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Polyomavirus-associated nephropathy is an important cause of dysfunction and failure of renal transplants. BK virus is an ubiquitous human polyoma virus that persistently infects the kidney. This otherwise silent infection can reactivate in immunosuppressed individuals, resulting in renal complications. Because polyoma viruses are highly species-specific, we developed a mouse polyoma virus-renal transplant model in order to investigate the pathogenesis of polyomavirus-associated nephropathy. Using this model, we found that polyoma virus preferentially replicates in the allogeneic kidney grafts, accelerating graft failure; thus, this animal model is able to mimic the polyomavirus-associated nephropathy seen in human renal transplant patients. Acute polyoma virus infection of mouse allograft recipients augmented the alloreactive CD8+ T-cell response, while maintaining the anti-viral CD8+ T-cell response. In addition to the known virus-induced cytopathology, these findings demonstrate a potential role for an enhanced anti-donor T-cell response in the pathogenesis of polyomavirus-associated nephropathy.

This project is a collaboration of Woolsey Petroleum Corporation (a small independent operator) and the Kansas Geological Survey. The project will investigate geologic and engineering factors critical for designing hydraulic fracture treatments in Mississippian ''chat'' reservoirs. Mississippian reservoirs, including the chat, account for 159 million m3 (1 billion barrels) of the cumulative oil produced in Kansas. Mississippian reservoirs presently represent {approx}40% of the state's 5.6*106m3 (35 million barrels) annual production. Although geographically widespread, the ''chat'' is a heterogeneous reservoir composed of chert, cherty dolomite, and argillaceous limestone. Fractured chert with micro-moldic porosity is the best reservoir in this 18- to 30-m-thick (60- to 100-ft) unit. The chat will be cored in an infill well in the Medicine Lodge North field (417,638 m3 [2,626,858 bbls] oil; 217,811,000 m3 [7,692,010 mcf] gas cumulative production; discovered 1954). The core and modern wireline logs will provide geological and petrophysical data for designing a fracture treatment. Optimum hydraulic fracturing design is poorly defined in the chat, with poor correlation of treatment size to production increase. To establish new geologic and petrophysical guidelines for these treatments, data from core petrophysics, wireline logs, and oil-field maps will be input to a fracture-treatment simulation program. Parameters will be established for optimal size of the treatment and geologic characteristics of the predicted fracturing. The fracturing will be performed and subsequent wellsite tests will ascertain the results for comparison to predictions. A reservoir simulation program will then predict the rate and volumetric increase in production. Comparison of the predicted increase in production with that of reality, and the hypothetical fracturing behavior of the reservoir with that of its actual behavior, will serve as tests of the geologic and petrophysical characterization of the oil field. After this feedback, a second well will be cored and logged, and procedure will be repeated to test characteristics determined to be critical for designing cost-effective fracture treatments. Most oil and gas production in Kansas, and that of the Midcontinent oil industry, is dominated by small companies. The overwhelming majority of these independent operators employ less than 20 people. These companies have limited scientific and engineering expertise and they are increasingly needing guidelines and technical examples that will help them to not be wasteful of their limited financial resources and petroleum reserves. To aid these operators, the technology transfer capabilities of the Kansas Geological Survey will disseminate the results of this study to the local, regional, and national oil industry. Internet access, seminars, presentations, and publications by Woolsey Petroleum Company and Kansas Geological Survey geologists and engineers are anticipated.

aDivision of Transplantation, Department of Surgery, Emory University, Atlanta, GA bSection of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL *Corresponding author: K. A. Newell, kanewel@emory.edu †K. A. Newell is a co-inventor on a patent application filed by the University of California, San Francisco that describes the expression of B lymphocyte genes in human tolerant renal transplant recipients.

Vancomycin-resistant enterococci (VRE) are increasingly important as pathogens in liver transplant patients. To guide control efforts, we conducted an epidemiological study of the frequency, source, and modes of transmission of VRE at our center.During September 1998 through August 1999, we obtained weekly surveillance cultures from consenting liver transplant patients and surfaces in their rooms. Pooled handwash specimens from personnel also were obtained. Specimens were processed on selective media to detect VRE, and isolates were typed by pulsed field gel electrophoresis. Information was collected from patient records concerning in-hospital treatment and clinical course.Serial cultures were obtained during 33 admissions of 29 patients. VRE were detected in initial specimens from 6 admissions, and nosocomial acquisition of VRE occurred in 12 (44%) of the remaining 27 admissions. Seven different strain types of VRE were detected. The initial site of acquisition was stool in all cases; bile became culture-positive in only two patients. Overall, 16 (55%) of the 29 patients became colonized, usually after transplantation. VRE were detected in environmental cultures during 10 admissions and in 2 of 21 pooled handwashes. No statistically significant differences in clinical status or treatment were found when colonized patients were compared to noncolonized controls. The only VRE infection resulted from a choledochojejunostomy anastomotic leak.Alimentary tract colonization by VRE occurred commonly in liver transplant patients, probably by cross-transmission. The clinical consequences were modest in the patients studied, but colonized transplant patients provide a substantial reservoir for continued VRE transmission in hospitals.

Effective in vivo T-cell depletion is a critical component of many transplantation tolerance protocols. We have previously demonstrated T-cell depletion in miniature swine using a CRM9-based CD3-immunotoxin, pCD3-CRM9. CRM9 is a mutant form of diphtheria toxin (DT) that binds less efficiently than wild-type DT to the DT receptor (proHB-EGF) of primates. In this report, we describe and characterize the dose-dependent neurotoxicity associated with CRM9-based immunotoxin administration in swine.Miniature swine were treated with varying doses of pCD3-CRM9 followed by daily monitoring for symptoms of neuropathy, including limb weakness, paresis, sluggishness, and/or respiratory distress. Animals demonstrating severe respiratory distress were euthanized and peripheral nerve, spinal cord, and skeletal muscle tissue samples were obtained at autopsy for microscopic examination. Unconjugated CRM9 was administered to one animal to define its toxicity independent of the effects of T-cell depletion.Excellent T-cell depletion was obtained using doses of pCD3-CRM9 greater than 0.1 mg/kg. However, neurotoxicity was observed at these doses, as manifested by transient muscle weakness or paresis, which in some cases progressed to respiratory failure and death. Dorsal root ganglia samples revealed pathological changes typical of diphtheritic polyneuropathy. The animal receiving unconjugated CRM9 exhibited the same neurotoxic side effects as those receiving the pCD3-CRM9 conjugate.Administration of pCD3-CRM9 immunotoxin provides excellent T-cell depletion in miniature swine but is associated with significant dose-dependent neurotoxicity. A possible reason for CRM9-associated neurotoxicity in swine, but not primates, is suggested on the basis of a known amino acid difference in the exodomain of the DT receptor (proHB-EGF) of swine compared with that of primates.

This study was designed to identify predisposing factors for tardive dyskinesia (TD) in youths and adults within a large, predominantly developmentally disabled and mentally ill population. The findings support previously reported risk factors for TD, including increasing age, use of anticholinergic medication for those over 40 years old, and long duration of neuroleptic exposure for those over 18 years of age. Higher cumulative levels of "typical" neuroleptic dosage decreased the risk for TD for those over 18. Novel findings included the benefit of personality disorder in individuals 18 to 40 years old and the strong risk factor of profound mental retardation in all age groups. These findings reveal further complex interactions to the risk factors for TD.

Tardive dyskinesia (TD) is a movement disorder that can be expressed at various body effector points, including the face, neck, arms, fingers, legs, and torso. In this prospective longitudinal study researchers examined whether the effector pattern of TD changed during the course of neuroleptic medication withdrawal in adults with mental retardation. Results indicated that the effector pattern of TD changed over the course of neuroleptic withdrawal. Peak dyskinesia was associated with the involvement of more body areas relative to baseline. Although dyskinesia decreased at follow-up and fewer body areas showed signs of dyskinesia, there were still differences in the effector pattern of dyskinesia relative to baseline at periods of 1 to 2 years following neuroleptic withdrawal. These findings suggest that TD is a dynamic disorder associated with changes in both severity and effector pattern over time.

We examined whether dynamic measures of postural stability differentiated persons with stereotyped movement disorder from persons with dyskinetic movement disorder. Participants from three groups (stereotypy, dyskinesia, control) were given a goal-oriented postural stability task, and performance was measured using a force platform and computerized posturographic techniques. The results showed that both movement disorder groups differed from the control group in the posture task. Further, the stereotypy and dyskinesia groups demonstrated markedly different postural movement profiles. The postural motion of the stereotypy group was characterized by greater amplitude and variability but lower complexity than the dyskinesia group. These results provide support for a motor control model of stereotypy.

The purposes of the study were to determine Minnesota dentists' perception of the adequacy of their dental record documentation, assess the general format and contents of dental records they used, and compare the self-reported contents of dental records with guidelines established by the American Dental Association (ADA).Using ADA's published recommendations for structure and guidelines of the dental record from 1987, a 20-item questionnaire was developed, pretested, and used to survey a random sample of 750 Minnesota dentists. Reminder postcards were sent two weeks after the initial survey mailing. A third mailing to nonrespondents, including cover letter and duplicate questionnaire, was conducted three weeks later. Of the surveys returned, 63% (N = 475) were analyzed. Data analyses, including frequencies and tests of chi-square, were conducted using Statview and SPSS.While 15% (N = 69) of respondents used a single-page record format, 44% (N = 209) used multiple forms filed in a specific location within the record. Of the dentists responding, 403 (85%) felt their record documentation was adequate without comparison to any specified criteria. However, statistically significant differences occurred between dentists' perception of record adequacy and the actual presence or absence of ADA criteria for all record components. Data analysis revealed that information was absent 9.4% to 87.1% of the time.A discrepancy exists between dentists' perception of dental record adequacy and the ADA recommendations for structure and guidelines. Inadequate dental record components should be targeted for improvement.

Basaloid carcinomas typically arise in the anal canal and there are only three well-documented cases of this neoplasm reported outside the anal canal, none more proximally than the sigmoid colon. The first occurrence of a basaloid colonic carcinoma arising outside the sigmoid colon, at the splenic flexure, is presented.A splenic flexure mass was resected from a 54-year-old man with a 3-week history of abdominal discomfort, diarrhoea and weight loss. This tumour, like typical anal canal basaloid carcinomas, was composed of islands of basaloid cells with peripheral nuclear palisading; within many islands there was central necrosis and focal squamous differentiation. Ultrastructural and immunohistochemical studies confirmed the basaloid nature and focal squamous differentiation within this neoplasm. Basaloid carcinoma of the anal canal has been associated with human papilloma virus. Using in-situ hybridization, HPV DNA was not detected in this case.Outside the anal canal, it has been postulated that basaloid colonic carcinomas may arise from cloacogenic embryologic rests, squamous metaplastic epithelium, or totipotential basal cells. The location and pathological findings of this tumour suggest that this rare colonic neoplasm arises from a totipotential basal cell.

CD28 antagonists have been shown to promote long-term graft survival and induce donor-specific tolerance. In this study, the role of CD28/B7 costimulation and the relative importance of host versus donor B7 expression in allograft rejection was assessed in a murine abdominal vascularized heterotopic heart transplant model. Wild-type, CD28-deficient, or B7-1/B7-2-deficient C57BL/6 (B6) mice were grafted with allogeneic wild type or B7-1/B7-2-deficient hearts. The results demonstrate allogeneic heart grafts survive long-term in mCTLA4Ig-treated B6 and untreated B7-1/B7-2-deficient B6 recipients but not CD28KO B6 mice. B7-1/B7-2KO B6 recipients treated with anti-CD28 (PV-1) or recombinant human IL-2 rejected the heart transplants indicating that these mice are immunologically competent to reject grafts if costimulatory signals are supplied or bypassed. Finally, there was no difference in rejection between normal animals transplanted with wild-type versus B7-1/B7-2-deficient hearts. These results support a critical role for B7-expressing host antigen presenting cells in the rejection of heart allografts in mice and differences among B7KO and CD28KO animals.

Two-dimensional regionalization can be extended to three dimensions by regarding a sedimentary basin fill as a stack of stratigraphically correlated layers, each of which is treated as a two-dimensional unit. The result is a subdivision of three-dimensional space into homogeneous three-dimensional subunits. Petrophysical parameters can be assigned to each homogeneous unit, producing a generalized layered model of the basin fill that can be used for backstripping to reconstruct the geological history of the basin.

The lip movements associated with dyskinesia in adults with mental retardation were investigated through a dynamic analysis at medication baseline, at the points of the highest level of withdrawal dyskinesia as indexed by the DISCUS rating scale, and at the lowest level of dyskinesia following complete withdrawal of the medication. Results showed that the changes in the amount of lip oscillations following medication reduction and eventual withdrawal were strongly linked to changes in the structural complexity of the dynamics of lip motions. These findings provide evidence that neuroleptic medication reduces the df of the dynamics of the movement output and that this change is inversely related to the level of tardive dyskinetic motion observed in the clinical setting.

Preexisting renal dysfunction has been reported to significantly increase the morbidity and mortality associated with orthotopic liver transplantation (OLT). OLT alone has been recommended for adults and children with end-stage liver disease and reversible causes of renal failure (i.e., hepatorenal syndrome), whereas combined liver and kidney transplantation (LKT) has been shown to be an effective treatment for adults with combined end-stage liver and kidney disease. The purpose of this study was to examine the role of LKT in children.Between October of 1984 and 1997, 385 children less than 18 years of age underwent OLT at the University of Chicago. During this same time period 12 patients underwent LKT. Data were gathered by retrospective review of the patients medical records and by interviews conducted with the patients' families.Actuarial patient survival was comparable for children who underwent OLT alone and LKT (69% versus 67% at 5 years). All allograft losses in the LKT group were the result of patient death and occurred within the first 90 postoperative days. Factors associated with decreased patient survival included severity of illness as reflected by United Network of Organ Sharing status and LKT after failed OLT or cadaveric renal transplant.In children with concomitant endstage liver and kidney disease, LKT can be considered an effective therapeutic option in selected patients. Long-term patient survival in patients undergoing LKT is comparable to that of patients with normal renal function undergoing OLT alone.

The adiabatic transformability hypothesis for non-conservative, non-rate-limited biological systems put forward by Kugler and Turvey [Kugler PN, Turvey MT (1987) Information, natural law, and the self-assembly of rhythmic movements, Erlbaum, Hillsdale, NJ] is evaluated in a ball-bouncing task as a function of skill level. We hypothesized that, when a basketball player increases or decreases the frequency of his limb motion in a vertical ball-bouncing task, the transformation should be characterized as adiabatic. Confirmation of this hypothesis would lend support to the body of knowledge that suggests that physical-biological laws guide the behavior of people engaged in motor tasks, including their acquisition of skill. We videotaped and analyzed four participants - two intermediates and two experts - bouncing a ball from various heights, and measured the energy and kinematic relations of the ball and the participants' body segments. The task presents a challenge to certain predictions of the adiabatic hypothesis in evaluating changes in movement velocity (v) or frequency (f), and energy as adiabatic transformations. Among these are the constant relation between kinetic energy (Ek) per cycle and v, constancy of energy dissipated per cycle (Et) over changes in v and Ek, the ratio of Ek to Et per cycle (the "Q" values), and the relation of amplitude to v. From our observations, which are examined in regard to the insights of Kugler and Turvey about the relation of Ehrenfest's adiabatic theorem to biological systems, we confirm the basic adiabatic character of the task in analyzing both the ball alone and the relations of various body segments. In the segmental frame of reference, we found evidence of differences in energy-kinematic relations in the Q values between skill levels.

Plastic bread-bag clips have been identified as a cause of local perforation or obstruction at many sites in the gastrointestinal tract. This study is the largest case series yet reported, consisting of 3 cases presenting as small-bowel perforation, 1 case in which the clip was found incidentally in the small bowel at laparotomy during vascular surgery and 1 case in which the clip was found incidentally in the small bowel at autopsy. In all cases there was no radiographic evidence to suggest a foreign body in the gastrointestinal tract. People older than 60 years of age who have either partial or full dentures seem to be particularly at risk for the accidental ingestion of these devices. If accidentally ingested, plastic bread-bag clips represent a significant health hazard. As the population ages, small-bowel perforation secondary to ingestion of such clips may occur with increasing frequency. The authors recommend elimination or redesign of the clips, to prevent their being swallowed and becoming impacted in the small bowel or to allow them to be identified in the gastrointestinal tract by conventional radiography.

This study examined the influence of body scale on the grip configurations used by young children (6-12 years old) to displace cubes that varied systematically in size (L) and mass (M). It was determined if the scaling relation we had developed for adults K = log Lc + ((log Mc)/(a + bLh + cMh)) where L(c) and M(c) is the length side and mass of the cubes, respectively, and L(h) and M(h) are the length and mass of the hand, respectively, it would also predict the change in grip configurations across this age range in a fashion consistent with the principle of similitude. The statistical and scaling analyses revealed that the invariant body-scaled relation that specified the adult grip transitions also held for the 6- to 12-year-old children.

Self-injurious behavior was examined in a case study of head-banging by an 8-year-old girl with profound mental retardation and an autistic disorder. Trajectories of the arm movements and impact forces of the head blows were determined from a dynamic analysis of videotapes. Results revealed a high degree of cycle-to-cycle consistency in the qualitative dynamics of the limb motions, with one hand motions being faster than those with two hands (inphase and antiphase) and the motions with the helmet about 25% faster than those without the helmet. The impact force of SIBs as a percentage of body weights are near the low end of forces generated in boxing blows and karate hits.

Background. The relative contribution of CD8 and CD4 T cells to allograft rejection remains an unresolved issue. Experimental results suggest that the relative importance of these T-cell subsets may vary depending on the model used and the organ studied. We have previously shown that treatment of murine recipients of intestinal allografts with a depleting anti-CD8 or a depleting anti-CD4 monoclonal antibody (mAb) significantly inhibited allograft rejection. This study was undertaken to further examine the contribution of CD8 and CD4 T cells to the rejection of intestinal allografts. Methods. Intestinal allografts from B6C3F1/J (C57BL/6 x C3H/HeJ) mice were transplanted into C57BL/6 recipients. Recipient groups included mice with an acquired deficiency in CD8 or CD4 T cells caused by treatment with depleting mAb or mice genetically deficient in CD8 or CD4 T cells as a result of disruption of the genes encoding major histocompatibility complex (MHC) class I, MHC class II, CD8, or CD4. In all cases, rejection was assessed histologically at predetermined time points. In some recipient groups, graft function was also assessed using a maltose absorption assay. Results. Rejection, assessed between days 10 and 28 after transplantation, was significantly inhibited in mice deficient in CD8 or CD4 T cells after treatment with depleting mAb. In contrast, mice genetically deficient in either CD8 T cells (MHC class I or CD8 knockouts) or CD4 T cells (MHC class II or CD4 knockouts) rejected intestinal allografts promptly. Both histologic and functional evaluation of anti-CD8 mAb-treated mice on day 60 showed that the inhibition of rejection persisted even after the return of a substantial number of CD8 T cells. Although intestinal allografts from anti-CD8 mAb-treated mice displayed little to no evidence of rejection on day 60 after transplantation, these mice were able to reject both donor and third-party skin grafts. Conclusions. These results demonstrate that the inhibition of intestinal allograft rejection associated with mAb treatment is not attributable solely to depletion of CD8 or CD4 T cells. Furthermore, anti-CD8 mAb administration did not induce donor-specific tolerance or cause nonspecific immune suppression, as indicated by the skin-grafting experiments. Our findings suggest that at least some depleting mAbs mediate their protective effect on allograft rejection via an alternative mechanism such as the induction of a regulatory cell population(s).

A MAJOR factor preventing the more widespread clinical application of intestinal transplantation is the unusual frequency and severity of allograft rejection. Using a murine model of intestinal transplantation, we have previously shown that allograft rejection was dependent on ab, but not gd, T cells and that this rejection could be significantly inhibited by tacrolimus, an immunosuppressive agent with potent anti-T-cell properties. In this study, the murine model was used to examine further the role of CD8 and CD4 T cells in the rejection of intestinal allografts.

Background. The limited supply of organ donors has led some groups to reconsider the role of retransplantation. Historically, except for children with malignancies, extrahepatic sources of sepsis, or severe irreversible neurologic injuries, our institution has offered all children with failing liver grafts the option of retransplantation regardless of their current severity of illness. The purpose of this study was to examine the outcome of hepatic retransplantation in children in an attempt to identify factors predictive of outcome and to assess the results of our approach to retransplantation. Methods. Between-October 1984 and December 1995, 314 children less than 15 years of age underwent a total of 441 liver transplants. Data were obtained retrospectively by review of hospital records. Results. With a mean follow-up period of 5.3±2.7 years, the overall patient survival rates at 1 and 5 years were 77.1% and 67.1%, respectively. Primary allograft survival rates were 65.6% and 56.5%, respectively. Of the 137 patients who developed failure of their primary allograft, 92 underwent retransplantation (29.3% of all primary transplants). Both patient and allograft survival rates were significantly decreased after retransplantation (P

A review of research on complementary and alternative treatments, specifically mind-body techniques, was conducted at Stanford University. The goals of the review were to establish a comprehensive literature review and to provide a rationale for future research concerning successful aging.Computerized searches were conducted using MEDLINE, PsychInfo, Stanford Library, Dissertation Abstracts, Lexus-Nexus, the Internet, and interviews conducted with practitioners. All studies since 1990 that examined mind-body treatments of cardiovascular disorders in the elderly were included. Mind-body practices evaluated were social support, cognitive-behavioral treatment, meditation, the placebo effect, hope, faith, imagery, spiritual healing, music therapy, hypnosis, yoga, t'ai chi, qigong and aikido. Studies conducted after 1990 were a priority, but when more recent literature was scarce, other studies using randomized, controlled trials were included.Mind-body techniques were found to be efficacious primarily as complementary and sometimes as stand-alone alternative treatments for cardiovascular disease-related conditions. Studies provided evidence for treatment efficacy, but the need for further controlled research was evident.Reviewers found only a handful of randomized, controlled research studies conducted in the United States. As a result, there is a lack of replicated studies with which to determine appropriate treatment dosage and the mechanisms by which many of the practices work. Compelling anecdotal evidence, the presence of some controlled research, overall cost effectiveness, and the lack of side effects resulting from mind-body treatments make further investigation a high priority.

Vancomycin-resistant Enterococcus (VRE) has become a significant nosocomial pathogen. For this study, the records of 325 patients who underwent orthotopic liver transplantation (OLT) were reviewed. Thirty-four patients were infected by VRE (incidence of 10.5%, 14% in adults vs. 5% in children, P < 0.01). Common features of patients who developed infections with VRE included previous antibiotic use (25 patients, 15 of whom received vancomycin), co-infection by other pathogens (28 patients), and relaparotomy following OLT (20 patients). Pulmonary and/or renal failure preceded infection by VRE in 11 and 4 adult patients, respectively. Biliary complications were exceedingly common in patients infected by VRE (28 patients) and significantly increased the risk of infection by VRE (21.5% vs. 3.1% for patients without biliary complications, P < 0.0001). Mortality associated with VRE infections was high (56% vs. 19% for patients not infected by VRE, P < 0.0005). The most frequent cause of death was sepsis (16 of 19 patient deaths), often polymicrobial. The high incidence of infection by VRE following OLT, the lack of effective antibiotics for the treatment of VRE, and the association of VRE with patient mortality emphasizes the need to define the risk factors associated with VRE infection. We suggest early surgical intervention to treat complications that may predispose patients to infection by VRE.

Although FK 506 has been shown to effectively reverse refractory renal allograft rejection, its ability to reverse accelerated renal allograft rejection as a primary agent has not been specifically addressed. Herein evidence of the ability of FK 506 to reverse accelerated renal allograft rejection is presented. A 16-yr-old highly sensitized (PRA 75%) male underwent a second cadaveric renal transplant procedure. Despite induction immunosuppression with ATGAM, cyclosporine, azathioprine, and corticosteroids, a marked elevation in serum creatinine (1.6--2.1 ng/dl) and reduction in urine output (4000 ml/d--1000 ml/d) were observed on the sixth post-transplant day. Renal allograft biopsy performed at that time revealed typical features of accelerated rejection including neutrophil margination in glomerular and interstitial capillaries, and C3, IgG, and fibrin deposition in glomerular and interstitial capillaries (by immunofluorescence). FK 506 therapy was promptly instituted and ATGAM therapy discontinued. Serum creatinine peaked within 3 d of FK 506 therapy (2.5 mg/dl) and subsequently progressively dropped to 1.2 mg/dl. Repeat biopsy on FK 506 treatment day 12 revealed marked histologic improvement. Renal function remains excellent (1.3 mg/dl) 18 months after initiation of FK 506 therapy, and recurrent rejection has not been observed. This experience provides evidence that FK 506 therapy may effectively reverse accelerated renal allograft rejection, and that it provides a means for treating antibody-mediated mechanisms of allograft rejection.

We developed an akathisia rating scale for use with persons who have mental retardation and screened for the occurrence of akathisia in three samples: 66 adults receiving maintenance neuroleptic treatment, 20 adults not receiving neuroleptics, and 8 adults undergoing neuroleptic dose reduction. The scale had an acceptable level of interrater reliability and validly measured group differences related to neuroleptic treatment status. Using an empirically derived cut-off-score, we estimated the prevalence rate for akathisia to be 5% in neuroleptic-free subjects, 17% in neuroleptic-maintenance subjects, and 25% in neuroleptic-reduction subjects. Akathisia, dyskinesia, and stereotypy manifested as qualitatively different movement topograhies. The occurrence of dyskinesia stereotyped movement disorder was associated significantly with an increased occurrence of akathisia.

Although bladder drainage of pancreatic exocrine secretions has been reported to decrease morbidity and improve pancreas allograft survival, significant complications remain associated with this technique. Furthermore, this technique requires systemic venous drainage of pancreas allografts. Evidence suggests that portal venous drainage of pancreas grafts prevents hyperinsulinemia and improves lipoprotein composition. This report documents our initial experience with portal venous and enteric exocrine drainage of pancreas allografts (portal/enteric technique) and compares it with the standard technique of systemic venous and bladder exocrine drainage (systemic/bladder technique). Patient and allograft survival, as well as allograft function, were comparable for the two procedures. There were no significant technical complications in this pilot series. Enteric exocrine drainage was associated with a significant reduction in the incidence of acidosis and dehydration when compared with bladder drainage (P

UNLABELLED Protocol biopsies were performed to define the histologic response to tacrolimus therapy in patients with refractory acute renal allograft rejection. Renal allograft biopsies were performed at defined intervals after initiation of tacrolimus therapy. Protocol biopsies were performed before tacrolimus therapy (within 48 hr of initiation of therapy) and after 1 week of therapy. If the 1-week biopsy did not show rejection reversal, repeat protocol biopsies were obtained at 1- to 2-week intervals, until histologic reversal was observed. Additional biopsies were obtained at 4 weeks and at 8-12 weeks after initiation of tacrolimus therapy. Indicated biopsies were also performed to evaluate increases in serum creatinine. A total of 92 biopsies were performed in 23 patients (average 4.0 biopsies/ patient). Biopsies were performed in each patient immediately before starting tacrolimus therapy (23 biopsies), and 69 biopsies (3.0 biopsies/patient) were performed during tacrolimus therapy. Rejection diagnosis was based on strict Banff criteria. Pretacrolimus biopsies demonstrated mild acute rejection in 64% of patients and moderate acute rejection in 36%. One week after initiation of tacrolimus therapy, protocol biopsies revealed the following: no rejection (60%), improvement (13%), no change (20%), and worsening rejection (7%). Histologic changes at 1 week did not correlate with changes in renal function, as 63% of patients that showed histologic improvement or reversal during the first 2 weeks of therapy did not show improvement in serum creatinine. A lack of histologic improvement (or worsening) at 1 week was demonstrated in a significant proportion of patients (27%); increased tacrolimus dosing provided rejection reversal or improvement in 1-2 weeks in each of these patients. Recurrent rejection was diagnosed on eight biopsies in seven patients, however six episodes were diagnosed by protocol biopsies alone (i.e., in the absence of an elevation in serum creatinine). Delayed improvement in renal function, despite histologic reversal, was likely due to physiologic effects of tacrolimus (i.e., afferent arteriolar vasoconstriction), as histologic evidence of tacrolimus toxicity was not observed during the first 2 weeks of therapy. Histologic evidence of tacrolimus nephrotoxicity (nodular arteriolar hyalinosis) was found in 21% (15 of 69) of biopsies in 39% of patients (9 of 23) at a median time of 60 days (range 12-150 days). Tacrolimus dose and blood levels (by IMx assay) did not correlate with development of clinically silent or clinically evident nephrotoxicity. IN CONCLUSION 1) protocol biopsies provide information that allows individualization of tacrolimus rejection therapy, 2) histologic resolution of rejection often precedes biochemical improvement, 3) histologic evidence of tacrolimus nephrotoxicity is seldom observed in the first 2 weeks of therapy, and 4) clinically silent recurrent rejection and clinically silent tacrolimus nephrotoxicity are observed with significant frequency during tacrolimus therapy for refractory renal allograft rejection.

Despite numerous options for pediatric transplantation, closure of the abdominal wall after liver transplantation is occasionally difficult, resulting in increased abdominal pressure and possible vascular compromise. Since 1990, we have utilized a 2-mm thick sheet of polytetrafluoroethylene (PTFE) to overcome this situation in 21 transplants for 17 patients. The median age was 0.9 months. Ten of the 21 transplants utilized full-size grafts. The donor to recipient weight ratio was 1.7+/-1.2. Cadaveric left lateral segments were used in 8 of 21 transplants (weight ratio, 7.4+/-5.9), living donor left lateral segments were used in 3 of 21 transplants (weight ratio, 13.2+/-6.7). We were able to remove 14 of 21 patches with one additional operation, whereas 4/21 patches required two operations and 3/21 required three operations. Reoperations identified two cases of hepatic artery thrombosis not previously identified by duplex ultrasonography. There were no technical problems or adverse effects associated with the use of the PTFE patch. After patch removal, the fascia was closed with a nonabsorbable suture and the skin was allowed to close by secondary intention. There were no wound infections, portal vein thrombosis, or fluid and electrolyte abnormalities. PTFE is a safe, temporary alternative to primary wound closure in liver transplantation when the size of the graft or intestinal and graft edema does not allow conventional closure of the abdomen. Infectious, fluid/electrolyte, or ventilatory complications were not noted. The necessity of a second-look operation is useful in assessing the graft and vascular patency. The majority of patches can be removed within the first postoperative week.

The aim of this study was to determine the outcome of venous conduits used in living donor liver transplantation (LDLT). We analyzed the portal vein complications in 66 LDLT recipients and 48 cadaveric reduced-size liver transplant (RLT) recipients performed from November 1989 through January 1995. Three different venous conduits were utilized in the LDLT recipients: Group 1, reconstructed vein from the living donor, n=18; Group 2, cadaveric cryopreserved iliac vein, n=37; and Group 3, cadaveric cryopreserved femoral vein, n=11. Overall, 47 percent of the patients were less than one year of age; the age distribution was not significantly different among the groups. The incidence of early thrombosis was significantly greater in LDLT Group 1, (33%) than any of the other groups (LDLT Group 2, 8%; LDLT Group 3, 9%; and RLT, 4%:P0.0005 vs. reduced graft and0.03 vs. other LDLT groups). The incidence of late portal vein stenosis or thrombosis was significantly higher in the LDLT Group 2, (51%) than any of the other groups (LDLT 1, 16%; LDLT Group 3, 9%; RLT 4%;P0.005 vs. cadaveric and0.02 vs. LDLT Group 1 and LDLT Group 3). Five year arterial graft and patient survival for patients who have experienced portal vein thrombosis or stenosis is 61% and 67%, respectively, versus 67% and 71% for those patients who have not experienced portal vein pathology, P=ns. Based on this experience, we recommend avoiding the use of cryopreserved iliac vein for portal vein reconstruction in liver transplantation. Every effort should be taken to eliminate the need for venous conduits in liver transplantation. If venous conduits must be utilized, cryopreserved femoral veins seem to provide superior patency rates. Careful clinical and ultrasonopraphic monitoring of patients at high risk for late venous thrombosis permits therapy with excellent graft and patient survival.

We screened for the occurrence of dyskinetic and stereotypic movement disorders using item-independent screening protocols to determine whether these forms of movement disorder can be distinguished among adults with mental retardation. Stereotypies and dyskinesias were reliably distinguished in terms of topography. Tardive dyskinesia occurred in 18.2% of a cohort of individuals receiving chronic neuroleptic treatment. Stereotypic movement disorder was associated with increased dyskinesia scores and increased prevalence of tardive dyskinesia. Increased dyskinesia scores were also found for subjects exhibiting stereotypy who had been free of neuroleptic treatment for 3 years. Results indicate that dyskinesia and stereotypy are discriminable movement disorders and provide preliminary support for the hypothesis that they may be related by common mechanisms.

FK 506 has proven to be an effective immunosuppressive agent in liver transplantation, but its role in renal transplantation remains to be defined. Since the initial availability of FK 506 for treatment of refractory renal allograft rejection, we have applied an aggressive approach consisting of institution of rescue therapy at an early point in the rejection process combined with assiduous monitoring of FK 506 blood levels and the histologic response to therapy. A total of 17 adult patients were treated for refractory renal allograft rejection with this approach. Median follow-up was 9 months post-initiation of FK 506 therapy. Median time to first rejection was 26 d post-transplant, and median time to FK 506 rescue therapy was 113 d post-transplant. Sixteen of 17 patients received either ATGAM or OKT3 induction therapy. Prior to FK 506 rescue therapy, patients received the following antirejection therapy: corticosteroids 40 + 21 mg/kg (prednisone or Solumedrol), OKT3 (median 14 d), ATGAM (3 patients, 14 d each). FK 506 rescue therapy was successful in reversing the rejection process in all 17 patients. Fifteen patients (88%) demonstrated rapid reversal of rejection (i.e. reversal within 14 d), whereas three patients demonstrated delayed reversal. Nine month actuarial patient and graft survivals were 92% and 84%. When censored for documented noncompliance, nine month actuarial graft survival was 92%. Good long-term renal function was observed (pre-FK 506 baseline creatinine 2.1 +/- 0.5 mg/dl, current serum creatinine 2.1 +/- 0.6 mg/dl. Six recurrent rejection episodes occurred in 5 patients (29%) with a median time to recurrent rejection of 59 d post-initiation of FK 506 rescue therapy. Each recurrent rejection episode was successfully treated by corticosteroids and/or increased FK 506 dose. CMV disease and lymphoma were not observed. Histologic evidence of FK 506 nephrotoxicity (hyaline necrosis in preglomerular arterioles) was observed in 6 patients 30% (median time to diagnosis 49 d). FK 506 blood levels (whole blood TDX) between 10 and 20 ng/ml provided effective reversal in most patients. Current FK 506 dose and blood levels are 0.18 +/- 0.09 mg/kg/d and 7 +/- 2 ng/dl). FK 506 rescue therapy also allowed aggressive reductions in prednisone dose: (mean current prednisone dose 0.08 +/- 0.05 mg/kg/d). In conclusion, an aggressive approach toward FK 506 rescue: 1) provides prompt, effective reversal of refractory renal allograft rejection, 2) good long-term renal allograft function, 3) balanced immunosuppression with respect to recurrent rejection, opportunistic infection and PTLD, 4) acceptable toxicity, and 5) aggressive reduction in corticosteroid dosing. Based on these findings, FK 506 rescue therapy is now the treatment of choice in our program for renal allograft rejection episodes that occur following antilymphocyte antibody therapy.

Dose-response relationships for anti-CD3 monoclonal antibody (mAb) therapy remain undefined, particularly with respect to higher dose ranges. The clinical efficacy and safety of an OKT3 dosing regimen that incorporates higher doses (escalating dose regimens) was examined in a pilot trial. Patients undergoing acute rejection were treated with a 7-d course of OKT3 in which the daily OKT3 dose was escalated during treatment course (daily doses 5, 5, 5, 5, 10, 15, 25 mg). The total amount of OKT3 given was equal to a standard 14-d course (70 mg). A total of 10 primary cadaveric renal transplant recipients were treated, and data analyzed from a median follow up of 5 months (range 3-13 months). Pre-OKT3 immunosuppressive therapy consisted of ATGAM induction therapy (n = 8), and corticosteroid rejection therapy (n = 6, 18.6 +/- 11.4 mg/kg). Median time of first rejection was 32 d (12-48 d) and median time to OKT3 was 33 d (range 15-42 d). Pre-OKT3 histology (by Banff criteria) included: mild ACR (n = 6), moderate ACR (n = 2), AVR (n = 1), ACR and acute transplant glomerulopathy (n = 1). Rejection reversal rate with escalating dose OKT3 was 100%, and each patient experienced a rapid reversal of rejection (i.e. reversal within 14 d initiation of OKT3 therapy). Six recurrent rejection episodes were diagnosed in 5 patients with a median time to recurrent rejection of 30 d following cessation of OKT3 therapy. All recurrent rejection episodes were successfully treated (FK 506 n = 4, corticosteroids n = 1, and OKT3 n = 1). CMV disease was limited to a single episode of CMV viremia in one patient. PTLD was observed in one patient who had coexisting vascular rejection at the time of PTLD diagnosis. Short- and long-term graft function is excellent (pre-rejection baseline creatinine 1.8 +/- 0.4 mg/dl, current creatinine 1.75 +/- 0.4 mg/dl). Monitoring of OKT3 serum levels revealed that patients maintained therapeutic serum levels for an average of 4 d following the last OKT3 dose. Circulating CD3+ and CD5+ cells were maintained below baseline levels for at least 10 d following the last OKT3 dose. Anti-OKT3 antibody formation occurred in 22% of patients, however, anti-idiotypic responses were of low titer. Adverse reactions experienced during dose escalation were minimal compared to first dose reactions, and consisted primarily of mild headaches and arthralgias in a minority of patients. OKT3 EDR, by obviating monitoring and administration costs, are cost effective [OKT3 EDR $8088, OKT3 SDR (10 d) $9684, OKT3 SDR (14 d) $13,224]. In conclusion, escalating dose regimens of OKT3: 1) provide rejection reversal rates similar to standard dose regimens, 2) provide high OKT3 serum levels and reliable CD3+ cell depletion, 3) induce minimal adverse reactions during dose escalation, and 4) may decrease costs by obviating the need for monitoring peripheral blood T cells and by decreasing administration costs and outpatient visits.