of recombinant toxins currently available for use in the construction of recombinant immunotoxins composed of gelonin fused to binding domains of antibodies, growth factors, or other cytokines.

False lateralization by subdural electrodes in two patients with temporal lobe epilepsy.

The authors present two patients with medically refractory partial seizures who had invasive recordings with stereotactic depth EEG (SEEG) and subdural electrodes (SDE) as part of their presurgical workup. SDE recordings were falsely lateralizing in both of these patients with pathologically proven mesial temporal sclerosis. In temporal lobe epilepsy, SEEG electrodes should be considered when presurgical studies are discordant.

Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: evidence for failure of dystrophin production in dystrophin-competent myonuclei.

We studied 19 symptomatic female carriers of the Duchenne muscular dystrophy (DMD) gene. Most of these dystrophinopathy patients had had an erroneous or ambiguous diagnosis prior to dystrophin immunofluorescence testing. We assessed clinical severity by a standardized protocol, measured X-chromosome inactivation patterns in blood and muscle DNA, and quantitated the dystrophin protein content of muscle. We found that patients could be separated into two groups: those showing equal numbers of normal and mutant dystrophin genes in peripheral blood DNA ("random" X-inactivation), and those showing preferential use of the mutant dystrophin gene ("skewed" X-inactivation). In the random X-inactivation carriers, the clinical phenotype ranged from asymptomatic to mild disability, the dystrophin content of muscle was > 60% of normal, and there were only minor histopathologic changes. In the skewed X-inactivation patients, clinical manifestations ranged from mild to severe, but the patients with mild disease were young (5 to 10 years old). The low levels of dystrophin (< 30% on average) and the severe symptoms of the older patients suggested a poor prognosis for those with skewed X-inactivation, and they all showed morphologic changes of dystrophy. The random inactivation patients showed evidence of biochemical "normalization," with higher dystrophin content in muscle than predicted by the number of normal dystrophin genes. Seventy-nine percent of skewed X-inactivation patients (11/14) showed genetic "normalization," with proportionally more dystrophin-positive nuclei in muscle than in blood. In 65% of the skewed X-inactivation patients, dystrophin was not produced by dystrophin-positive nuclei; an average of 20% of myofiber nuclei were genetically dystrophin-positive but did not produce stable dystrophin. Biochemical normalization seems to be the main mechanism for rescue of fibers from dystrophin deficiency in the random X-inactivation patients. In the skewed X-inactivation patients, genetic normalization is active, but production failure of dystrophin by dystrophin-normal nuclei may counteract any effect of biochemical normalization. In the skewed X-inactivation patients, the remodeling of the muscle through cycles of degeneration and regeneration led to threefold increase in the number of dystrophin-competent nuclei in muscle myofibers (3.3 +/- 4.6), while dystrophin content was on the average 1.5-fold less then expected (-1.54 +/- 3.38). Our results permit more accurate prognistic assessment of isolated female dystrophinopathy patients and provide important data with which to estimate the potential effect of gene delivery (gene therapy) in DMD.

An adult-onset myopathy characterized by a double ring appearance of muscle fibers.

We report a 33-yr-old man with an unusual neuromuscular disorder characterized by progressive generalized weakness of 3 yr duration whose muscle biopsy showed a double ring appearance in most muscle fibers. This double ring appearance was due to a peripheral outer sarcoplasmic mass and an inner ring of annular myofibrils surrounding a core of normal longitudinally oriented myofibrils. Nerve conduction studies were normal. Electromyography showed fibrillations, positive waves, and increased brief duration, low amplitude, polyphasic potentials.

Small bowel allograft rejection detected by serum intestinal fatty acid-binding protein is reversible.

We hypothesized that, following experimental small bowel transplantation, immunosuppressive therapy initiated on the day of the initial rise in serum intestinal fatty acid-binding protein (I-FABP) would result in graft salvage. In previously published work, we showed that I-FABP was not detectable in the serum of isografted Lewis rats, but could be measured in the peripheral circulation during small bowel allograft rejection. A clinically useful method to monitor trans- planted allografts for rejection should detect the problem early in its evolution so that treatment to reverse the process would salvage a functional organ. Lewis rats served as recipients of LBNF1 out-of-continuity small bowel allografts and were studied in two groups: group I (control) received no immunosuppression and group II received cyclosporine (CsA, 15 mg/kg/d, p.o.) when I-FABP rose to > or = 80 ng/ml. Serum I-FABP was measured daily until the time of sacrifice. Full-thickness graft biopsies were obtained on postoperative days 3 (baseline), 6 or 7 (elevated I-FABP), 10, and 14 (sacrifice). Following transplantation baseline serum I-FABP (day 2 or 3) averaged < or = 10.0 ng/ml. I-FABP remained at baseline through day 5 (range 0-50 ng/ml) in all animals and then rose abruptly on either day 6 or 7 (range 86-150 ng/ml; P < 0.001 vs. baseline). Histology on day 6 or 7 revealed a mild-to-moderate cellular rejection. Cyclosporine therapy reversed the rejection reaction and restored the bowel to normal histology. Serum I-FABP returned to baseline. In untreated animals, serum I-FABP remained elevated for several days and then returned to baseline levels coincident with fulminant rejection and mucosal sloughing. I-FABP was released into the peripheral circulation early in the evolution of acute rejection in this model of small bowel transplantation. Immunosuppressive therapy initiated when elevated levels of I-FABP were detected in the serum resulted in graft salvage. Cyclosporine immunotherapy consistently reversed rejection in this model. This article represents the first report of salvage of small bowel allografts when immunosuppressive therapy was instituted prospectively on the basis of a serum marker. Immunoreactive I-FABP appears to hold significant potential as a biochemical screening tool for acute rejection occurring In small bowell allografts.

A three-year experience with serum anodal trypsinogen as a biochemical marker for rejection in pancreatic allografts. False positives, tissue biopsy, comparison with other markers, and diagnostic strategies.

Serum values of immunoreactive anodal trypsinogen (sAT) have been claimed to correlate well with rejection occurring in pancreatic allografts. We have studied the behavior of sAT in serial serum samples obtained from 39 type I diabetics undergoing whole-organ pancreas transplantation during the past 3 years. Patients had either received a pancreatic allograft simultaneously with a transplanted kidney (SPK, n = 33) or after a previous kidney transplant (pancreas after kidney [PAK] n = 6). The behavior of sAT was studied in relation to the clinical diagnosis of rejection. Graft amylase output for all 39 patients and serum creatinine for the 33 SPK recipients were also studied. Tissue biopsies were obtained from 11 patients with elevated sAT values and a presumptive diagnosis of rejection. Nine of these patients had SPK grafts and simultaneously elevated creatinine values. Tissue was obtained from the simultaneously transplanted kidney; all specimens revealed rejection. Two of the 11 patients had PAK allografts. Biopsies performed on the graft duodenum were consistent with acute rejection. Three additional patients with unchanged sAT values had biopsies for other reasons; these biopsies failed to demonstrate signs of acute rejection. Thus graft biopsy correlated exactly with sAT behavior in every case in which rejection was suspected. Five patients had elevations of sAT not associated with rejection: one resulted from direct trauma, two had outlet obstruction, and two had clinical diagnoses of graft pancreatitis. The sAT was more sensitive and specific than GAO and as sensitive as creatinine for SPK recipients. These studies confirm that sAT is a reliable, graft-specific biochemical marker for the early diagnosis of pancreatic rejection. The use of sAT should allow for the proper timing of graft biopsies and the judicious use of immunosuppressive agents, which will result in increased allograft survival for PAK and pancreas-alone allografts.