Primary biliary cirrhosis: Dutch application of the Mayo Model before and after orthotopic liver transplantation.

BACKGROUND/AIMS: A retrospective study of primary biliary cirrhosis (PBC) was performed to study the Original Mayo Model for predicting survival by a Dutch data-set of patients, presentation of disease progression; assessment of liver transplantation, prediction of post-transplantation survival; and the addition of two laboratory variables to the Original Mayo Model. MATERIALS AND METHODS: Survival of 83 patients, 37 of whom underwent transplantation, were studied. Mean follow-up was 6.0 +/- 0.45 SEM years. Risk score at diagnosis, platelet count, and serum sodium were analyzed in a Cox model. RESULTS: The Original Mayo Model estimated survival for low-, medium-, and high-risk groups accurately and it also presented disease progression. Baseline Mayo risk score in a Cox model had a regression coefficient of 1.01, indicating an excellent predictor p < 0.0001. Platelet count was a predictor of survival (p < 0.002), whereas serum sodium did not (p = 0.67). A new model combined of the Original Mayo risk score and platelet count predicted survival in high-risk patients somewhat better compared to the Original Mayo Model. With both models, liver transplantation had a significant beneficial effect on survival (p < 0.001). The scores revealed no significant influence (p = 0.47) for overall post-transplantation survival. CONCLUSIONS: The Original Mayo Model remains the model of choice for patients with PBC for prognostication from 3-8 years, is a useful tool in the assessment of liver transplantation but not an indicator of post-transplantation survival. Platelet count showed to have additional prognostic value. A new model combined of platelet count and the Original Mayo risk score did predict survival in high-risk groups slightly better compared to the Original Mayo Model.

Correlation of trunk muscle strength with age in children 5 to 18 years old.

OBJECTIVE: To determine the correlation of trunk muscle strength with age in children and the effect of gender on changes in trunk muscle strength. MATERIAL AND METHODS: Strength of the back extensors and back flexors was evaluated in 137 healthy boys and 109 healthy girls who were 5 to 18 years old. Anthropometric determinations of height and weight were done in all study subjects. Maximal back muscle strength was measured with an isometric dynamometer (BID-2000). Standardized positioning techniques were used to allow comparison with the follow-up evaluations. RESULTS: Regression analysis revealed significant increases in trunk strength with increasing age; the strength of the boys began diverging from that of the girls at age 9 to 10 years. Back extensor strength also increased with increasing height and weight, and expected differences were noted between boys and girls. Strength levels ranged from 80 to 774 newtons (18 to 174 lb). Mean back extensor strength in 2-year age intervals ranged from 153 newtons (34.4 lb) in girls 5 to 7 years old to 504 newtons (113.3 lb) in boys 16 to 18 years of age. (Each newton is equal to 0.2248 lb.) CONCLUSION: Results of this study demonstrated that age, height, and weight are all important predictors of trunk strength in children, and the effects of these factors are modulated by gender.

ROC curves with multiple marker measurements.

Properties of receiver operating characteristic (ROC) curves are explored for markers that are measured repeatedly, through space or time, for each subject. The true underlying response, positive or negative, of each subject is assumed to be constant across marker measurements, and is determined from assessment of some "gold standard." A marker-based test is considered positive when at least one of a subject's marker values exceeds a designated cutoff. If subjects with positive and negative underlying responses differ in the number of marker measurements per subject, the ROC curve for a noninformative marker is bowed above or below the diagonal line representing the "null" curve for a marker that is measured just once per subject. If subjects with negative responses tend to have more measurements than those with positive responses, the ROC curve for even an informative marker may lie beneath the curve for the same marker measured once per subject. The form of the ROC curve for a marker used in this way is strongly influenced by the strength of the correlation of measurements within subjects.

The surprisingly high acceptability of low-efficacy vaccines for otitis media: a survey of parents using hypothetical scenarios.

OBJECTIVE: To determine parental thresholds for accepting vaccines for otitis media prevention given tradeoffs of efficacy, adverse effects, and administration mode. METHOD: We interviewed 601 randomly selected parents with children 0 through 6 years of age presenting to our community pediatric clinic. For each of five hypothetical vaccines, which varied administration mode from nasal spray to two injections and adverse effects from mild to severe, parents indicated the lowest number of otitis media episodes that the vaccine had to prevent in the next 6 months for them to accept the vaccine. RESULTS: About half the parents would accept any one of the vaccines if it would prevent three or more infections in the next 6 months. When the vaccine would prevent one episode of otitis media over the next 6 months, 33% of parents would accept the medial vaccine (one injection in the thigh, with some children getting a red, sore injection site and a few having a fever of < or = 102 degrees F for one day). Seventeen percent accepted a vaccine requiring two injections (influenza vaccine-like) or having increased adverse effects (pneumococcal vaccine-like) despite the vaccine only preventing one episode of otitis media over the next 6 months. No substantial differences in these proportions were found when compared among groups by reason-for-visit, recent occurrence of otitis media, or a history of recurrent otitis media in a sibling. CONCLUSION: Many parents will accept low efficacy vaccines for otitis media prevention. Parental acceptance does not vary with the child's otitis media experience but does vary with severity of adverse effects and administration mode of the vaccine.

Statistical analysis of food webs.

The numbers of species in different trophic levels of a food web are modeled as a trinomial random vector, with cell probabilities potentially depending on the total number of species in the web. A maximum likelihood method is developed to test the hypothesis that the fractions of species in different levels are independent of the total number of species. The method is applied to a data set whose properties have been debated in the literature, and it is shown to be a powerful alternative to the simple linear regression approach used in previous analyses.

Primary biliary cirrhosis: prediction of short-term survival based on repeated patient visits.

The progression of primary biliary cirrhosis was studied in 312 patients who were seen at the Mayo Clinic between January 1974 and May 1984. Follow-up was extended to April 30, 1988, by which time 140 of the patients had died and 29 had undergone orthotopic liver transplantation. These patients generated 1,945 patient visits that enabled us to study the change in the prognostic variables of primary biliary cirrhosis (age, bilirubin value, albumin value, prothrombin time and edema) from the time of referral. Also, using this database and the Cox proportional-hazards regression model, we developed an updated model for primary biliary cirrhosis that can be used to predict short-term survival at any time in the course of the disease. This model uses the values of the prognostic variables measured at the latest patient visit. Comparison of predicted survival from the update model and the natural history model of primary biliary cirrhosis showed that the updated model was superior to the original model for predicting short-term survival. This finding applied to both the Mayo Clinic patients and an independent set of 83 Dutch patients. The Mayo updated model is recommended for improving the accuracy of predictions of survival during the 2 yr after a patient visit.

The role of portosystemic shunts for variceal bleeding in the liver transplantation era.

OBJECTIVE: To review our experience with portosystemic shunts during the era of liver transplantation at the Mayo Clinic to provide insight into the selection of patients for these procedures. DESIGN: We reviewed the charts of a cohort of 57 patients who underwent portosystemic shunting between 1985 and 1990 for the management of variceal bleeding. A follow-up survey by letter and telephone was also conducted. SETTING: The Mayo Clinic, a tertiary referral center. PATIENTS: These patients were not considered transplantation candidates at the time of the shunt because of active alcoholism, extensive portal vein thrombosis, coexistent myelodysplastic syndromes, or malignant neoplasms. INTERVENTION: Portosystemic shunts; the exact type was at the surgeon's discretion. OUTCOME: Survival after shunt surgery among patients with various liver diseases. RESULTS: Twenty-two patients died during follow-up after being shunted for bleeding, and one of the shunted patients subsequently required liver transplantation. Comparison of Kaplan-Meier survival curves between various groups of patients indicated that patients who were actively alcoholic had a poorer chance of survival (P < .003) than did those who were abstinent. Patients with portal vein obstruction or chronic cholestatic liver disease appeared to do better after shunt surgery than did patients with other causes of portal hypertension. Other factors such as age, Child-Pugh score, or presence of malignant neoplasms did not reliably predict outcome from portosystemic shunts. CONCLUSIONS: In well-selected patients who may not be deemed candidates for liver transplantation, portacaval shunts can be effectively employed to prevent bleeding from esophageal varices that are resistant to obliteration by sclerotherapy.

Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.

BACKGROUND/AIMS: A double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) was conducted in 180 patients with primary biliary cirrhosis (PBC) to define the efficacy and safety of UDCA. Efficacy was assessed by time to treatment failure defined as death; liver transplantation; histological progression; development of varices, ascites, or encephalopathy; doubling of total serum bilirubin levels; progression of fatigue or pruritus; drug toxicity; or voluntary withdrawal. METHODS: Patients with well-defined PBC underwent complete history, physical examination, liver chemistries, ultrasonography, upper endoscopy, and liver biopsy at entry as well as at 2 years. Liver chemistries were determined every 3 months. RESULTS: In patients receiving UDCA, treatment failure was delayed compared with the placebo-treated group (P = 0.0003, log rank test). Seven patients receiving UDCA died or required transplantation compared with 12 in the placebo group (P = 0.18). No patients discontinued UDCA because of side effects of toxicity. CONCLUSIONS: UDCA was extraordinarily safe and well tolerated, and its use was associated with delayed progression of the disease as defined in this study. However, the lack of effects on symptoms, histology, and the need for liver transplantation or survival indicate that further evaluation is necessary to determine the ultimate role of UDCA in the treatment of PBC.

Prophylactic agents for venous thrombosis in elective hip surgery. Meta-analysis of studies using venographic assessment.

BACKGROUND: We determined the relative efficacy of various agents or combinations of agents in the prophylaxis of deep venous thrombosis after elective hip arthroplasty. METHODS: Peer-reviewed, English-language, human studies articles from 1975 through 1991 were obtained through a MEDLINE database search. Additional references were obtained from bibliographies. Articles that compared the effect of two or more prophylactic agents or placebo in preventing deep venous thrombosis as assessed by venography were selected for further review. Only studies of elective hip surgery in which all patients had venographic screening for thrombosis were included. Twenty-three of 101 studies met these criteria. Data were abstracted by one of us. Methodologic criteria and outcome data from each study were recorded and analyzed. RESULTS: There was significant heterogeneity in the deep venous thrombosis rate among studies. Although the rates were lowest for low-molecular-weight heparin with or without the use of stockings, adjusted-dose heparin, and warfarin, many agents had similar low rates. There was less heterogeneity when the relative risk was used as a summary statistic for studies in which two agents were compared. With pairwise comparisons, low-molecular-weight heparin performed better than every agent with which it was compared. Other agents performed well but were not consistently better. CONCLUSIONS: Multiple agents or combinations are effective prophylaxis for deep venous thrombosis, but none decreases the rate to zero. There was overlap in the 95% confidence intervals for the probability of deep venous thrombosis for various agents and especially for the probabilities for proximal thrombi. Many agents have not been compared directly with each other, but low-molecular-weight heparin consistently performed well.

Efficacy of hepatic transplantation in patients with primary sclerosing cholangitis.

Controlled trials to assess the therapeutic benefit of orthotopic hepatic transplantation (OHTx) for primary sclerosing cholangitis (PSC) cannot be justified in view of improvement of patient survival after this operation since 1981. However, the actual patient survival with OHTx can be compared with the Mayo model estimated survival probabilities without OHTx. This model, which encompasses physical, biochemical and histopathologic parameters of PSC, was constructed from a study of 392 conservatively treated PSC patients at five international centers in England and North America. We compared the actual survival of 216 adult patients with the diagnosis of advanced PSC who underwent hepatic replacement with the expected survival estimated by the Mayo PSC natural history model, "the simulated control technique." OHTx was performed at the University of Pittsburgh and Mayo Medical Center between 5 December 1981 and 26 December 1990. The mean (plus or minus standard deviation) post-OHTx follow-up period was 34 +/- 25 months (range of zero to 104 months). Before transplantation, biliary or portal hypertensive operation, or both, was performed upon 104 patients. At operation, the mean age of recipients was 42.1 +/- 11.3 years and the mean value of total serum bilirubin was 13.3 +/- 13.0 milligrams per deciliter. Extensive septal fibrosis and cirrhosis were histologically documented in 97 percent of the patients, with splenomegaly in 63 percent. Immunosuppressive therapy was based primarily on cyclosporin in 184 recipients and FK-506 in 32. Within six months, the Kaplan-Meier survival probability after OHTx (0.89) already was higher than predicted by the Mayo model (0.83). At five years, the Kaplan-Meier actual survival with OHTx was 0.73 compared with 0.28 expected Mayo model survival. The overall increased survival rate with transplantation was statistically significant (chi-square equals 126.6; p < 0.001). At all risk stratifications, OHTx significantly improved survival with a p value of 0.031 (low risk), 0.001 (moderate risk) and < 0.001 (high risk). Thus, OHTx is effective therapy for PSC. Disease gravity and unsuspected cholangiocarcinoma in the excised native liver adversely influenced short and long term survival rates after transplantation, respectively.

Muscle strength in osteoporotic versus normal women.

Strong back muscles contribute to good posture and skeletal support. Osteoporosis, being a metabolic bone disease, should not affect muscle strength. In this study we were interested in comparing the back extensor strength (BES) of osteoporotic and normal women. Fifty-five women ages 40-85 years who had a documented diagnosis of osteoporosis and were referred for initiation of proper exercise programs were included in our study after meeting the inclusion criteria. They all had evaluation of their posture, back and upper extremity strength, and physical activity score through our Rehabilitation of Osteoporosis Program--Exercise (ROPE). In addition, to avoid the interference of pain on application of maximal effort, we did not include subjects with acute back pain or those who experienced back pain with maximal effort during the testing trial. BES for osteoporotic women ranged from 16 to 65 lb (mean +/- SD, 36.5 +/- 15.5) for ages 40-59 years, 9 to 55 lb (mean +/- SD, 29.9 +/- 10.6) for ages 60-69 years, 6 to 52 lb (mean +/- SD, 24.3 +/- 10.2) for ages 70-79 years, and 17 to 27 lb (mean +/- SD, 21.2 +/- 4.2) for ages 80 years or older. Comparison of these data with the BES of 25 normal women, with statistical adjustment for age, demonstrated that the osteoporotic women had significantly lower BES than the normal women. A longitudinal study of a larger group of women would be of great interest for clarifying whether the weakness of back extensors precedes and, indeed, contributes to compression fractures of the spine.

Primary sclerosing cholangitis: refinement and validation of survival models.

The natural history of primary sclerosing cholangitis was studied in 426 patients from five medical centers. The median follow-up time was 3.0 years (range, 0.01-16.6 years); 100 patients had died by the time of last follow-up. Survival analysis (Cox proportional-hazards regression) was used to identify the variables most useful in predicting survival of patients with primary sclerosing cholangitis. Serum bilirubin concentration, histological stage on liver biopsy, age, and the presence of splenomegaly were independent predictors of a high risk of dying. A mathematical model to predict survival of patients with primary sclerosing cholangitis (based on referral values of those predictors) was statistically validated using two methods. Confidence intervals for predicting patient-specific survival probabilities are also presented. This model to predict survival could be used to stratify participants in therapeutic trials, counsel patients and their families, decide on candidacy for and timing of liver transplantation, and provide mathematical controls for evaluating the efficacy of therapies for primary sclerosing cholangitis, including transplantation.

Snow skiing injuries in physically disabled skiers.

This study, through retrospective review, examines the injury rate of selected disable skiing populations in general and as compared to able-bodied skiers in areas where comparison was possible. Data on disabled skiers gathered from instructional programs at multiple sites indicate that the disabled skier had a very low rate of injury occurrence. Where comparison could be make, it was found that there was no significant difference in overall injury rates between able-bodied and physically disabled skiers. Disabled skiers appear to sustain less severe injuries, and they do not show the trend in increasing injury rates that able-bodied skiers in this study show. In addition, the uphill transport of skiers with a disability who use sit- or mono-skis was examined in one large program and found to be efficient and exceedingly safe, with no injuries reported. A major limitation of this study is the inconsistency in methods of data collection and reporting. There is a need for further prospective studies in the general able-bodied and disabled skiing populations with direct comparisons of rate, location and severity of injury, type of disability, and experience level of the skier. We hope that this study will stimulate more ski areas to allow disabled skiers on their slopes, even it limited to participation in supervised, instructional programs.

Hypercholesterolemia and atherosclerosis in primary biliary cirrhosis: what is the risk?

Hypercholesterolemia is commonly associated with primary biliary cirrhosis. In the general population, elevated serum cholesterol is associated with an increased risk of atherosclerosis. The relative risk has been poorly defined in primary biliary cirrhosis patients with hyperlipidemia. In addition, the hyperlipidemic state seen with primary biliary cirrhosis has not been well studied. We prospectively observed 312 patients with primary biliary cirrhosis for a median of 7.4 yr. During this period, 128 patients died. The incidence of atherosclerotic death in patients with primary biliary cirrhosis was not statistically different when compared with an age-matched and sex-matched U.S. control population. A similar group of 50 consecutive PBC patients had detailed serum lipid profiles. Findings included progressive increases in total cholesterol and low-density lipoprotein cholesterol with an increasing histological stage or severity of disease. High-density lipoprotein cholesterol was elevated in all stages, with the highest levels in histological stage 2 and 3 disease. Triglycerides were normal or slightly elevated in all stages. Apoprotein A-I was elevated in all but histological stage 4 disease. Our study suggests the hyperlipidemia associated with primary biliary cirrhosis does not place these patients at risk for atherosclerotic death. In light of the limitations imposed by our relatively small sample size, however, additional patients should be studied. Furthermore, an examination of the pathophysiological mechanisms leading to hypercholesterolemia should be the topic of further study.

Bronchoalveolar carcinoma: factors affecting survival.

One hundred thirty-four consecutive patients (65 men and 69 women) underwent pulmonary resection for bronchoalveolar carcinoma. Mean age was 65 years. Lobectomy was done in 100 patients, pneumonectomy in 10, segmentectomy in 5, and wedge excision in 19. Only 10 patients had lymph node metastases (7.5%). The neoplasm was solitary in 111 patients (82.8%); 97 were in stage I, 4 were in stage II, 9 were in stage IIIa, and 1 was in stage IIIb. There were two operative deaths (1.5%). Thirty-nine complications occurred in 31 patients. Median follow-up was 5.1 years. Recurrent bronchoalveolar carcinoma developed in 45 patients. Five- and 10-year survival for patients in stage I was 75.2% and 62.0%, respectively. Survival for patients with T1 N0 M0 neoplasms was identical to expected survival and was 90.5% at 5 years, as compared with 55.4% for patients with T2 N0 M0 disease, only 35.9% for patients with multiple bilateral disease, and 0.0% for patients with bilateral disease (p less than 0.0001). Other significant factors adversely affecting survival included the presence of signs and symptoms, diffuse malignant invasion, mucin-producing tumors, and the histological absence of scar. We conclude that bronchoalveolar carcinoma has a unique natural history that is more influenced by local neoplastic processes than by lymph node metastases. Early aggressive pulmonary resection is safe and offers the potential for cure. The presence of bilateral cancer, however, is ominous.

Comparison of the cross-linking patterns of lamprey fibrinogen and fibrin by the action of the intrinsic lamprey factor XIII and human factor XIII during the process of blood coagulation.

Intrinsic lamprey factor XIII cross-links the gamma chain of lamprey fibrin (50,000 daltons) to the gamma-dimer (100,000 daltons). The alpha-chain (110,000 daltons) is cross-linked very slowly to alpha-dimer (210,000 daltons) and alpha-trimer (330,000 daltons). In contrast, human factor XIII, when added in combination with intrinsic lamprey factor XIII, cross-links the alpha-chain of lamprey fibrin to a high molecular weight polymer, and any remaining gamma-chain is also cross-linked to a polymer. However, the gamma-chain that has previously cross-linked to the gamma-dimer by the intrinsic lamprey factor XIII remains as a gamma-dimer. Factor XIII-free lamprey fibrin cross-links all its subunits (alpha, beta, gamma) to high molecular weight polymers when human factor XIII is added. In contrast to human and bovine fibrin where alpha-chain cross-linking in the process of blood coagulation commences when all of the gamma-chain has cross-linked, the lamprey alpha-chain will begin to cross-link when approximately half of the gamma-chain has cross-linked to the gamma-dimer.