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J L Mills

Publications and source records attributed to J L Mills.

At least 37 records · Page 2Linked to original sources
PubMed2000

An economic appraisal of lower extremity bypass graft maintenance.

OBJECTIVE: Infrainguinal graft surveillance leads to intervention on the basis of duplex-identified stenoses. We have become increasingly concerned about the high frequency with which such revisions are required to maximize graft patency and limb salvage rates. The economic implications of these procedures have not been carefully analyzed or justified. METHODS: We retrospectively reviewed 155 consecutive autogenous infrainguinal bypass grafts performed for chronic leg ischemia in 141 patients. All patients were enrolled in a prospective surveillance program using color flow duplex imaging. Full economic appraisal (cost analysis, cost-effect analysis, and cost-benefit analysis) was performed for all graft surveillance and limb salvage-related interventions through use of standard accounting and valuation techniques. RESULTS: Mean follow-up was 27 months. Five-year assisted primary patency (72%) and limb salvage rates (91%) were calculated by means of life table analysis. A total of 61 grafts required 86 revisions. Within 1 year of implantation, 36% of the grafts required revision. During this first year, the mean cost per graft enrolled was $9417. Time intervals after the initial year demonstrated a reduced annual revision rate (6%) and cost ($1725 per graft). The mean 5-year cost of graft maintenance ($16,318) approached that of the initial bypass graft ($19,331). The sum of the initial cost of bypass graft and 5-year graft maintenance cost ($35,649) was similar to the cost of amputation ($36,273). Grafts revised for duplex-detected stenoses (n = 46), in comparison with those revised after thrombosis (n = 15), had an improved 1-year patency (93% vs 57%; P <.01), required fewer amputations (2% vs 33%; P <.01), less frequently required multiple graft revisions (P =.06), and generated fewer expenses (at 12 months after revision, $17,688 vs $45,252, P <.01). CONCLUSION: The cost associated with graft maintenance is significant, particularly within the first year, and demands consideration. Revision of a duplex-identified stenosis was significantly less costly than revision after graft thrombosis. Compared with the cost of limb amputation, limb salvage-related expenses appear to be justified.

Aged↗
PubMed2000

Distal revascularization-interval ligation for maintenance of dialysis access and restoration of distal perfusion in ischemic steal syndrome.

Ischemic steal syndrome after hemodialysis access challenges the clinician to reconcile the dichotomy of maintenance of access patency and restoration of distal limb perfusion. Results from traditional procedures directed toward increasing the resistance in the fistula (eg, banding, lengthening) have yielded unreliable results and frequently eventuate in fistula thrombosis. The recently described technique of distal revascularization, interval ligation (DRIL) provides a more physiological approach. Based on several recent series, application of the technique has provided excellent resolution of ischemic symptoms and superior preservation of fistula patency.

Arteriovenous Shunt, Surgical↗
PubMed1999

Methylenetetrahydrofolate reductase thermolabile variant and oral clefts.

Folic acid can prevent neural tube defects; in some cases the mechanism is probably a correction of a metabolic defect caused by thermolabile methylenetetrahydrofolate reductase (MTHFR) found in increased frequency in cases. It is less clear whether folic acid can prevent oral clefts, in part because it is not known whether thermolabile MTHFR is more common in those with oral clefts. This study examined the prevalence of the mutation (677 C-->T) that causes thermolabile MTHFR in subjects with oral clefts from a national Irish support group, and an anonymous control group randomly selected from a neonatal screening program covering all births in Ireland. Eighty-three of 848 control subjects were homozygous (TT) thermolabile MTHFR (9.8%). This defect was almost three times as common in the 27 subjects (25.9%) with isolated cleft palate (odds ratio 3.23, 95% confidence interval 1.32 -7.86, P = 0. 02) and somewhat more common in the 66 subjects with cleft lip with or without cleft palate (15.2%, odds ratio 1.65, 95% confidence interval 0.81-3.35, P = 0.20). When the two groups with different etiologies were combined, the overall odds ratio was 2.06 (95% confidence interval 1.16-3.66, P = 0.02). In the Irish population homozygosity for the common folate-related polymorphism associated with thermolabile MTHFR is significantly more frequent in those with isolated cleft palate, and could be etiologically important. Am. J. Med. Genet. 86:71-74, 1999. Published 1999 Wiley-Liss, Inc.

Child↗
PubMed1999

Prostacyclin and thromboxane changes predating clinical onset of preeclampsia: a multicenter prospective study.

CONTEXT: An imbalance in vasodilating (prostacyclin [PGI2]) and vasoconstricting (thromboxane A2 [TxA2]) eicosanoids may be important in preeclampsia, but prospective data from large studies needed to resolve this issue are lacking. Because most trials using aspirin to reduce TxA2 production have failed to prevent preeclampsia, it is critical to determine whether eicosanoid changes occur before the onset of clinical disease or are secondary to clinical manifestations of preeclampsia. OBJECTIVE: To determine whether PGI2 or TxA2 changes occur before onset of clinical signs of preeclampsia. DESIGN, SETTING, AND PARTICIPANTS: Multicenter prospective study from 1992 to 1995 of subjects from the placebo arm of the Calcium for Preeclampsia Prevention Trial. Women who developed preeclampsia (n = 134) were compared with matched normotensive control women (n = 139). MAIN OUTCOME MEASURES: Excretion of urinary metabolites of PGI2 (PGI-M) and TxA2 (Tx-M) as measured from timed urine collections obtained prospectively before 22 weeks', between 26 and 29 weeks', and at 36 weeks' gestation. RESULTS: Women who developed preeclampsia had significantly lower PGI-M levels throughout pregnancy, even at 13 to 16 weeks' gestation (long before the onset of clinical disease); their gestational age-adjusted levels were 17% lower than those of controls (95% confidence interval [CI], 6%-27%; P=.005). The Tx-M levels of preeclamptic women were not significantly higher overall (9% higher than those of controls; 95% CI, -3% to 23%; P=.14). The ratio of Tx-M to PGI-M, used to express relative vasoconstricting vs vasodilating effects, was 24% higher (95% CI, 6%-45%) in preeclamptic women throughout pregnancy (P=.007). CONCLUSIONS: Our results show that reduced PGI2 production, but not increased TxA2 production, occurs many months before clinical onset of preeclampsia. Aspirin trials may have failed because an increase in thromboxane production is not the initial anomaly. Future interventions should make correcting prostacyclin deficiency a major part of the strategy to balance the abnormal vasoconstrictor-vasodilator ratio present in preeclampsia.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Folate status and neural tube defects.

Periconceptional folic acid supplementation prevents approximately 70% of neural tube defects (NTDs). While most women carrying affected fetuses do not have deficient blood folate levels, the risk of having an NTD affected child is inversely correlated with pregnancy red cell folate levels. Current research is focused on the discovery of genetic abnormalities in folate related enzymes which might explain the role of folate in NTD prevention. The first candidate gene to emerge was the C677T variant of 5,10-methylenetetrahydrofolate reductase. Normal subjects who are homozygous for the mutation (TT) have red cell folate status some 20% lower than expected. It is now established that the prevalence of the TT genotype is significantly higher among spina bifida cases and their parents. Nevertheless, our studies show that the variant does not account for the reduced blood folate levels in many NTD affected mothers. We conclude that low maternal folate status may in itself be the most important risk factor for NTDs and that food fortification may be the only population strategy of benefit in the effort to eliminate NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1999

Methionine synthase: high-resolution mapping of the human gene and evaluation as a candidate locus for neural tube defects.

Periconceptual folate supplementation has been found to prevent the occurrence of many neural tube defects (NTDs). Consequently, genetic variation in folate metabolism genes is expected to contribute to the risk for neural tube defects. Methionine synthase catalyzes the vitamin B(12)-dependent conversion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahydrofolate. The observation that homocysteine and vitamin B(12) levels are independent predictors of NTD risk suggested that methionine synthase could be a candidate gene for NTDs. To assess the role of the MS gene in NTDs, we performed high-resolution physical mapping of the MS locus, isolated highly polymorphic markers linked to the MS gene, and tested for an association between specific MS alleles and NTDs. We mapped the MS gene to a position between 909 and 913 cR(10000) on chromosome 1 by radiation hybrid mapping. Polymorphic markers D1S1567 and D1S1568 map to locations no more than 900 and 194 kb from the MS gene, respectively. The segregation of these polymorphic markers was measured in 85 Irish NTD families. No allele of either marker showed a significant association with NTDs using the transmission disequilibrium test. A lack of association was also observed for the D1919G missense mutation within the gene. Our results suggest that inherited variation in the MS gene does not contribute to NTD risk in this population.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1999

The correlation of early flow disturbances with the development of infrainguinal graft stenosis: a 10-year study of 341 autogenous vein grafts.

PURPOSE: Although duplex surveillance of infrainguinal bypass grafts is widely accepted, the optimal frequency and intensity of graft surveillance remains controversial. Earlier reports have suggested that grafts can be stratified into high-risk and low-risk groups based on the presence or absence of early graft flow disturbances. The purpose of this study was to provide long-term data in determining whether early graft flow disturbances detected by means of duplex scanning can predict the development of intrinsic vein graft stenosis. METHODS: We reviewed a series of patients undergoing prospective duplex graft surveillance after autogenous infrainguinal bypass grafting procedures from 1987 to 1997. Patients included in the study underwent at least one duplex scan within 3 months of graft implantation and were observed for a minimum of 6 months. Grafts were categorized as abnormal when a focal flow disturbance with a peak systolic velocity greater than 150 cm/s was identified within 3 months of graft implantation. RESULTS: Of 341 vein grafts in 296 patients who met inclusion criteria, 89 grafts (26%) required revision for intrinsic stenosis; the mean follow-up period was 35 months (range, 6 months to 10 years). Early flow disturbances were detected in 84 (25%) grafts. Grafts with early flow disturbances were more likely to ultimately require revision (43% vs 21%; P =. 0001) and required initial revision earlier (8 months vs 16 months; P =.019). Eighty-two percent of initial graft revisions occurred in the first 2 postoperative years; 69% occurred in the first year. However, an annual 2% to 4% incidence of late-appearing graft stenosis persisted during long-term follow-up. An additional 24 patients (7% of grafts) required an inflow or outflow reconstruction. CONCLUSION: Grafts with early postoperative flow disturbances detected by means of duplex scanning have nearly three times the incidence of graft-threatening stenosis and an earlier requirement for revision, when compared with normal grafts. This suggests that the biology and etiology of these lesions may differ. These data support not only aggressive efforts to detect early graft lesions to stratify grafts at highest risk, but also continued lifelong graft surveillance to detect late-appearing lesions, inflow and outflow disease progression, and maximize graft patency.

Aged↗
PubMed1999

Characterization of cellular density and determination of neointimal extracellular matrix constituents in human lower extremity vein graft stenoses.

UNLABELLED: Arterial restenosis has been attributed to a hyperproliferative smooth muscle cell response. Paradoxically, studies of human coronary atherectomy and vein graft stenotic lesions have demonstrated a relatively low nuclear proliferative rate with the majority of the neointimal mass consisting of extracellular matrix. The purpose of the present study was to characterize the cellular density and determine the relative composition of the extracellular matrix protein constituents in stenotic, human lower extremity vein-bypass graft lesions. METHODS: Duplex surveillance of 148 consecutive infrainguinal bypass grafts identified 17 patients with 22 preocclusive autogenous vein graft stenoses (mean graft age 7 months). Morphological analyses of these stenotic lesions were compared with excised samples of 20 greater saphenous vein segments taken at the time of graft implantation from matched control patients. Intimal and medial areas were compared and cell density was determined with fluorescent nuclear (Bisbenzimide) staining. Differential light microscopy with pentachrome staining was performed to determine the relative percent composition of intimal matrix constituents by stereological morphometric (point-count) techniques. RESULTS: The intimal areas for control and stenotic vein segments were 1.64 x 10(6) microm2 and 3.85 x 10(6) microm2, P < 0.0001, whereas the intimal nuclear densities (cells/unit volume) were 1.42 x 10(3) and 1.70 x 10(3) cells/microm2, P = 0.03. respectively. The corresponding medial area and medial nuclear densities were 5.01 x 10(6) microm2, 3.31 x 10(6) microm2; P = 0.08, and 2.27 x 10(3), 3.29 x 10(3); P = 0.001, for control and stenotic specimens, respectively. The intima:media area ratios were much greater, whereas the intimal and medial cell densities were only slightly greater in the stenotic compared with control veins. The relative composition of intimal extracellular matrix proteins of stenotic vein graft segments consisted of 21% cellular (fibrous) material, 33% collagen, and 46% glycosaminoglycan ground substance. CONCLUSION: The intimal lesions responsible for lower extremity vein graft stenosis are more hypertrophic than hyperplastic. Therapies aimed at preventing arterial and vein graft restenosis may thus need to inhibit matrix biosynthetic processes in addition to cellular proliferation.

Aged↗
PubMed1999

The "thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother.

Recent reports have implicated the "thermolabile" (T) variant of methylenetetrahydrofolate reductase (MTHFR) in the causation of folate-dependent neural tube defects (NTDs). We report herein the largest genetic study of NTD cases (n=271) and families (n=218) to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P=.0005). The maternal and paternal TT genotypes have intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P=.02) but no evidence of a maternal TT genotypic effect (P=. 83). The log-linear model predicted that the risk of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype.

Alleles↗
PubMed1999

The influence of 5,10 methylenetetrahydrofolate reductase genotypes on enzyme activity in placental tissue.

OBJECTIVE: To study the effects of heterozygosity and homozygosity for the C677T mutation of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene on the activity of this enzyme in placental tissue from pregnancies not affected by neural tube defect. DESIGN: Placental tissue was genotyped for the C677T variants of MTHFR. Total enzyme activity and residual activity after heating to 46 degrees C for 5 minutes was then measured. SETTING: A teaching hospital. SAMPLE: Placental samples (n = 200), one from each of 200 uncomplicated term deliveries. MAIN OUTCOME MEASURES: Total and residual enzyme activity for MTHFR. RESULTS: Placentae heterozygous for the C677T mutation of the MTHFR gene had significantly lower total enzyme activity than those without the mutation; the lowest activity occurred in homozygotes for the mutation. The same pattern was seen in relation to enzyme activity after heating. CONCLUSION: This study demonstrates that reduced enzyme activity is associated with the C677T variant of MTHFR in placental tissue. This is an important metabolic step in folic acid metabolism and pro-

Biomarkers↗
PubMed1998

Topography of cell replication in human vein graft stenoses.

BACKGROUND: Analysis of the cellular composition of human autogenous vein graft lesions at the time of revision provides an opportunity to identify the cellular processes leading to the development of stenosis in humans after vascular reconstruction. METHODS AND RESULTS: Human vein graft-threatening stenotic lesions were identified by duplex scanning within 3 to 18 months after infrainguinal bypass and surgically removed. They were serially studied by immunocytochemistry for expression of the proliferating cell nuclear antigen (PCNA) in different cell types: alpha-actin-positive smooth muscle cells (SMCs), endothelial cells (ECs), monocytes, and macrophages. Proliferation indexes were separately obtained for each layer of the vessel wall by determining the mean percentage of PCNA-positive nuclei among the total number of nuclei present within the intima, the media, and the adventitia, respectively. The percentage distribution of the replicating cell types was also determined. We report that in autogenous vein graft (n = 14) the intima of the lesion displayed fewer PCNA + nuclei (1.03 +/- 0.88) than the underlying media (3.14 +/- 0.74) or the adventitia (3.01 +/- 0.74). Replicating SMCs were predominantly in the medial layer (68% of PCNA + cells) of stenotic vein grafts. In the adventitia, the proliferation was most intense in the endothelium of microvessels (65% of PCNA + nuclei). CONCLUSIONS: Our findings reveal a 3-fold greater proliferative activity in the media and the adventitia as compared with the intima of autogenous vein graft lesions, in contrast to cellular proliferation identified in recurrent coronary stenotic plaques. Moreover, there are distinctive patterns of distribution of the different cell populations among the 3 layers. The results indicate a proliferative response of the media and the adventitia of autogenous vein grafts transplanted into the arterial circulation, in addition to the cellular proliferation observed in the intima of the lesion.

Actins↗
PubMed1998

Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: low folate status alone may be the critical factor.

Thermolabile 5,10-methylenetetrahydrofolate reductase (MTHFR) is the first folate-related variant to be associated with an increased risk of neural tube defects (NTDs). The variant causes high plasma homocysteine levels and reduced red cell folate (RCF) levels, both of which have also been linked to an increased risk of NTDs. We examined the relationship between folate status and presence of the common mutation MTHFR C677T in 82 NTD-affected and 260 control mothers. Homozygosity for the TT genotype was associated with very low folate status among both the cases (n = 13) and the controls (n = 21). However, after exclusion of TT homozygotes, only 10% of the remaining 240 controls had RCF levels less than 200 microg/L compared with 29% of the 69 cases (odds ratio, 3.67; 95% confidence interval, 1.88-7.18; P < 0.001), and those with RCF less than 150 microg/L had eight times higher risk of NTD than subjects with levels over 400 microg/L. Plasma homocysteine levels of non-TT cases were also higher than those of controls (P = 0.047). This study shows that homozygosity for the C677T MTHFR variant cannot account for reduced blood folate levels in many NTD-affected mothers. Thus, a strategy of genetic screening of all childbearing women for this variant would be ineffective as a method of primary prevention of NTDs. The data suggest that low maternal folate status is itself the major determinant of NTD risk, or else that other folate-dependent genetic variants confer risk through the reduction of folate levels. These results emphasize the importance of a food-fortification program as a population strategy for reducing the occurrence of NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1998

Smoking in adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Health-related behaviors are of particular concern in survivors of childhood cancer as they are at increased risk for second cancers and long-term organ dysfunction. The purpose of this study was to compare the smoking behavior and associated factors in young-adult survivors of childhood acute lymphoblastic leukemia (ALL) with those in sibling controls. METHODS: A telephone interview that surveyed smoking behavior was conducted with 592 young-adult survivors, treated before age 20 years on Children's Cancer Group ALL protocols, and 409 sibling controls. Using stratified chi-squared analyses and Cox proportional hazards models, we compared the rates of smoking initiation and smoking cessation between survivors and control subjects. Demographic characteristics (age, sex, race, and education) and psychological factors (mood and self-concept) were examined as predictors interacting with survivorship in logistic regression analyses to try to distinguish a subgroup of survivors who may be at greater risk for smoking. RESULTS: Survivors were significantly less likely to have ever smoked (23.0% versus 35.7%; P<.0001) and thus were less likely to ever be regular, daily smokers than sibling controls (19.1% versus 31.3%; P<.0001). Survivors were less likely to quit smoking than sibling controls (26.6% versus 35.2%), although this result was not statistically significant. There were no interactions between survivor status and either demographic or psychological features on smoking behavior. CONCLUSIONS: Young-adult survivors of childhood ALL are less likely to experiment with smoking but, once having started, are at similar risk for becoming habitual, persistent smokers as sibling controls.

Actuarial Analysis↗
PubMed1998

The histologic characteristics of primary and restenotic carotid plaque.

BACKGROUND: Although smooth muscle cell proliferation is a prominent feature of restenosis in experimental models, the role of cellular proliferation in the initiation and progression of carotid restenosis is not well documented. METHODS: Between 1985 and 1995, 35 carotid endarterectomies (CEA) in 34 patients were performed for restenosis. Patient risk factors, cerebrovascular symptoms, and operative findings were recorded. Tissue specimens from 29 of these cases and 14 original specimens from the same patient were examined by light microscopy (H&E, trichrome, elastochrome, and Alcian blue) and immunohistochemistry (alpha actin, CD 68, vWF, and proliferating nuclear cell antigen (PCNA)) in order to determine the morphologic characteristics and cellular proliferative activity of the plaque. RESULTS: Hemodynamically significant recurrent stenosis occurred in the 29 patients (69% symptomatic) between 2 months and 30 years after their initial CEAs. Eleven of 29 (38%) lesions were removed early (< 3 years). Recurrent lesions were characterized based on their components as neointimal thickening, 24% (7/29), neointimal thickening and atherosclerosis, 55% (16/29), or atherosclerotic, 21% (6/29). Nineteen of 29 (66%) plaques were complicated by mural thrombus or intraplaque hemorrhage. An inflammatory cell infiltrate consisting of macrophages and T lymphocytes was observed adjacent to areas of recurrent atherosclerosis and macrophages in regions of intimal thickening. Although infrequently present (generally 1-3% of cells) PCNA-positive cells were detected in 41% (12 of 29) of recurrent and 14% (2 of 14) of primary plaques. No PCNA-positive cells were detected in the remaining 67% (29 of 43) of specimens. There was no statistical difference in the number of PCNA-positive cells in early recurrent lesions compared to those recurring after 3 years (36% vs 44%). PCNA immunoreactivity when present was most commonly noted in macrophages associated with thrombus or atheroma rather than smooth muscle cells. CONCLUSIONS: Although evidence of cellular proliferation was observed in 40% of recurrent carotid endarterectomy lesions, the proliferation rate was low (1-3%) and unrelated to the time interval of recurrence. Proliferative activity was most pronounced in macrophages associated with intraplaque hemorrhage or atheroma. The contribution of inflammatory cells to the biologic behavior of restenotic lesions requires further investigation.

Adult↗
PubMed1998

Analysis of the human Sonic Hedgehog coding and promoter regions in sacral agenesis, triphalangeal thumb, and mirror polydactyly.

The human Sonic Hedgehog gene (SHH) is one of the vertebrate homologs related to the Drosophila segment polarity gene hedgehog. The entire coding and promoter region of the SHH gene, including 2 kb 5' of the transcriptional start site has been screened for mutations in families with autosomal dominant sacral agenesis and autosomal dominant triphalangeal thumb, two conditions previously known to be linked to 7q36. We have also studied the SHH gene in five families with mirror polydactyly associated with tibial hemimelia and in 51 unrelated patients with neural tube defects. Except for two sequence variants in exon 3, no mutations were found in these disease categories. OFF

Abnormalities, Multiple↗