The Impact of Compliance with Imaging Follow-up on Mortality After Endovascular Abdominal Aortic Aneurysm Repair: A Population Based Cohort Study.

OBJECTIVE: Compliance with regular imaging follow-up after endovascular aortic aneurysm repair (EVAR) is inconsistent, and evidence of benefit from scheduled long-term surveillance is limited. This study sought to characterize the association between post-EVAR imaging frequency and long-term survival. METHODS: Using administrative health databases for the province of Ontario, Canada, a cohort of patients was identified who underwent EVAR between 2004 and 2014. Minimum appropriate imaging follow-up (MAIFU) was defined as a CT scan or ultrasound of the abdomen within 90 days of EVAR as well as every 15 months thereafter. Multivariate time to event analyses characterized the association between compliance with MAIFU over time and all-cause mortality. RESULTS: 4988 patients treated by EVAR were identified. Median follow-up was 3.4 years (IQR 2.0-5.3 years) and 90 day mortality was 1.6%. Among those who survived over 90 days, 87% (N = 4251 of 4902) underwent at least one CT scan or ultrasound of the abdomen within 90 days, but only 58% (N = 2859 of 4902) went on to meet MAIFU criteria. Infrequent imaging correlated with lower follow-up by a vascular surgeon, but not with infrequent primary care or specialist consultations. Consistently meeting MAIFU criteria was associated with a lower risk of death when compared with missing the first imaging follow-up within 90 days (HR 0.82, 95% CI 0.69-0.96, p = .014), or when compared with having first imaging follow-up within 90 days but subsequently not meeting MAIFU criteria (HR 0.78, 95% CI 0.68-0.91, p = .001). A larger proportion of the follow-up period meeting MAIFU criteria was associated with a lower risk of death. CONCLUSIONS: These data support efforts to improve compliance with imaging surveillance after EVAR.

γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate.

BACKGROUND: γ-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect. METHODS: We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo. RESULTS: Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased. CONCLUSION: Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects.

Exclusion of patients with sequential primary total joint arthroplasties from arthroplasty outcome studies biases outcome estimates: a retrospective cohort study.

OBJECTIVE: Total joint arthroplasty (TJA) outcome studies have largely focused on recipients of a single primary TJA, which may bias outcome estimates. DESIGN: This retrospective cohort study utilized health administrative databases from Ontario, Canada, to assemble a cohort that received a first primary elective hip or knee TJA for osteoarthritis (OA) between 2002 and 2009 (index TJA). Characteristics of TJA recipients at their index TJA were compared for those who did vs did not go on to receive one or more subsequent primary, elective hip/knee TJAs (multiple TJAs - yes/no) over a 2-year follow-up period. Cox proportional hazards, censored on death, was used to examine the relationship of receipt of multiple TJAs (yes/no) on rates of surgical complications for the index TJA, controlling for confounders. RESULTS: Among 97,374 eligible patients, 19,856 (20.4%) received a second primary elective TJA procedure within 2 years. In bivariate analyses, recipients of multiple primary TJAs were significantly more likely than single TJA recipients to be female, younger, with fewer co-morbidities (P < 0.0001), and to experience surgical complications with the index surgery, including early revision (P < 0.0001). Controlling for patient differences, receipt of >1 primary TJAs over 2 years was independently and significantly associated with lower odds of having experienced a surgical complication following the index arthroplasty (adjusted HR 0.65, 95%CI 0.59-0.72). CONCLUSIONS: One in five patients receiving their first elective primary hip or knee TJA received a second hip/knee TJA within 2 years. Our results indicate that exclusion of this large subsample of TJA recipients from TJA outcomes studies over-estimates surgical risks and may underestimate patient-reported benefits.

Continental variations in IgA nephropathy among Asians.

BACKGROUND/AIMS: Local variations in patient demographics and medical practice can contribute to differences in renal outcomes in patients with IgA nephropathy. We report the experiences of two groups of Asians with IgA nephropathy across continents. MATERIALS AND METHODS: We retrospectively examined two cohorts of Asian patients with IgA nephropathy from The King Chulalongkorn Memorial Hospital registry, Thailand (1994 - 2005), and The Metropolitan Toronto Glomerulonephritis registry, Canada (1975 - 2006), and compared their baseline characteristics. Slope of estimated glomerular filtration rate (eGFR) in each group was approximated using separate repeated measures regression models for each country. RESULTS: There were 152 Canadian and 76 Thai patients. At the time of first presentation, Thai patients were more likely to be female (63.2 vs. 44.1%, p = 0.01), have less baseline proteinuria (1.2 vs. 1.7 g/d, p = 0.08) and more likely to receive angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) (64.0 vs. 15.2%, p < 0.01), or prednisone (41.3 vs. 4.6%, p < 0.01). The annual change in estimated glomerular filtration rate (eGFR) for the Thai and Canadian groups were -0.82 ml/min/1.73 m2/year and -3.35 ml/min/1.73 m2/year, respectively, after adjustment for age, sex, mean arterial pressure (MAP), proteinuria, body mass index, Haas histological grade, chronicity scores and baseline medications. CONCLUSIONS: Although disease severity was similar among IgA nephropathy patients in Canada and Thailand, more Thai patients were on ACE-I/ARB or prednisone therapy at baseline. Further prospective research is needed to explore international differences in demographic and environmental factors, health resources, and disease management to determine how they may impact long-term outcomes in Asians with IgA nephropathy.

Effects of folylpolyglutamate synthetase modulation on chemosensitivity of colon cancer cells to 5-fluorouracil and methotrexate.

BACKGROUND: Folylpoly-gamma-glutamate synthetase (FPGS) converts intracellular folates and antifolates (for example, methotrexate (MTX)) to polyglutamates. Polyglutamylated folates and antifolates are retained in cells longer and are better substrates than their monoglutamate counterparts for enzymes involved in one carbon transfer. Polyglutamylation of intracellular 5,10-methylenetetrahydrofolate may also enhance the cytotoxicity of 5-fluorouracil (5-FU) by allowing more efficient formation and stabilisation of the inhibitory ternary complex involving thymidylate synthase and a 5-FU metabolite. AIM: We investigated the effects of FPGS modulation on the chemosensitivity of colon cancer cells to 5-FU and MTX. METHODS: Human HCT116 colon cancer cells were stably transfected with the sense or antisense FPGS cDNA or blank (control). FPGS protein expression and enzyme activity, growth rate, intracellular folate content and composition, and in vitro chemosensitivity to 5-FU and MTX were determined. RESULTS: Compared with cells expressing endogenous FPGS, those overexpressing FPGS had significantly faster growth rates and higher concentrations of total folate and long chain folate polyglutamates while antisense FPGS inhibition produced opposite results. FPGS overexpression significantly enhanced, whereas FPGS inhibition decreased, chemosensitivity to 5-FU. No significant difference in chemosensitivity to MTX was observed. CONCLUSIONS: These data provide functional evidence that FPGS overexpression and inhibition modulate chemosensitivity of colon cancer cells to 5-FU by altering intracellular folate polyglutamylation, providing proof of principle. Thus FPGS status may be an important predictor of chemosensitivity of colon cancer cells to 5-FU based chemotherapy, and FPGS gene transfer may increase the sensitivity of colon cancer cells to 5-FU-based chemotherapy.

Socio-economic status and surgery in children: myringotomies and tonsillectomies in Ontario, Canada, 1996-2000.

AIM: To examine the relation between socio-economic status and (1) receipt of paediatric otolaryngological surgery, and (2) inclusion of adjuvant procedures. METHODS: Using data on myringotomies with insertion of tympanostomy tube and tonsillectomies for all children in Ontario, Canada, from 1996 to 2000, and census data on socio-economic status, we examined the association between socio-economic status and (1) the probability of surgery (myringotomy or tonsillectomy), and (2) the probability that surgery was accompanied by an adjuvant procedure. RESULTS: Lower socio-economic status was associated with increased likelihood that a child's initial surgery was a tonsillectomy rather than a myringotomy (odds ratio per unit increase in the deprivation index = 1.09, p = 0.01, confidence interval 1.06-1.11), and with increased likelihood that those children having a myringotomy would undergo a tonsillectomy during the same hospitalization (odds ratio 1.14, p < 0.0001, confidence interval 1.11-1.16). Children from neighbourhoods with larger immigrant populations were less likely to receive either procedure (odds ratios per 1% increase in the proportion of immigrants = 0.97 (p < 0.0001, confidence interval 0.96-0.97) for myringotomies and 0.97 (p < 0.0001, confidence interval 0.97-0.98) for tonsillectomies). CONCLUSIONS: Socio-economic status was associated with treatment selection for the two most common paediatric surgical procedures. Further research should examine whether differences in treatment arise at the level of the primary care physician, the specialist, and/or are due to parental preference.

Physician and population determinants of rates of middle-ear surgery in Ontario.

CONTEXT: Small-area variations in surgical rates raise concerns about access to care, treatment appropriateness, and the quality and cost of care. OBJECTIVE: To measure small-area variations in rates of myringotomy with insertion of tympanostomy tubes (TTs) and to identify determinants of rate variation. DESIGN AND SETTING: Retrospective analyses using hospital discharge data for patients who had undergone a myringotomy with insertion of TT by county in Ontario between April 1, 1996, and March 31, 1999. Information on possible determinants was taken from a survey of otolaryngologists and primary care physicians in 1996 and from the 1996 Canadian census and physician demographic databases for 1996-1999. PARTICIPANTS: A total of 75 358 hospitalizations for TT placement of children and adolescents (aged

The role of adjuvant adenoidectomy and tonsillectomy in the outcome of the insertion of tympanostomy tubes.

BACKGROUND: Otitis media is the most common medical problem in young children. The usual surgical treatment is myringotomy with insertion of tympanostomy tubes. There is debate about the usefulness of concomitant adenoidectomy or adenotonsillectomy. We examined the effects of these adjuvant procedures on the rates of reinsertion of tympanostomy tubes and rehospitalization for conditions related to otitis media. METHODS: Using hospital discharge records for the period 1995 through 1997, we examined the results of surgery for all 37,316 children (defined as persons 19 years of age or younger) in Ontario, Canada, who received tympanostomy tubes as their first surgical treatment for otitis media. We determined the time to the first readmission for conditions related to otitis media and the time to the first reinsertion of tympanostomy tubes. RESULTS: As compared with treatment involving the insertion of tympanostomy tubes alone, adjuvant adenoidectomy was associated with a reduction in the likelihood of reinsertion of tympanostomy tubes (relative risk, 0.5; 95 percent confidence interval, 0.5 to 0.6; P<0.001) and the likelihood of readmission for conditions related to otitis media (relative risk, 0.5; 95 percent confidence interval, 0.5 to 0.6; P<0.001). The risk of these outcomes was further reduced if an adjuvant adenotonsillectomy was performed. The effect was age-related. Children as young as one year appeared to benefit from adjuvant adenotonsillectomy; the benefit of an adjuvant adenoidectomy was apparent in two-year-olds and was greatest for children three years of age or older. CONCLUSIONS: Performing an adenoidectomy at the time of the initial insertion of tympanostomy tubes substantially reduces the likelihood of additional hospitalizations and operations related to otitis media among children two years of age or older.

Otolaryngologists' perceptions of the indications for tympanostomy tube insertion in children.

BACKGROUND: Bilateral myringotomy with insertion of tympanostomy tubes is the most common operation that children in Canada undergo. Area variations in surgical rates for this procedure have raised questions about indications used to decide about surgery. The objective of this study was to describe the factors that influence otolaryngologists to recommend tympanostomy tube insertion in children with otitis media and their level of agreement about indications for surgery. METHODS: A survey was sent to all 227 otolaryngologists in Ontario in the fall of 1996. The influence of 17 clinical and social factors on recommendations to insert tympanostomy tubes were assessed. Case vignettes were used to determine the effect of multiple factors in decisions about the need for surgical management. RESULTS: Surveys were returned by 138 (68.3%) of the 202 eligible otolaryngologists. There was agreement (more than 90% of respondents) about 6 indications for surgery: persistent effusion, a lack of improvement after 3 months of antibiotic therapy, a history of persistent effusion for 3 or more months per episode of otitis media, more than 7 episodes of otitis media in 6 months, a bilateral conductive hearing loss of 20 dB or more and a persistently abnormal tympanic membrane. Some respondents were more likely to recommend tube insertion if there were parental concerns about hearing problems or the frequency or severity of episodes of otitis media. Otolaryngologists agreed about the role of tympanostomy tubes in 1 of 4 case vignettes but disagreed about whether adenoidectomy should also be performed in that instance. Most viewed tympanostomy tube insertion as beneficial, with few adverse effects. INTERPRETATION: There is a lack of consensus among practising otolaryngologists in Ontario as to which children with recurrent otitis media or persistent effusion should undergo bilateral myringotomy with tympanostomy tube insertion. These findings suggest the need to revisit clinical guidelines for this procedure.

Costs and outcomes associated with alternative discharge strategies following joint replacement surgery: analysis of an observational study using a propensity score.

We estimated the impact of alternative discharge strategies, following joint replacement (JR) surgery, on acute care readmission rates and the total cost of a continuum of care. Following surgery, patients were discharged to one of four destinations. Propensity scores were used to adjust costs and outcomes for potential bias in the assignment of discharge destinations. We demonstrated that the use of rehabilitation hospitals may lower readmission rates, but at a prohibitive incremental cost of each saved readmission, that patients discharged with home care had longer acute care stays than other patients, that the provision of home care services increased health system costs, and that acute care readmission rates were greatest among patients discharged with home care. Our study should be seen as one important stepping stone towards a full economic evaluation of the continuum of care for patients.

Physician enthusiasm as an explanation for area variation in the utilization of knee replacement surgery.

BACKGROUND: Explanations for regional variation in the use of many medical and surgical treatments is controversial. OBJECTIVES: To identify factors that might be amenable to intervention, we investigated the determinants of regional variation in the use of knee replacement surgery. RESEARCH DESIGN: We examined the effect of the following factors: characteristics and opinions of surgeons; family physicians and rheumatologists; patients' severity of disease before knee replacement; access to knee-replacement surgery; surgeons' use of other surgical treatment; and county population characteristics. OUTCOMES MEASURE: County utilization rates of knee replacement in Ontario, Canada. RESULTS: Counties that had higher rates of knee replacement had older patients (P = 0.0001), higher percentage of medical school affiliated hospital beds (P = 0.04), with more male (P = 0.02) non-North American trained referring physicians (P = 0.002) and orthopedic surgeons who had higher propensities to operate and better perceptions of outcome (P = 0.0001). CONCLUSIONS: After controlling for population characteristics and access to care (including the number of hospital beds, and the density of orthopaedic and referring physicians), orthopaedic surgeons' opinions or enthusiasm for the procedure was the dominant modifiable determinant of area variation. Thus, research needs to focus on the opinions of surgeons which may be important in reducing regional variation for knee replacement.

Rates of revision knee replacement in Ontario, Canada.

BACKGROUND: The present study was designed to measure the longevity of knee replacements and to assess the determinants of revision knee replacements in order to enhance the potential for informed decision-making. METHODS: Data on all hospitalizations for knee replacement that occurred in Ontario, Canada, between April 1, 1984, and March 31, 1991, were acquired. To calculate the rates of revision knee replacement, two algorithms were developed: one distinguished primary knee replacements from revision knee replacements, and the second linked revision knee replacements to primary knee replacements. The Kaplan-Meier method was used to assess survivorship (absence of a revision) for primary knee replacement. A proportional-hazards regression model was estimated to assess the role of independent variables on the survival of primary knee replacements. RESULTS: During the period of the study, 7.0 percent (1301) of 18,530 knee replacements were classified as revisions. Significant differences were identified between hospitalizations for primary and revision knee replacements in terms of the patient and hospital characteristics. Patients who were more than fifty-five years old, lived in a rural area, or had a diagnosis of rheumatoid arthritis had a significantly (p < 0.05) longer duration before revision than did other patients. Primary knee replacements performed in a teaching or specialty hospital had a significantly (p < 0.05) shorter duration before revision than did those performed in a non-teaching hospital. The long-term rates of revision were uniformly low. Estimates of the proportion of knee replacements that would need to be revised within seven years ranged from a low of 4.3 percent, with use of the algorithm for the longest time to revision, to a high of 8.0 percent, with use of the algorithm for the shortest time to revision. CONCLUSIONS: Revision of a primary knee replacement was a rare event that depended on a patient's age, gender, and place of residence as well as on the hospital where the primary knee replacement was performed. Estimates of the rates of revision knee replacement after almost seven years ranged from a low of 4.3 percent to a high of 8.0 percent.

Expression of p210 and p190 BCR-ABL due to alternative splicing in chronic myelogenous leukaemia.

The hallmark of chronic myelogenous leukaemia (CML) is the presence of the Philadelphia chromosome and its resultant fusion message, BCR-ABL, and fusion protein, p210. Patients with CML in blast crisis, or with Philadelphia positive acute lymphoblastic leukaemia (ALL), can have a smaller BCR-ABL fusion transcript possessing only the first exon of BCR fused to ABL. This smaller transcript encodes a 190 kD protein which is more strongly transforming than the p210 protein derived from the larger CML-associated transcript. We performed RT-PCR on samples from CML patients in chronic phase to determine the frequency and mechanism of p190 and p210 co-expression and to see if this correlated with clinical indices. We examined the peripheral blood or marrow of 67 patients with CML and found that 35 of them expressed both transcripts whereas the remainder expressed the p210-encoding transcript exclusively. Additional PCR products of an intermediate size were also frequently detected and have been isolated and sequenced. Data from two of these products indicate that they are the result of alternative splicing and include variable combinations of BCR exons. We believe that the expression of the p190-encoding transcript in the chronic phase of CML is also due to alternative splicing. A comparison of patients co-expressing the p190- and p210-encoding transcripts with those patients who expressed only the p210-encoding transcript detected significantly higher white blood cell (WBC) counts and blast cell counts at time of testing as well as significantly higher white blood cell counts at diagnosis.

Health-related quality of life after knee replacement.

A cross-sectional, community-based survey of a random sample of 1750 of 242,311 Medicare recipients was performed. The patients were at least sixty-five years old and had had a primary or revision knee replacement (either unilaterally or bilaterally) between 1985 and 1989. Three samples were surveyed separately: a national sample (to reflect the United States as a whole) and samples from Indiana and the western part of Pennsylvania (sites chosen for convenience to assess the validity of the findings for the national sample on a regional level). Each sample was stratified by race, age, residence (urban or rural), and the year of the procedure. Valid and reliable questionnaires were used to elicit the participants' assessments of pain, physical function, and satisfaction two to seven years after the knee replacement. Of the 1486 patients who were eligible for inclusion in the survey, 1193 (80.3 per cent) responded. The mean age of the respondents was 72.6 years. Eight hundred and forty-nine respondents (71.2 per cent) were white, and 849 (71.2 per cent) were women. The participants reported that they had little or no pain in the knee at the time of the survey, regardless of the age at the time of the knee replacement, the body-mass index, or the length of time since the knee replacement. After adjustment for potential confounding variables, predictors of better physical function after the replacement were an absence of problems with the contralateral knee, primary knee replacement (rather than revision) (Indiana sample only), and a lower body-mass index (Indiana and western Pennsylvania samples). Four hundred and fifteen (85.2 per cent) of the 487 patients in the national sample were satisfied with the result of the knee replacement. In what we believe to be the first community-based study of the outcome of knee replacement, patients reported having significant (p = 0.0001) and persistent relief of pain, improved physical function, and satisfaction with the result two to seven years postoperatively. The findings of the present study suggest that age and obesity do not have a negative impact on patient-relevant outcomes (pain and physical function). Dissemination of these findings has the potential to increase appropriate referrals for knee replacement and thereby reduce the pain and functional disability due to osteoarthrosis of the knee.

Variation in rheumatologists' and family physicians' perceptions of the indications for and outcomes of knee replacement surgery.

OBJECTIVE: To assess agreement among rheumatologists and family physicians (FP) about the indications for knee replacement (KR) referral, use of nonsurgical management options, and perceived outcomes of KR, and to determine the relationship between these opinions and the number of patients seen with severe osteoarthritis (OA) of the knee. METHODS: 98 adult rheumatologists and a random sample of 250 FP in Ontario, Canada were surveyed. Of the practising and traceable rheumatologists and FP, 70.0 and 5.16% responded, respectively. RESULTS: FP disagreed on how 28 of 32 patient factors affected their KR referral decision, while rheumatologists disagreed on 26 of these 32 factors (p = 0.03). Rheumatologists and FP consistently disagreed on the use of 8 of 10 treatments for knee OA (p = 0.37). While rheumatologists and FP reported similar KR outcomes, FP were less in agreement (p = 0.03). Clinical disagreement for the indications for KR (p < 0.0001) and KR outcomes (p < 0.0001) were greater among FP than among orthopedic surgeons who were surveyed in a prior study. Clinical disagreement about the indications for KR was greater among rheumatologists than among surgeons (p = 0.04), but there was no difference in perceived KR incomes (p = 0.18). CONCLUSION: Referring physicians disagreed on the indications for KR referral an on the treatments for knee arthritis, but were in general agreement regarding KR outcomes. Clinical disagreement was greater among FP than among rheumatologists, who in turn reported more disagreement than orthopedic surgeons. Explanations for these difference in perceptions should be the focus of research, but guidelines specifically tailored for each physician specialty may be required to reduce clinical uncertainty.

Familial segregation in the occurrence and severity of periampullary neoplasms in familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) patients often develop periampullary adenomas that may progress to periampullary cancer, a common cause of death in this population. The risk of periampullary cancer in FAP is unclear, and variables that predict the occurrence and severity of periampullary tumors are not well understood. The specific aim of this study was to determine whether the risk of periampullary neoplasia segregates in specific FAP families. MATERIALS AND METHODS: A total of 144 FAP patients from 74 families were either screened by gastroduodenoscopy (n = 132) or information was obtained from surgical or autopsy reports (n = 12). The severity of periampullary neoplasia was recorded for each patient and graded based on maximum polyp size and histology. Linear regression was used to determine the significance of a number of variables with respect to periampullary neoplasia. A blood sample was available from at least one member of 50 unrelated families and used to detect germline mutations in codons 686 through 1693 of the adenomatous polyposis coli (APC) gene. RESULTS: Statistically significant familial segregation was found for the incidence and severity of periampullary neoplasia (P < 0.02). Age was also a statistically significant variable (P < 0.01). No correlation was observed between specific APC germline mutations and periampullary polyp frequency and severity. CONCLUSIONS: The occurrence and severity of periampullary neoplasms in patients with FAP segregates in families. This familial association may be related to as yet unidentified modifier genes or perhaps common environmental factors. These results should prove useful in developing upper gastrointestinal screening protocols for FAP patients at risk for periampullary neoplasia.

Definition and classification of negative outcomes in solid organ transplantation. Application in liver transplantation.

OBJECTIVE: This study defined negative outcomes of solid organ transplantation, proposed a new classification of complications by severity, and applied the classification to evaluate the results of orthotopic liver transplantation (OLT). SUMMARY AND BACKGROUND DATA: The lack of uniform reporting of negative outcomes has made reports of transplantation procedures difficult to interpret and compare. In fact, only mortality is well reported; morbidity rates and severity of complications have been poorly described. METHODS: Based on previous definition and classification of complications for general surgery, a new classification for transplantation in four grades is proposed. Results including risk factors of the first 215 OLTs performed at the University of Toronto have been evaluated using the classification. RESULTS: All but two patients (99%) had at least one complication of any kind, 92% of patients surviving more than 3 months had grade 1 (minor) complications, 74% had grade 2 (life-threatening) complications, and 30% had grade 3 (residual disability or cancer) complications. Twenty-nine per cent of patients had grade 4 complications (retransplantation or death). The most common grade 1 complications were steroid responsive rejection (69% of patients) and infection that did not require antibiotics or invasive procedures (23%). Grade 2 complications primarily were infection requiring antibiotics or invasive procedures (64%), postoperative bleeding requiring > 3 units of packed red cells (35%), primary dysfunction (26%), and biliary disease treated with antibiotics or requiring invasive procedures (18%). The most frequent grade 3 complication was renal failure, which is defined as a permanent rise in serum creatinine levels > or = twice the pretransplantation values (11%). Grade 4 complications (retransplantation or death) mainly were infection (14%) and primary dysfunction (11%). Comparison between the first and last 50 OLTs of the series indicates a significant decrease in the mean number of grade 1 and 2 complications. This was partially a result of better medical status of patients at the time of transplantation. Using univariate and multivariate analyses of risk factors, the best predictor of grade 1 complications was donor obesity; for grade 2 complications, the best predictor was a donor liver rewarming time of > 90 minutes, and for grade 3 and 4 complications, the best predictor was the APACHE II scoring system and donor cardiac arrest. CONCLUSIONS: Standardized definitions and classifications of complications of transplantation will allow us to better evaluate and compare results of transplantation among centers and over time, and better compare effectiveness of new therapies. Orthotopic liver transplantation still is a procedure with high morbidity that requires careful analysis of risk factors to optimize selection of patients and organ sharing.

Opiate-seeking behavior under conditions of methadone detoxification and removal.

This study was carried out to determine whether heroin-dependent persons, having completed methadone detoxification, can be maintained on an inert substance which has previously been associated with methadone. Forty heroin-dependent men and women were randomly allocated to either a "standard detoxification" group or a cordial substitution group. Results showed that subjects administered methadone-associated cordial after methadone detoxification could not be retained at the clinic for a time significantly beyond that of subjects in the standard detoxification group despite the inability of the subjects to accurately estimate methadone dosage. The role of cognitive factors is discussed.

Some functional and morphological characteristics of an acutely dispersed purified cell suspension of rat lactotrophs prepared with Percoll.

A cell suspension containing more than 90% lactotrophs can be prepared from enzymically dispersed adenohypophyses obtained from male rats pretreated with estradiol. The lactotrophs are separated from the mixed cell population by centrifugation on a discontinuous density gradient prepared from a commercial preparation of colloidal silica (Percoll, Pharmacia). The method allows isopycnic separation of these delicate cells under very mild conditions; normal ionic strength and normal pH were maintained throughout the gradient, centrifugal acceleration did not exceed 1600 X g, and all procedures were done at room temperature. Histological verification that at least 90% of the cells were lactotrophs was done using specific immunoperoxidase staining. The functional capability of the lactotrophs was established by measuring the dose--response to the dopamine agonist bromocriptine and to thyrotropin-releasing hormone (TRH). Bromocriptine decreased spontaneous release in a dose-related way over the concentration range of 10(-10) to 10(-8) M. TRH, which causes an in vivo release of prolactin (PRL) in estrogen-primed rats, produced a dose-related increase in the release of PRL over the concentration range of 3 X 10(-10) to 3 X 10(-8) M after the high spontaneous release had been previously reduced by bromocriptine (3 X 10(-8) M).

Bromocriptine suppression of dispersed pituitary lactotrophs from estrogen-pretreated rats: a quantitative electron microscopic study.

Dispersed rat lactotrophs were treated with bromocriptine (10(-10) M) for either 30 min or 3 h to investigate its effect on cell morphology using light and electron microscopy and ultrastructural morphometry. After 30 min, lactotrophs treated with bromocriptine exhibited an increase in storage granule size (p less than 0.05). Crinophagy was also evident and a significant increase in lysosome volume density was observed (p less than 0.001). However, no significant change in prolactin content in the media was detected until 3 h of incubation in bromocriptine (p less than 0.05). At this time a nonsignificant decrease in Golgi region volume density was also observed.