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R J Carroll

Publications and source records attributed to R J Carroll.

At least 55 records · Page 3Linked to original sources
PubMed1995

A transgene coding for a human insulin analog has a mitogenic effect on murine embryonic beta cells.

We have investigated the mitogenic effect of three mutant forms of human insulin on insulin-producing beta cells of the developing pancreas. We examined transgenic embryonic and adult mice expressing (i) human [AspB10]-proinsulin/insulin ([AspB10]ProIN/IN), produced by replacement of histidine by aspartic acid at position 10 of the B chain and characterized by an increased affinity for the insulin receptor; (ii) human [LeuA3]insulin, produced by the substitution of leucine for valine in position 3 of the A chain, which exhibits decreased receptor binding affinity; and (iii) human [LeuA3, AspB10]insulin "double" mutation. During development, beta cells of AspB10 embryos were twice as abundant and had a 3 times higher rate of proliferation compared with beta cells of littermate controls. The mitogenic effect of [AspB10]ProIN/IN was specific for embryonic beta cells because the rate of proliferation of beta cells of adults and of glucagon (alpha) cells and adrenal chromaffin cells of embryos was similar in AspB10 mice and controls. In contrast to AspB10 embryos, the number of beta cells in the LeuA3 and "double" mutant lines was similar to the number in controls. These findings indicate that the [AspB10]ProIN/IN analog increased the rate of fetal beta-cell proliferation. The mechanism or mechanisms that mediate this mitogenic effect remain to be determined.

Amino Acid Sequence↗
PubMed1995

International comparison of waiting times for selected cardiovascular procedures.

OBJECTIVES: This study was designed to compare waiting times for cardiovascular procedures in five different health care delivery/financing systems. BACKGROUND: A recurrent criticism of national health care systems is long waiting times, or "queues," for high technology procedures. However, no objective data exist comparing waiting times in the United States with those in other systems. METHODS: Directors of cardiac catheterization laboratories, directors of cardiac surgery in the United States, U.S. Department of Veterans Affairs (VA) system, Canada and the United Kingdom and directors of cardiology clinics in Sweden were asked to respond to a mailed questionnaire as to how long it would take to obtain coronary angiography or coronary artery bypass surgery, or both, for specified case scenarios at their institutions. RESULTS: Significant differences in waiting times (p < 0.00001) were found among the systems for all four scenarios (elective and urgent angiography, elective and urgent bypass surgery). Compared with non-VA hospitals in the United States, waiting times were significantly longer in all systems, with the exception of waiting times for urgent surgery in the U.S. VA hospitals (p = 0.9). The longest waiting times for all four procedures were reported in the United Kingdom, Sweden and Canada, with some waiting times for elective procedures > 9 months. CONCLUSIONS: Physicians report that patients treated in health care systems structured differently from the non-VA hospital system in the United States wait significantly longer for cardiac catheterization and coronary artery bypass surgery.

Canada↗
PubMed1995

Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity.

Mice homozygous for the fat mutation develop obesity and hyperglycaemia that can be suppressed by treatment with exogenous insulin. The fat mutation maps to mouse chromosome 8, very close to the gene for carboxypeptidase E (Cpe), which encodes an enzyme (CPE) that processes prohormone intermediates such as proinsulin. We now demonstrate a defect in proinsulin processing associated with the virtual absence of CPE activity in extracts of fat/fat pancreatic islets and pituitaries. A single Ser202Pro mutation distinguishes the mutant Cpe allele, and abolishes enzymatic activity in vitro. Thus, the fat mutation represents the first demonstration of an obesity-diabetes syndrome elicited by a genetic defect in a prohormone processing pathway.

Amino Acid Sequence↗
PubMed1995

Adjusting for time trends when estimating the relationship between dietary intake obtained from a food frequency questionnaire and true average intake.

In measuring food intake, three common methods are used: 24-hour recalls, food frequency questionnaires and food records. Food records or 24-hour recalls are often thought to be the most reliable, but they are difficult and expensive to obtain. The question of interest to us is to use the food records or 24-hour recalls to examine possible systematic biases in questionnaires as a measure of usual food intake. In Freedman, et al. (1991), this problem is addressed through a linear errors in variables analysis. Their model assumes that all measurements on a given individual have the same mean and variance. However, such assumptions may be violated in at least two circumstances, as in for example the Women's Health Trial Vanguard Study and in the Finnish Smokers' Study. First, some studies occur over a period of years, and diets may change over the course of the study. Second, measurements might be taken at different times of the year, and it is known that diets differ on the basis of seasonal factors. In this paper, we will suggest new models incorporating mean and variance offsets, i.e., changes in the population mean and variance for observations taken at different time points. The parameters in the model are estimated by simple methods, and the theory of unbiased estimating equations (M-estimates) is used to derive asymptotic covariance matrix estimates. The methods are illustrated with data from the Women's Health Trial Vanguard Study.

Analysis of Variance↗
PubMed1995

Analysis of tomato root initiation using a normal mixture distribution.

We attempt to identify the number of underlying physical phenomena behind tomato lateral root initiation by using a normal mixture distribution coupled with the Box-Cox power transformation. An initial analysis of the data suggested the possibility of two (possibly more) subpopulations, but upon taking reciprocals, the data appear to be very nearly Gaussian. A simulation study explores the possibility of erroneously detecting a second subpopulation by fitting data which are improperly scaled. A power calculation suggests that only unrealistically large sample sizes can detect the unbalanced mixtures one might expect with data of this type.

Biometry↗
PubMed1994

Measurement error, instrumental variables and corrections for attenuation with applications to meta-analyses.

MacMahon et al. present a meta-analysis of the effect of blood pressure on coronary heart disease, as well as new methods for estimation in measurement error models for the case when a replicate or second measurement is made of the fallible predictor. The correction for attenuation used by these authors is compared to others already existing in the literature, as well as to a new instrumental variable method. The assumptions justifying the various methods are examined and their efficiencies are studied via simulation. Compared to the methods we discuss, the method of MacMahon et al. may have bias in some circumstances because it does not take into account: (i) possible correlations among the predictors within a study; (ii) possible bias in the second measurement; or (iii) possibly differing marginal distributions of the predictors or measurement errors across studies. A unifying asymptotic theory using estimating equations is also presented.

Bias↗
PubMed1992

Estimating HIV prevalence and projecting AIDS incidence in the United States: a model that accounts for therapy and changes in the surveillance definition of AIDS.

The AIDS incubation distribution is changing in calendar time because of treatment and changes in the surveillance definition of AIDS. To obtain reliable estimates of HIV prevalence and projections of AIDS incidence in the 1990s using the method of backcalculation, we constructed an appropriate incubation distribution for each calendar date of infection. We parameterized the impact of treatment on the incubation distribution by specifying the relative hazard for AIDS in treated versus untreated people as a function of duration of HIV infection. To account for trends in the incubation distribution, we modelled the prevalence of treatment, the distribution of treatment onset times, and the impact of the revision of the AIDS surveillance definition in 1987. We selected and evaluated backcalculation models based on consistency with external information. We defined a 'plausible range' of estimates that took into account uncertainty about the natural incubation distribution and treatment efficacy, as well as bootstrap assessment of stochastic error. Using these methods, we projected that national United States AIDS incidence will plateau during 1991-1994 at over 50,000 cases per year. Projections exhibited substantial systematic uncertainty, and we calculated a plausible range for AIDS incidence in 1994 of 42,300 to 70,700 cases. An estimated 628,000 to 988,000 cumulative HIV infections occurred as of 1 January 1991. After accounting for AIDS mortality, we estimated that 484,000 to 844,000 people were living with HIV infection on 1 January 1991. Favourable trends in HIV incidence appeared in gay men and intravenous drug users. Plausible ranges for our estimates overlapped with those from a 'stage model' approach to incorporating treatment effects in backcalculations. Our approach, however, tended to yield smaller estimates of epidemic size, mainly because the parameters used with the stage model implied that more treatment was in use and that treatment was more effective than in our model.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.

We reviewed all studies since 1940 on the prognosis of squamous cell carcinoma (SCC) of the skin and lip. The following variables are correlated with local recurrence and metastatic rates: (1) treatment modality, (2) prior treatment, (3) location, (4) size, (5) depth, (6) histologic differentiation, (7) histologic evidence of perineural involvement, (8) precipitating factors other than ultraviolet light, and (9) host immunosuppression. Local recurrences occur less frequently when SCC is treated by Mohs micrographic surgery. This local recurrence rate differential in favor of Mohs micrographic surgery holds true for primary SCC of the skin and lip (3.1% vs 10.9%), for ear SCC (5.3% vs 18.7%), for locally recurrent (previously treated) SCC (10% vs 23.3%), for SCC with perineural involvement (0% vs 47%), for SCC of size greater than 2 cm (25.2% vs 41.7%), and for SCC that is poorly differentiated (32.6% vs 53.6%).

Carcinoma, Squamous Cell↗
PubMed1991

Estimating the relation between dietary intake obtained from a food frequency questionnaire and true average intake.

Knowledge of the regression relation between dietary intake reported on a food frequency questionnaire and true average intake is useful in interpreting results from nutritional epidemiologic studies and in planning such studies. Studies which validate a questionnaire against a food record may be used to estimate this regression relation provided the food record is completed by each subject on at least two occasions. Using data collected from women aged 45-69 years during 1985-1986 in the pilot study of the Women's Health Trial, the authors show how variation in diet over time and intraindividual correlation between a questionnaire and food record obtained close together in time affects the estimation of the regression. The authors' method provides estimates of the regression slope and the questionnaire "bias" that are corrected for these effects, together with standard errors. A computer program in the SAS language, for carrying out the analysis, is provided.

Aged↗
PubMed1990

Lack of islet amyloid polypeptide regulation of insulin biosynthesis or secretion in normal rat islets.

We examined the effects of rat islet amyloid polypeptide (IAPP) on insulin biosynthesis and secretion by isolated rat islets of Langerhans. Culture of islets for 24 h in the presence of 10(-6) M IAPP and 5.5 mM glucose had no effect on insulin mRNA levels. Similarly, the rates of proinsulin biosynthesis were not altered in islets incubated in 10(-4)-10(-9) M IAPP and 5.5 mM glucose, nor was the rate of conversion of proinsulin to insulin changed at 10(-6) M IAPP. Addition of 10(-5) M IAPP to islets incubated in 11 mM glucose decreased the fractional insulin secretion rate; however, the secretion of newly synthesized proinsulin and insulin was not affected. These data indicate that it is unlikely that IAPP is a physiologically relevant modulator of insulin biosynthesis or secretion.

Amyloid↗
PubMed1989

Weights for data related by a tree.

How can one characterize a set of data collected from different biological species, or indeed any set of data related by an evolutionary tree? The structure imposed by the tree implies that the data are not independent, and for most applications this should be taken into account. We describe strategies for weighting the data that circumvent some of the problems of dependency.

Animals↗
PubMed1989

Covariance analysis in generalized linear measurement error models.

We summarize some of the recent work on the errors-in-variables problem in generalized linear models. The focus is on covariance analysis, and in particular testing for and estimation of treatment effects. There is a considerable difference between the randomized and non-randomized models when testing for an effect. In randomized studies, simple techniques exist for testing for a treatment effect. In some instances, such as linear and multiplicative regression, simple methods exist for estimating the treatment effect. In other examples such as logistic regression, estimating a treatment effect requires careful attention to measurement error. In non-randomized studies, there is no recourse to understanding and modelling measurement error. In particular ignoring measurement error can lead to the wrong conclusions, for example the true but unobserved data may indicate a positive effect for treatment, while the observed data indicate the opposite. Some of the possible methods are outlined and compared.

Analysis of Variance↗
PubMed1989

Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up.

We reviewed all studies (since 1947) reporting recurrence rates for treatment of primary (previously untreated) basal cell carcinomas using surgical excision, radiotherapy, cryotherapy, curettage and electrodesiccation, and Mohs micrographic surgery. Our findings indicate that recurrences following treatment of primary basal cell carcinoma appear later than is generally acknowledged in the literature. We found that less than one-third of all recurrences appear in the first year following treatment; only 50% appear within the first 2 years following treatment; and only 66%, or nearly two-thirds, appear within the first 3 years following treatment. A good rule of thumb is that the 10-year recurrence rate is double, or 2 times, that of the 2-year recurrence rate. Furthermore, 18% of recurrences appear between the fifth and tenth year following treatment. These results held true, irrespective of treatment modality examined. Seventy-two studies reporting short-term recurrence rates (follow-up less than 5 years) had a weighted average recurrence rate of 4.2%, whereas 34 long-term studies (follow-up of 5 years) had a weighted average recurrence rate of 8.7%, or more than 2 times the short-term rate. Five-year recurrence rates by treatment modality are as follows: Mohs micrographic surgery 1.0%, surgical excision 10.1%, curettage and electrodesiccation 7.7%, radiation therapy 8.7%, and cryosurgery 7.5%. We conclude that the reporting of recurrence rate data for basal cell carcinoma should be standardized using 5-year life table analysis, and even more important is our conclusion that lifetime follow-up is necessary after treatment of primary basal cell carcinoma in order both recurrences and new primaries.

Basal Cell Carcinoma↗
PubMed1989

Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma.

We reviewed all studies (since 1945) reporting recurrence rates for treatment of recurrent (previously treated) basal cell carcinomas (BCC) using surgical excision, radiotherapy, cryotherapy, curettage and electrodesiccation, and Mohs micrographic surgery. The 5-year recurrence rate for Mohs micrographic surgery is 5.6%. The recurrence rate for non-Mohs modalities of 19.9% is nearly four times higher. Individual recurrence rates for the non-Mohs modalities are 17.4% for surgical excision, 40.0% for curettage and electrodesiccation, and 9.8% for radiation therapy. There are no studies reporting 5-year data for cryotherapy. However, the recurrence rate is 13.0% for cryotherapy when the follow-up period is less than five years. The data support the following conclusions: (1) Mohs surgery is the treatment of choice for recurrent BCC; (2) if the patient is not a surgical candidate and the lesion is small, radiation therapy is an alternative that offers a better chance for cure than the other non-Mohs modalities; and (3) curettage and electrodesiccation should not be used to treat recurrent basal cell carcinoma.

Basal Cell Carcinoma↗
PubMed1988

A mutant human proinsulin is secreted from islets of Langerhans in increased amounts via an unregulated pathway.

A coding mutation in the human insulin gene (His-B10----Asp) is associated with familial hyperproinsulinemia. To model this syndrome, we have produced transgenic mice that express high levels of the mutant prohormone in their islets of Langerhans. Strain 24-6 mice, containing about 100 copies of the mutant gene, were normoglycemic but had marked increases of serum human proinsulin immunoreactive components. Biosynthetic studies on isolated islets revealed that approximately 65% of the proinsulin synthesized in these mice was the human mutant form. Unlike the normal endogenous mouse proinsulin, which was almost exclusively handled via a regulated secretory pathway, up to 15% of the human [Asp10]proinsulin was rapidly secreted after synthesis via an unregulated or constitutive pathway, and approximately 20% was degraded within the islet cells. The secreted human [Asp10]proinsulin was not processed proteolytically. However, the processing of the normal mouse and human mutant proinsulins within the islets from transgenic mice was not significantly impaired. These findings suggest that the hyperproinsulinemia of the patients is the result of the continuous secretion of unprocessed mutant prohormone from the islets via this alternative unregulated pathway.

Animals↗
PubMed1986

Mechanism of in vitro collagen fibril assembly. Kinetic and morphological studies.

The kinetics of in vitro fibril assembly of Type I collagen preparations that contain different amounts of covalently cross-linked oligomers was studied with turbidimetry. Fibril formation showed a lag phase with no solution turbidity and a growth phase with a sigmoidal increase in the solution turbidity. The length of the lag phase was inversely related to both the total collagen concentration and the amount of covalently cross-linked oligomers in the solution. Double logarithmic plots of t1/4, the amount of time it takes for 1/4 of the collagen to assemble into fibrils, versus the total collagen concentration were linear but the slope decreased from -0.84 to -2.3 with decreasing amounts of covalently cross-linked oligomers in the samples. Electron microscopy showed the formation of unbanded microfibrils with diameters in the range of 3-15 nm early in the lag phase and larger diameter banded fibrils coexisting with the microfibrils near the end of the lag phase. Centrifugation of the solution at the lag phase prolonged the lag time, presumably by removal of microfibrils, but subsequent growth of the fibrils was unaffected. The results suggest a cooperative nucleation-growth mechanism for the in vitro assembly of collagen fibrils which is consistent with the results of an equilibrium study of the fibril assembly reaction we reported earlier (Na, G. C., Butz, L. J., Bailey, D. G., and Carroll, R. J. (1986) Biochemistry 25, 958-966).

Animals↗
PubMed1986

In vitro collagen fibril assembly in glycerol solution: evidence for a helical cooperative mechanism involving microfibrils.

Glycerol inhibits the in vitro self-association of monomeric collagen into fibrils and induces the dissociation of fibrils preassembled from NaBH4-reduced collagen. These effects were investigated in an effort to understand the mechanism of fibril assembly of the protein. In PS buffer (0.03 M NaPi and 0.1 M NaCl, pH 7.0) containing 0.1-1.0 M glycerol, the self-association of type I collagen from calf skin took place only if the protein concentration was above a critical value. This critical protein concentration increased with increasing glycerol concentration. Velocity sedimentation studies showed that below the critical protein concentration and under fibril assembly conditions, the collagen was predominantly in a monomeric state. Electron microscopic examinations revealed that the collagen aggregates formed above the critical concentration consisted mostly of microfibrils of 3-5-nm diameter along with some banded fibrils were found. Collagen treated with pepsin to remove its nonhelical telopeptides also self-associated into microfibrils and fibrils in the presence of glycerol, but the reaction did not exhibit any critical concentration. These results are consistent with a mechanism of in vitro collagen fibril assembly which involves the initial formation of microfibrils through a helical cooperative mechanism. They also suggest that contacts of the nonhelical telopeptides of each collagen with its neighboring molecules provide the necessary negative free energy change for the cooperativity and that subsequent lateral association of the microfibrils leads to banded fibrils.

Animals↗