Showing papers by "University of Texas Medical Branch published in 1995"
TL;DR: The results of the present study suggest that the total score of the BIS-11 is an internally consistent measure of impulsiveness and has potential clinical utility for measuring impulsiveness among selected patient and inmate populations.
Abstract: The purpose of the present study was to revise the Barratt Impulsiveness Scale Version 10 (BIS-10), identify the factor structure of the items among normals, and compare their scores on the revised form (BIS-11) with psychiatric inpatients and prison inmates. The scale was administered to 412 college undergraduates, 248 psychiatric inpatients, and 73 male prison inmates. Exploratory principal components analysis of the items identified six primary factors and three second-order factors. The three second-order factors were labeled Attentional Impulsiveness, Motor Impulsiveness, and Nonplanning Impulsiveness. Two of the three second-order factors identified in the BIS-11 were consistent with those proposed by Barratt (1985), but no cognitive impulsiveness component was identified per se. The results of the present study suggest that the total score of the BIS-11 is an internally consistent measure of impulsiveness and has potential clinical utility for measuring impulsiveness among selected patient and inmate populations.
6,818 citations
TL;DR: Results indicate that, during recovery after resistance exercise, muscle protein turnover is increased because of an acceleration of synthesis and degradation and a postexercise acceleration of amino acid transport may contribute to the relatively greater stimulation of protein synthesis.
Abstract: The rates of protein synthesis and degradation and of amino acid transport were determined in the leg muscle of untrained postabsorptive normal volunteers at rest and approximately 3 h after a resistance exercise routine. The methodology involved use of stable isotopic tracers of amino acids, arteriovenous catheterization of the femoral vessels, and biopsy of the vastus lateralis muscle. During postexercise recovery, the rate of intramuscular phenylalanine utilization for protein synthesis increased above the basal value by 108 +/- 18%, whereas the rate of release from proteolysis increased by 51 +/- 17%. Muscle protein balance improved (P < 0.05) after exercise but did not become positive (from -15 +/- 12 to -6 +/- 3 nmol phenylalanine.min-1.100 ml leg volume-1). After exercise, rates of inward transport of leucine, lysine, and alanine increased (P < 0.05) above the basal state from 132 +/- 16 to 208 +/- 29, from 122 +/- 8 to 260 +/- 8, and from 384 +/- 71 to 602 +/- 89 nmol.min-1.100 ml leg-1, respectively. Transport of phenylalanine did not change significantly. These results indicate that, during recovery after resistance exercise, muscle protein turnover is increased because of an acceleration of synthesis and degradation. A postexercise acceleration of amino acid transport may contribute to the relatively greater stimulation of protein synthesis.
715 citations
TL;DR: It is concluded that increasing testosterone concentrations in elderly men increases skeletal muscle protein synthesis and strength, and this increase may be mediated by stimulation of the intramuscular IGF-I system.
Abstract: Aging men develop a significant loss of muscle strength that occurs in conjunction with a decline in serum testosterone concentrations. We investigated the effects of testosterone administration to six healthy men [67 +/- 2 (SE) yr] on skeletal muscle protein synthesis, strength, and the intramuscular insulin-like growth factor I (IGF-I) system. Elderly men with serum testosterone concentrations of 480 ng/dl or less were given testosterone injections for 4 wk to produce serum concentrations equal to those of younger men. During testosterone administration muscle strength (isokinetic dynamometer) increased in both right and left hamstring and quadricep muscles as did the fractional synthetic rate of muscle protein (stable-isotope infusion). Ribonuclease protection assays done on total RNA from muscle showed that testosterone administration increased mRNA concentrations of IGF-I and decreased mRNA concentrations of insulin-like growth factor binding protein-4. We conclude that increasing testosterone concentrations in elderly men increases skeletal muscle protein synthesis and strength. This increase may be mediated by stimulation of the intramuscular IGF-I system.
596 citations
TL;DR: CD22 is a molecular switch for SHP that may bias mIg signaling to anatomic sites rich in T cells and be sequestered away from mIG through interactions with counterreceptors on T cells.
Abstract: CD22 is a membrane immunoglobulin (mIg)-associated protein of B cells. CD22 is tyrosine-phosphorylated when mIg is ligated. Tyrosine-phosphorylated CD22 binds and activates SHP, a protein tyrosine phosphatase known to negatively regulate signaling through mIg. Ligation of CD22 to prevent its coaggregation with mIg lowers the threshold at which mIg activates the B cell by a factor of 100. In secondary lymphoid organs, CD22 may be sequestered away from mIg through interactions with counterreceptors on T cells. Thus, CD22 is a molecular switch for SHP that may bias mIg signaling to anatomic sites rich in T cells.
544 citations
TL;DR: Data support the occurrence of neurite growth followed by synaptogenesis in the neocortex, ipsilateral and contralateral to neocortical ischemia, in a pattern that corresponds both spatially and temporally with behavioral recovery.
Abstract: Background and Purpose Neuroanatomical plasticity is well described in lesions of the hippocampus but remains a subject of some controversy in the neocortex. The purpose of the present study was to measure the neocortical distribution and density of expression of proteins known to be involved in neurite growth or synaptogenesis and to correlate the neocortical expression with behavioral recovery after a focal neocortical infarction. Focal neocortical infarction creates a circumscribed lesion in the neocortex that provides a denervation stimulus for neurite growth and synaptogenesis. Methods Unilateral neocortical ischemia was induced in male spontaneously hypertensive Wistar rats (n=4 per time point) by permanent occlusion of the distal middle cerebral artery and ipsilateral common carotid artery. To determine the spatial and temporal distribution of neurite growth and/or synaptogenesis, GAP-43, a growth-associated protein expressed on axonal growth cones, and synaptophysin, a calcium-binding protein foun...
539 citations
TL;DR: It is demonstrated that GH3/B6 rat pituitary tumor cells contain a membrane ER (mER), and confocal scanning laser microscopy of cells labeled live with the anti‐peptide antibody further supports a membrane localization of ER, suggesting that mER may be structurally similar to iER.
Abstract: GH3/B6 rat pituitary tumor cells exhibit rapid prolactin release (within 5 min) when treated with nanomolar amounts of estrogen. However, the putative protein mediator of this nongenomic action has not been described. Using antibodies directed against a peptide representing the hinge region of the intracellular estrogen receptor (iER), we have demonstrated that these cells contain a membrane ER (mER). We now report that confocal scanning laser microscopy of cells labeled live with the anti-peptide antibody further supports a membrane localization of ER. The monoclonal antibodies H226 and H222 and a polyclonal antibody, ER21, each recognizing a unique epitope on iER (NH2 terminal to the DNA-binding region, within the steroid binding region, and the NH2-terminal end, respectively), also immunohistochemically label membrane proteins of immuno-selected GH3/B6 cells. These cells also specifically bind a fluorescent estrogen-BSA conjugate. Coincubation of cells with anti-ER antibody and the fluorescent estrogen...
532 citations
TL;DR: Results presented here indicate that only the RAD51-ssDNA nucleoprotein filament is functionally relevant and pairing and strand exchange initiate at the 5' end of the complementary strand in the linear duplex, a reaction polarity opposite to that of the bacterial prototype RecA.
507 citations
TL;DR: Famciclovir, a new antiviral agent, was approved for marketing by the Food and Drug Administration in June 1994 for the management of acute herpes zoster and its effect on postherpetic neuralgia remains controversial.
Abstract: Objective: To document the effects of treatment with famciclovir on the acute signs and symptoms of herpes zoster and postherpetic neuralgia. Design: A randomized, double-blind, placebo-controlled,...
443 citations
TL;DR: The side chains were found collectively to favor exposure to the osmolyte in comparison to exposure in water, and in this sense the side chains favor protein unfolding.
Abstract: Transfer free energy measurements of amino acids from water to the osmolytes, sucrose and sarcosine, were made as a function of osmolyte concentration. From these data, transfer free energies of the amino acid side chains were obtained, and the transfer free energy of the peptide backbone was determined from solubility measurements of diketopiperazine (DKP). Using static accessible surface evaluations of the native and unfolded states of ribonuclease A, solvent exposed side chain and peptide backbone areas were multiplied by their transfer free energies and summed in order to evaluate the transfer free energy of the native and unfolded states of the protein from water to the osmolyte solutions. The results reproduced the main features of the free energy profile determined for denaturation of proteins in the presence of osmolytes. The side chains were found collectively to favor exposure to the osmolyte in comparison to exposure in water, and in this sense the side chains favor protein unfolding. The major factor which opposes and overrides the side chain preference for denaturation and results in the stabilization of proteins observed in osmolytes is the highly unfavorable exposure of polypeptide backbone on unfolding. Except for urea and guanidine hydrochloride solutions, it is shown that all organic solvents (e.g., dioxane, ethanol, ethylene glycol) and solutes (osmolytes) for which transfer free energy measurements have been determined exhibit unfavorable transfer free energy of the peptide backbone.(ABSTRACT TRUNCATED AT 250 WORDS)
434 citations
TL;DR: It is concluded that insulin promoted muscle anabolism, primarily by stimulating protein synthesis independently of any effect on transmembrane transport.
Abstract: We have investigated the mechanisms of the anabolic effect of insulin on muscle protein metabolism in healthy volunteers, using stable isotopic tracers of amino acids. Calculations of muscle protein synthesis, breakdown, and amino acid transport were based on data obtained with the leg arteriovenous catheterization and muscle biopsy. Insulin was infused (0.15 mU/min per 100 ml leg) into the femoral artery to increase femoral venous insulin concentration (from 10 +/- 2 to 77 +/- 9 microU/ml) with minimal systemic perturbations. Tissue concentrations of free essential amino acids decreased (P < 0.05) after insulin. The fractional synthesis rate of muscle protein (precursor-product approach) increased (P < 0.01) after insulin from 0.0401 +/- 0.0072 to 0.0677 +/- 0.0101%/h. Consistent with this observation, rates of utilization for protein synthesis of intracellular phenylalanine and lysine (arteriovenous balance approach) also increased from 40 +/- 8 to 59 +/- 8 (P < 0.05) and from 219 +/- 21 to 298 +/- 37 (P < 0.08) nmol/min per 100 ml leg, respectively. Release from protein breakdown of phenylalanine, leucine, and lysine was not significantly modified by insulin. Local hyperinsulinemia increased (P < 0.05) the rates of inward transport of leucine, lysine, and alanine, from 164 +/- 22 to 200 +/- 25, from 126 +/- 11 to 221 +/- 30, and from 403 +/- 64 to 595 +/- 106 nmol/min per 100 ml leg, respectively. Transport of phenylalanine did not change significantly. We conclude that insulin promoted muscle anabolism, primarily by stimulating protein synthesis independently of any effect on transmembrane transport.
418 citations
TL;DR: The author develops these events into complex frames and scripts, and describes in some detail the representation of an isa hierarchy using the statements in typicality logic.
Abstract: el->e2. The intended interpretation here is that whenever el occurs, so does e2 (or, el causes e2). However, the typicality operator can be used here to represent the fact that \"typically\" el causes e2, but not always. For example, if el=strike-thematch and e2=light-the-match, then typically, el causes e2, but not when additional information such as e3=match-is-wet is added. Thus, the preference criteria developed to deal with declarative statements can be used to retract unplausible chains of causal effects given new information. The author than develops these events into complex frames and scripts, and describes in some detail the representation of an isa hierarchy using the statements in typicality logic. It should be noted here that this effort does not differ substantially fi'om similar work on formalizing semantic networks except in the identification ofstatements in a given frame. For example, while every slot-value pair in a frame can be represented by a wff in predicate logic, a number of these formulas will be monotonic, while some will be typicality statements.
TL;DR: The results suggest that the dorsolateral and ventrolateral parts of the PAG are organized into longitudinal columns that extend throughout the length of the C5 noradrenergic cell group.
Abstract: The descending projections of the periaqueductal gray (PAG) have been studied in the rat using the anterograde tracer Phaseolus vulgaris-leucoagglutinin. The tracer was injected into the dorsolateral or ventrolateral subdivisions of the PAG at rostral or caudal sites. It was found that the patterns of the descending projections of the rostral and caudal parts of the dorsolateral PAG were the same and that the patterns of the descending projections of the rostral and caudal parts of the ventrolateral PAG were the same. However, the patterns of projections of the dorsolateral and ventrolateral PAG subregions were substantially different. These results suggest that the dorsolateral and ventrolateral parts of the PAG are organized into longitudinal columns that extend throughout the length of the PAG. The axons of PAG neurons descended through the pons and medulla via two routes. A small fiber bundle was present in the periaqueductal gray and in the periventricular area. This bundle distributed fibers and terminals locally within the periaqueductal gray and in the locus coeruleus and Barrington's nucleus. A larger bundle had a diffuse arrangement in the pontine reticular formation, however, and it had a more restricted distribution in the medulla, where it occupied a position dorsolateral to the pyramid. This bundle supplied structures in the pontine and medullary tegmentum. The dorsolateral column preferentially supplied the locus coeruleus, subcoeruleus, the gigantocellular nucleus pars alpha, the rostral part of the paragigantocellular nucleus, and the region of the A5 noradrenergic cell group. The ventrolateral column preferentially supplied the nucleus raphe magnus, the caudal part of the lateral paragigantocellular nucleus, and the rostroventrolateral reticular nucleus. © 1995 Willy-Liss, Inc.
TL;DR: Results with purified proteins corroborated results obtained with the crude extract and indicate that β-pol is responsible for the single-nucleotide gap filling reaction involved in this in vitro base excision repair system.
TL;DR: The biology and significance of the epidermal growth factor (EGF) family is reviewed, with particular emphasis on understanding the integrated function of the family and the relationships between family members in the context of gastrointestinal physiology and pathophysiology.
TL;DR: It is demonstrated that treatment of affected animals with 2–(2–nitro–4–trifluoro–methylbenzyol)–1,3–cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs.
Abstract: Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH-/- mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.
TL;DR: This study tested an integrated interpersonal theory of depression, which combines J. C. Coyne's (1976b) interpersonal theories of depression with work on the interplay between self-enhancement and self-consistency theory, and found the combination of negative feedback seeking, high reassurance seeking, and depression at T1 predicted T1 to T2 increases in rejection by roommates.
Abstract: This study tested an integrated interpersonal theory of depression, which combines J. C. Coyne's (1976b) interpersonal theory of depression with work on the interplay between self-enhancement and self-consistency theory. Students' (targets') and their same-gender roommates' appraisals of each other, depression and anxiety levels, reassurance seeking, and negative feedback seeking were assessed at Time 1 (T1), and again at Time 2 (T2), 3 weeks later. Consistent with the theoretical integration (a) Depressed targets reported engaging in more negative feedback seeking than nondepressed targets, and tended to report seeking more reassurance than nondepressed targets at T1; (b) For male (but not female) targets, the combination of negative feedback seeking, high reassurance seeking, and depression at T1 predicted T1 to T2 increases in rejection by roommates; and (c) Rejection effects applied to depressive symptoms, but not anxious symptoms or anhedonic mood.
TL;DR: The model-derived rate of protein synthesis was highly correlated with the same value calculated by means of the tracer incorporation technique and amino acid transport rates were in the range expected from literature values.
Abstract: We have used stable isotopic tracers of amino acids to measure in vivo transmembrane transport of phenylalanine, leucine, lysine, alanine, and glutamine as well as the rates of intracellular amino acid appearance from proteolysis, de novo synthesis, and disappearance to protein synthesis in human skeletal muscle. Calculations were based on data obtained by the arteriovenous catheterization of the femoral vessels and muscle biopsy. We found that the fractional contribution of transport from the bloodstream to the total intracellular amino acid appearance depends on the individual amino acid, varying between 0.63 +/- 0.02 for phenylalanine and 0.22 +/- 0.02 for alanine. Rates of alanine and glutamine de novo synthesis were approximately eight and five times their rate of appearance from protein breakdown, respectively. The model-derived rate of protein synthesis was highly correlated with the same value calculated by means of the tracer incorporation technique. Furthermore, amino acid transport rates were in the range expected from literature values. Consequently, we conclude that our new model provides a valid means of quantifying the important aspects of protein synthesis, breakdown, and amino acid transport in human subjects.
TL;DR: The results indicate that H. pylori stimulates the gastric epithelium to initiate inflammation and neutrophil recruitment and activation.
TL;DR: It is shown that the spread of B‐HRP‐labelled axons into lamina II is detectable at 1 week, maximal by 2 weeks and persists for over 6 months postlesion, which implies that A‐fiber terminal reorganization is a prominent and long‐lasting but not permanent feature of peripheral axotomy.
Abstract: We have investigated the time course and extent to which peripheral nerve lesions cause a morphological reorganization of the central terminals of choleragenoid-horseradish peroxidase (B-HRP)-labelled primary afferent fibers in the mammalian dorsal horn. Choleragenoid-horseradish peroxidase is retrogradely transported by myelinated (A) sensory axons to laminae I, III, IV and V of the normal dorsal horn of the spinal cord, leaving lamina II unlabelled. We previously showed that peripheral axotomy results in the sprouting of numerous B-HRP-labelled large myelinated sensory axons into lamina II. We show here that this spread of B-HRP-labelled axons into lamina II is detectable at 1 week, maximal by 2 weeks and persists for over 6 months postlesion. By 9 months, however, B-HRP fibers no longer appear in lamina II. The sprouting into lamina II occurs whether regeneration is allowed (crush) or prevented (section with ligation), and does not reverse at times when peripheral fibers reinnervate the periphery. We also show that 15 times more synaptic terminals in lamina II are labelled by B-HRP 2 weeks after axotomy than in the normal. We interpret this as indicating that the sprouting fibers are making synaptic contacts with postsynaptic targets. This implies that A-fiber terminal reorganization is a prominent and long-lasting but not permanent feature of peripheral axotomy. We also provide evidence that this sprouting is the consequence of a combination of an atrophic loss of central synaptic terminals and the conditioning of the sensory neurons by peripheral axotomy. The sprouting of large sensory fibers into the spinal territory where postsynaptic targets usually receive only small afferent fiber input may bear on the intractable touch-evoked pain that can follow nerve injury.
TL;DR: A review of 27 studies including more than 4,000 subjects indicates that attributional style is clearly cross-sectionally associated with self-reported depression and with clinical depression, and that this appears to hold across age, gender, and sample type as discussed by the authors.
TL;DR: Exogenous insulin may be useful in promoting muscle protein synthesis in severely catabolic patients and investigates the hypothesis that changes in protein kinetics during insulin infusion are associated with an increased rate of transmembrane amino acid transport from plasma into the intracellular free amino acid pool.
Abstract: Objective To determine if long-term (7 days) infusion of insulin can ameliorate altered protein kinetics in skeletal muscle of severely burned patients and to investigate the hypothesis that changes in protein kinetics during insulin infusion are associated with an increased rate of transmembrane amino acid transport from plasma into the intracellular free amino acid pool. Background Data In critically ill patients, vigorous nutritional support alone may often fail to entirely curtail muscle catabolism ; insulin stimulates muscle protein synthesis in normal volunteers. Methods Nine patients with severe burns were studied once during enteral feeding alone (control period), and once after 7 days of high-dose insulin. The order of treatment with insulin was randomized. Data were derived from a model based on a primed-continuous infusion of L-[ 15 N]phenylalanine, sampling of blood from the femoral artery and vein, and biopsies of the vastus lateralis muscle. Results Net leg muscle protein balance was significantly (p < 0.05) negative during the control period. Exogenous insulin eliminated this negative balance by stimulating protein synthesis approximately 350% (p < 0.01). This was made possible in part by a sixfold increase in the inward transport of amino acids from blood (p < 0.01). There was also a significant increase in leg muscle protein breakdown. The new rates of synthesis, breakdown, and inward transport during insulin were in balance, such that there was no difference in the intracellular phenylalanine concentration from the control period. The fractional synthetic rate of protein in the wound was also stimulated by insulin by approximately 50%, but the response was variable and did not reach significance. Conclusions Exogenous insulin may be useful in promoting muscle protein synthesis in severely catabolic patients.
TL;DR: Biochemical assays show that the nitric oxide-cyclic guanosine monophosphate system exists in the human uterus and that it inhibits contractility, and the relaxation responsiveness to Nitric oxide is elevated during pregnancy and decreased during labor.
TL;DR: It is shown that these protein factors are both necessary and sufficient for dual incision of DNA damaged by either ultraviolet light or N-acetoxy-2-aminoacetylfluorene, suggesting that the hydrolysis of ATP is indispensable for the incision reaction.
TL;DR: Patients with favorable histology are probably best managed by resection postpolypectomy, whereas in the absence of unfavorable histology, they probably can be treated by polypectomy only.
TL;DR: The results suggest that KSHV is associated with lesions other than KS in non-AIDS immunocompromised patients, and may also be involved in the pathogenesis of the various forms of proliferative skin lesions from organ-transplant patients.
TL;DR: Epistasis analyses were consistent with the hypothesis that this RTH1-encoded nuclease has a role in the MSH2-MLH-1-PMS1 mismatch repair pathway, which is shown to increase the rate of instability of simple repetitive DNA by as much as 280 times.
Abstract: Simple repetitive DNA sequences are unstable in human colorectal cancers and a variety of other cancers. Mutations in the DNA mismatch repair genes MSH2, MLH1, and PMS1 result in elevated rates of spontaneous mutation and cause a marked increase in the instability of simple repeats. Compared with the wild type, a null mutation in the yeast RTH1 gene, which encodes a 5' to 3' exonuclease, was shown to increase the rate of instability of simple repetitive DNA by as much as 280 times and to increase the spontaneous mutation rate by 30 times. Epistasis analyses were consistent with the hypothesis that this RTH1-encoded nuclease has a role in the MSH2-MLH-1-PMS1 mismatch repair pathway.
TL;DR: The protein/energy ratio required for optimum growth appears to be significantly greater than for other aquatic invertebrates or fishes and indicates that protein should not be considered separately from energy in cephalopods.
Abstract: Cephalopods offer a unique model for studying animal nutrition due to the predominance of their amino acid metabolism. Since cephalopods grow at rapid rates for most of their life cycle (3–10% body weight d‐1), the demands on protein synthesis are high. As a result, cephalopod body composition ranges between 75–85% protein on a dry weight basis and they are efficient at assimilating proteins (apparent protein digestibility >85%). Furthermore, the protein/energy ratio required for optimum growth (>50 g protein MJ energy‐1) appears to be significantly greater than for other aquatic invertebrates or fishes (20–30 g protein MJ energy‐1). This high protein/energy ratio indicates that protein should not be considered separately from energy in cephalopods. Attempts to supply high levels of protein (>35% of diet on a wet weight basis) to cuttlefishes with moist prepared diets (pellets and surimi) have been successful in terms of palatability (feeding rates ≈ 8% body weight d‐1) but growth rates (0.7–1.0% body wei...
TL;DR: Calculation of a preliminary reference dose for OTC zinc that assumed high bioavailability and uncertain copper intakes established 9 mg as a safe amount for 60-kg adults as shown by experiments, copper deficiency can occur in humans.
TL;DR: In a case-control study at four hospitals in La Paz, Bolivia, and at one hospital in Mexico City, Mexico, 80-four patients with newly diagnosed, histologically confirmed gallbladder cancer were compared with 126 control subjects without stones and with 264 control subjects with cholelithiasis or choledocholithiasis without cancer as mentioned in this paper.
Abstract: Background. Gallbladder cancer has an unusual geographic and demographic distribution, suggesting many possible etiologies.
Methods. A case-control study was undertaken at four hospitals in La Paz, Bolivia, and at one hospital in Mexico City, Mexico. Eighty-four patients with newly diagnosed, histologically confirmed gallbladder cancer were compared with 126 control subjects without stones and with 264 control subjects with cholelithiasis or choledocholithiasis without cancer. All study subjects underwent abdominal surgery. Study subjects were interviewed regarding demographic characteristics, medical history, family history, diet, and exposure to agents presumed to be risk factors for biliary cancer.
Results. Virtually all subjects in Mexico were judged to be mestizos (i.e., persons of mixed ancestry). In contrast, race was a very strong risk factor for gallbladder cancer in Bolivia. Relative to mestizos who spoke neither language, the odds ratio (95% confidence interval [CI]) for cases versus control subjects without stones for those who spoke Aymara well was 15.9 (CI, 1.9–179), whereas it was 1.4 (CI, 0.2–8.2) for those who spoke Quechua well. An increased risk was also noted for elevated maximum body mass index (P = 0.03), family history of gallstones (odds ratio [OR] = 3.6 [CI, 1.3–11.4]), and physician-diagnosed typhoid (OR = 12.7 [CI, 1.5-598]). An increased risk was also seen with elevated maximum body mass index; compared with those with a body mass index less than 24 kg/m2, those with an index of 24–25 kg/m2, 26–28 kg/m2, and greater than 28 kg/m2 had odds ratios of 1.6 (CI, 0.4–7.6), 1.3 (CI, 0.3–5.6), and 2.6 (CI, 0.5–18.6), respectively (asymptotic test for trend, P = 0.03). Finally, a number of associations were noted with certain dietary and cooking habits.
Conclusions. Patients with gallbladder cancer differed from control subjects in race, body mass, physician-diagnosed typhoid, and certain dietary patterns. These findings may provide useful clues to the pathogenesis of gallbladder cancer, but given the number of analyses performed, additional cases need to be studied. Cancer 1995:76:1747–56.
TL;DR: Data indicate that specific 4-hydroxylation of estradiol in human uterine tissues is catalyzed by a form of cytochrome P450 related to P450 IB1, which contribute(s) little to 2-hydroxyylation and is therefore a marker for uterine myomata and may play a role in the etiology of the tumor.
Abstract: Estradiol is converted to catechol estrogens via 2- and 4-hydroxylation by cytochrome P450 enzymes. 4-Hydroxyestradiol elicits biological activities distinct from estradiol, most notably an oxidant stress response induced by free radicals generated by metabolic redox cycling reactions. In this study, we have examined 2- and 4-hydroxylation of estradiol by microsomes of human uterine myometrium and of associated myomata. In all eight cases studied, estradiol 4-hydroxylation by myoma has been substantially elevated relative to surrounding myometrial tissue (minimum, 2-fold; mean, 5-fold). Estradiol 2-hydroxylation in myomata occurs at much lower rates than 4-hydroxylation (ratio of 4-hydroxyestradiol/2-hydroxyestradiol, 7.9 +/- 1.4) and does not significantly differ from rates in surrounding myometrial tissue. Rates of myometrial 2-hydroxylation of estradiol were also not significantly different from values in patients without myomata. We have used various inhibitors to establish that 4-hydroxylation is catalyzed by a completely different cytochrome P450 than 2-hydroxylation. In myoma, alpha-naphthoflavone and a set of ethynyl polycyclic hydrocarbon inhibitors (5 microM) each inhibited 4-hydroxylation more efficiently (up to 90%) than 2-hydroxylation (up to 40%), indicating > 10-fold differences in Ki ( 5 microM). These activities were clearly distinguished from the selective 2-hydroxylation of estradiol in placenta by aromatase reported previously (low Km, inhibition by Fadrozole hydrochloride or ICI D1033). 4-Hydroxylation was also selectively inhibited relative to 2-hydroxylation by antibodies raised against cytochrome P450 IB1 (rat) (53 vs. 17%). These data indicate that specific 4-hydroxylation of estradiol in human uterine tissues is catalyzed by a form(s) of cytochrome P450 related to P450 IB1, which contribute(s) little to 2-hydroxylation. This enzyme(s) is therefore a marker for uterine myomata and may play a role in the etiology of the tumor.