Biomedical subjects

M A Brown

Publications and source records attributed to M A Brown.

At least 73 records · Page 4Linked to original sources

PubMed2001

Blunt abdominal trauma: screening us in 2,693 patients.

PURPOSE: To evaluate the accuracy of screening abdominal ultrasonography (US) in patients with blunt abdominal trauma. MATERIALS AND METHODS: Patients with blunt abdominal trauma underwent US. The abdomen and pelvis were scanned for free fluid, the visceral organs were assessed for heterogeneity, and duplex US was performed if necessary. Empty bladders were filled with 200-300 mL of sterile saline through a Foley catheter. US findings were considered positive if free fluid was present or if parenchymal abnormalities that could be consistent with trauma were detected. Screening US results were compared with findings of diagnostic peritoneal lavage, repeat US, computed tomography (CT), cystography, surgery, and/or autopsy and/or the clinical course. RESULTS: Findings from 2,693 US examinations were evaluated and were positive in 145 of 172 patients with injuries (sensitivity, 84%) and 64 (89%) of 72 patients who ultimately underwent laparotomy with surgical repair of injuries. False-negative findings were retroperitoneal injury, bowel injury, and intraperitoneal solid organ injury without hemoperitoneum. No patient with false-negative findings died. Specificity of US was 96% (2,429 of 2,521 patients), and overall accuracy was 96% (2,574 of 2,693 patients). Positive predictive value was 61% (145 of 237 patients), and negative predictive value was 99% (2,429 of 2,456 patients). CONCLUSION: Abdominal US is useful in screening for injury in patients with blunt abdominal trauma, and its use represents a notable change in institutional practice. Diagnostic peritoneal lavage is rarely performed, and CT is used when screening US findings are positive, when injury is clinically suspected despite negative US findings, or when US is not available.

Abdominal Injuries↗

PubMed2001

Us of blunt abdominal trauma: importance of free pelvic fluid in women of reproductive age.

PURPOSE: To assess the importance of free fluid and to determine the accuracy of screening ultrasonography (US) in female patients of reproductive age with trauma. MATERIALS AND METHODS: US was performed in 1,047 patients, aged 10-60 years, to evaluate blunt trauma. Patients were retrospectively assigned to groups on the basis of presence and location of intraperitoneal free fluid. Injury and surgical injury rates were assessed by comparing US results with computed tomographic, repeat US, cystographic, peritoneal lavage, surgical, and/or autopsy findings in 144 patients and with final clinical outcome in 903. US scans were positive if fluid was outside the cul-de-sac or if suspicious parenchymal abnormalities were present. RESULTS: In 939 patients, no fluid was seen: Eight had injuries; three were surgical. In 56, anechoic fluid was isolated to the cul-de-sac: Two had injuries; one was surgical. In 26, fluid was isolated to the upper abdomen: Fifteen had injuries; five were surgical. In 22, fluid involved the pelvis and abdomen: Nineteen had injuries; 14 were surgical. In four, questionable fluid was isolated to the supravesical space. Patients with fluid in the cul-de-sac had similar injury and surgical injury rates as those with no fluid but had lower rates than those of patients with fluid elsewhere (P<.02 to P<.001). US screening had 89% sensitivity, 98% specificity, 97% accuracy, a 61% positive predictive value, and a 99% negative predictive value. CONCLUSION: In female patients of reproductive age with trauma, free fluid isolated to the cul-de-sac is likely physiologic; clinical follow-up should suffice. Patients with fluid elsewhere usually have clinically important injury and require further evaluation.

Abdominal Injuries↗

PubMed2001

Efficient fat storage in premenopausal women and in early pregnancy: a role for estrogen.

There is a sexual dimorphism in body fat in humans. Adipose tissue increases with puberty and early pregnancy in women, suggesting gonadal steroids can influence body fat. Previously, we have observed that oral estrogen, compared with transdermal estrogen, reduced postprandial lipid oxidation and increased body fat, possibly due to suppressed hepatic lipid oxidation. If estrogen effects lipid oxidation, we predicted that subjects with significantly different endogenous estrogen production would oxidize lipids at different rates. The aim of this study was to compare energy metabolism in 12 pregnant (19 wk gestation, 29 +/- 1 yr, 1.66 +/- 0.02 m, 73.5 +/- 2.4 kg), 11 nonpregnant premenopausal (29 +/- 2 yr, 1.68 +/- 0.02 m, 63.1 +/- 1.8 kg), and 28 postmenopausal (58 +/- 1 yr, 1.62 +/- 0.01 m, 69.9 +/- 1.0 kg) women who were not receiving estrogen, and to relate these findings to endogenous estrogen concentrations. All women underwent indirect calorimetry under identical situations in the basal and postprandial state following a standard mixed meal. Basal (5998 +/- 184 vs. 5712 +/- 184 vs. 5800 +/- 121 kJ.24 h, respectively) and postprandial energy expenditure (7172 +/- 239 vs. 6964 +/- 210 vs. 6955 +/- 147 kJ.24 h) was similar among groups. However, basal lipid oxidation was reduced in pregnant (45.3 +/- 6.1 mg/min, P < 0.05) and nonpregnant women (44.5 +/- 6.3 mg/min, P < 0.05) compared with postmenopausal women (58.4 +/- 2.9 mg/min). Postprandial lipid oxidation differed among groups, being least in pregnant women (8.8 +/- 6.2 mg/min) compared with nonpregnant (28.9 +/- 6.4 mg/min, P < 0.04) and postmenopausal (48.1 +/- 4.0 mg/min, P = 0.0001) women. There was a significant reciprocal increase in postprandial carbohydrate oxidation. Mean postprandial glucose levels were slightly but nonsignificantly higher in pregnant women. Insulin levels were significantly higher in postmenopausal compared nonpregnant, but not pregnant, women. In a multiple regression analysis, serum estradiol (log transformed) correlated negatively with postprandial lipid oxidation (r = -0.66, P = 0.0001) and positively with postprandial nonesterified free fatty acid levels, whereas no correlation was found with postprandial insulin, glucose, fat free mass, and fat mass. In summary, postprandial lipid oxidation is reduced in pregnancy compared with that in healthy nonpregnant women, who in turn have lower postprandial lipid oxidation than postmenopausal women. This implies that the premenopausal years and early pregnancy are states of efficient fat storage, possibly mediated through reduced lipid oxidation due to estrogen, therefore increasing body fat for reproduction, thus supporting the notion that fat mass can be regulated.

Adult↗

PubMed2001

The effects of a multi-modal intervention trial of light, exercise, and vitamins on women's mood.

The purpose of this study was to test the efficacy of a tri-modal intervention (LEVITY) to improve women's mood. This eight-week randomized experiment with a placebo-control group targeted women with symptoms of mild to moderate depression. Women in the intervention group were instructed to take a brisk 20-minute outdoor walk at target heart rate of 60% of maximum heart rate, to increase light exposure throughout the day and to take a specific vitamin regimen. Women in the control group took a daily placebo vitamin. The sample consisted of 112 women ages 19-78 who reported mild to moderate depressive symptoms. They were in otherwise good health and were not currently taking any mood-altering medication. Pre- and post-intervention assessment utilized live measures of mood: Center for Epidemiology Studies Depression Scale, Profile of Mood States, Depression-Happiness Scale, Rosenberg Self-Esteem Scale, and the General Well-Being Schedule. Analysis of covariance indicated that the intervention was effective in improving women's overall mood, self-esteem, and general sense of well-being and in decreasing symptoms on two measures of depression. Of particular note, the data from all five outcome measures supported the efficacy of the intervention. In addition, a high level of adherence to the intervention protocol was observed with two-thirds of the women reporting 100% adherence. Study implications suggest that this type of intervention may provide an effective, clinically manageable therapy for mild-to-moderately depressed women who prefer a self-directed approach or who have difficulties with the cost or side-effects of medication or psychotherapy.

Adult↗

PubMed2001

Genetic control of bone density and turnover: role of the collagen 1alpha1, estrogen receptor, and vitamin D receptor genes.

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1alpha (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.

Absorptiometry, Photon↗

PubMed2001

Genetic x environment interactions on blood constituents of Angus, Brahman, and reciprocal-cross cows and calves grazing common bermudagrass or endophyte-infected tall fescue.

Over a 2-yr period, effects of genotype and forage on blood metabolites, enzymes, and minerals were determined in Angus, Brahman, Angus x Brahman (sire x dam), and Brahman x Angus cows, and 129 calves from these cows sired by Hereford bulls. Cows and calves continuously grazed either common bermudagrass or endophyte-infected 'Kentucky-31' tall fescue pastures throughout the year. Blood samples were collected via jugular venipuncture in April, August, October (weaning), and November (after 30 d in a feedlot) of each year. Plasma urea N concentrations of cows and calves were affected by forage (P < 0.01) and breed (P < 0.05). Plasma cholesterol and FFA concentrations of cows were affected by forage (P < 0.01) and breed (P < 0.05). In calves, antibody titers to infectious bovine rhinotracheitis virus were not affected by forage but were affected by breed. Serum inorganic P concentrations of calves and cows were affected by forage (P < 0.05). Serum P concentrations and alkaline phosphatase activity of calves were affected by breed (P < 0.05). Calves grazing bermudagrass had higher (P < 0.05) serum concentrations of Fe and total iron binding capacity (TIBC). There was evidence of maternal heterosis for concentrations of free fatty acids, cholesterol, aspartate aminotransferase, Ca, Mg, alkaline phosphatase, ceruloplasmin, Fe, and TIBC. There was evidence of grandmaternal effects for plasma concentrations of urea N, cholesterol, Ca, P, Mg, and alkaline phosphatase. These results suggest that calves and cows grazing tall fescue are generally on a lower plane of nutrition than those grazing bermudagrass and that Brahman x Angus and Angus x Brahman crossbred cows and their calves seen to be more tolerant of the negative effects of tall fescue than the average of their purebred contemporaries.

Animals↗

PubMed2001

Genotype x environment interactions for postweaning performance in crossbred calves grazing winter wheat pasture or dormant native prairie.

Data from 403 calves from Angus, Brahman, and reciprocal-cross cows sired by Polled Hereford bulls were used to evaluate the impact of postweaning backgrounding forages on postweaning BW, gains, and carcass traits. Calves were born (spring of 1991 through 1994) and reared on either endophyte-infected tall fescue or common bermudagrass pastures. After weaning, calves were transported 360 km to the Grazinglands Research Laboratory, west of El Reno, OK, and, within breed and preweaning forage, were assigned to one of the following winter stocker treatments: 1) winter wheat pasture or 2) dormant native prairie plus supplemental CP. In March, winter stocker treatments were ended and calves were grazed as a single group on cool-season grasses until early July (1992, 1993, and 1994) or late May (1995), when the feedlot phase began. In the feedlot, calves were fed a high concentrate diet for an average of 120 d until a backfat thickness of > 10 mm was reached. Calves were shipped in truck load lots to Amarillo, TX (350 km), for processing and collection of carcass data. Averaged over calf breed group, calves wintered on wheat pasture gained faster (P < 0.01) during the stocker phase (0.71 vs 0.43 kg); had heavier (P < 0.01) final feedlot weights (535 vs 512 kg); lower feedlot (P < 0.01) ADG (1.37 vs 1.53 kg); heavier (P < 0.01) carcass weights (337 vs 315 kg); larger (P < 0.01) longissimus muscle (84.9 vs 81.8 cm2); higher percentage (P < 0.01) of kidney, heart, and pelvic fat (2.32 vs 2.26); and higher (P < 0.01) dressing percentage (62.2 vs 61.3) than calves backgrounded on native prairie. Maternal heterosis for stocker ADG was evident in calves backgrounded on native prairie but not on winter wheat (P < 0.10), but the two environments were similar in maternal heterosis for feedlot ADG and carcass traits. Calves wintered on native prairie were restricted in growth and expressed compensatory gain during the feedlot phase but not during the spring stocker phase. Dormant native grasses can be used to winter stocker calves excess to the winter wheat pasture needs, but ownership of these calves would have to be retained through the feedlot phase to realize any advantage of built-in compensatory gain. Finally, these data suggest that expression of maternal heterosis for weight gain is more likely in calves backgrounded on native prairie than in calves grazed on winter wheat.

Animal Feed↗

PubMed2001

Genotype x environment interactions in milk yield and quality in Angus, Brahman, and reciprocal-cross cows on different forage systems.

Milk yield and quality were observed on 93 Angus, Brahman, and reciprocal-cross cows over 3 yr to evaluate the interactions of direct and maternal breed effects and heterosis with forage environment. Forage environments were common bermudagrass (BG), endophyte-infected tall fescue (E+), and a rotational system (ROT) of both forages, in which each forage (BG or E+) was grazed during its appropriate season, usually June through October for BG and November through May for E+. Milk yield was estimated each of 6 mo (April through September) via milking machine and converted to a 24-h basis. Milk fat, milk protein, and somatic cell count were analyzed by a commercial laboratory. Heterosis for milk yield was similar among forages, averaging 2.4 kg (P < 0.01). Expressed as percentages of purebred means, heterosis for milk yield was largest on E+ (52.8%), intermediate on ROT (39.3%), and smallest on BG (23.7%). Direct breed effects for milk yield favored Brahman, and they were similar among forages but tended to be larger for E+ (2.5 kg) and ROT (2.8 kg) than for BG (1.3 kg). Direct breed effects for milk fat favored Brahman and were similar among forages but tended to be larger for E+ (1.0%) and ROT (1.0%) than for BG (0.6%). Purebred cows exceeded crossbreds in milk protein by 0.1% on ROT (P < 0.10). Crossbred cows had lower somatic cell counts than purebreds on BG (P < 0.05), E+ (P < 0.01), or ROT (P > 0.30). Heterosis for somatic cell counts as percentages of purebred means was similar for BG (-68.3%) and E+ (-68.9%) and less favorable for ROT (-31.6%). Maternal breed effects for somatic cell count favored Angus on ROT (P < 0.10) with a similar nonsignificant trend on BG and E+. Direct breed effects for somatic cell count favored Brahman on ROT (P < 0.10) with similar nonsignificant trends on BG and E+. These results suggested that a rotation of cows from E+ to BG in the summer can partially alleviate negative effects of E+ on milk yield. Conclusions also indicated an advantage to crossbred cows in somatic cell count and provided evidence of both direct and maternal breed effects for this trait. The results also suggested that direct breed effects for milk yield, milk fat, and somatic cell count and heterosis for milk yield and somatic cell count (as percentages of purebred means) tended to vary with forage environment, indicating a potential for genotype x environment interaction for these traits.

Animal Feed↗

PubMed2001

Patterns of fluid accumulation on screening ultrasonography for blunt abdominal trauma: comparison with site of injury.

The objectives of this study were to define where fluid accumulation is shown on screening ultrasonography after blunt abdominal trauma and to determine how fluid accumulation patterns are associated with the site of injury. From 1994 to 1998, 2,693 screening examinations for blunt abdominal trauma were performed, in which 7 regions were examined for fluid. On the basis of a preliminary analysis of patients with solitary injuries, all 194 patients with sonographically detected fluid were grouped by fluid accumulation pattern. Fluid patterns were compared with sites of injury. The patterns differed between hepatic and splenic injuries. Fluid in the left upper quadrant, in both upper quadrants, or diffusely distributed suggested splenic injury, whereas fluid in the right upper quadrant or the right upper quadrant and lower recesses suggested hepatic injury (P < .0001). Fluid accumulation was random after enteric injury. Patients with extraperitoneal injury had no fluid or had fluid focally at the injury site. The ability to predict the injury site on the basis of fluid patterns should expedite treatment of hemodynamically unstable patients with blunt abdominal trauma.

Abdominal Injuries↗

PubMed2001

Quantification of fluid on screening ultrasonography for blunt abdominal trauma: a simple scoring system to predict severity of injury.

A simple ultrasonographic method of fluid quantification, which counted the number of fluid recesses, was developed to predict the severity of injury after blunt abdominal trauma. From 1994 to 1998, 2,693 screening ultrasonographic examinations were performed for blunt abdominal trauma. Of this group, 2,499 patients had a fluid score of 0 (no fluid), and 1.4% had injuries (0.4% requiring surgery); 110 had a score of 1 (fluid in a single examined region), and 59% had injuries (13% requiring surgery); 33 had a score of 2, and 85% had injuries (36% requiring surgery); 30 had a score of 3, and 83% had injuries (63% requiring surgery); and 21 had a score of 4, and 95% had injuries (81 % requiring surgery). Patients with scores of 3 or greater had significantly higher rates of injury (P < .002) and injury requiring surgery (P < .0001) than patients with lower scores. The ability to predict injury severity on the basis of a simple ultrasonographic scoring system should expedite treatment of patients with severe trauma.

Abdominal Injuries↗

PubMed2001

Importance of evaluating organ parenchyma during screening abdominal ultrasonography after blunt trauma.

OBJECTIVE: To determine the benefit of screening ultrasonography for parenchymal abnormalities as well as free fluid during screening abdominal ultrasonography in patients with blunt trauma. METHODS: A total of 2693 patients with blunt trauma who were triaged to a level 1 trauma center underwent screening abdominal ultrasonography in the resuscitation suite. Examinations were performed by experienced sonographers and included a screen for free intraperitoneal fluid and evaluation of the abdominal organ parenchyma and heart for traumatic injury. Screening ultrasonographic findings were reviewed and compared with findings from autopsy, laparotomy, diagnostic peritoneal lavage, computed tomography, repeated ultrasonography, cystography, and clinical outcome. Imaging studies of all patients with confirmed or suspected injuries were reviewed to identify those in whom parenchymal findings aided diagnosis. RESULTS: One hundred seventy-two patients were found to have evidence of abdominal injury due to blunt trauma on the basis of clinical data, imaging, laparotomy, or autopsy. Forty-four of these patients had no sonographic evidence of hemoperitoneum at the time of initial ultrasonography. Screening ultrasonographic findings were positive for injury in 19 of 44 patients on the basis of parenchymal findings or small retroperitoneal collections of fluid thought to be indicative of trauma. In the remaining 25 patients, screening ultrasonography showed no abnormalities, and injuries were detected by repeated ultrasonography, subsequent computed tomography, or diagnostic peritoneal lavage performed for suspected occult injury on the basis of clinical parameters. In addition, 47 of 126 injured patients with sonographically detected free fluid had parenchymal findings that helped localize injury. Sixteen of those patients were taken to the operating room on the basis of clinical and sonographic findings without undergoing computed tomography. CONCLUSIONS: The inability to show injuries with no hemoperitoneum or with delayed hemoperitoneum has been shown to be a limitation of ultrasonography in patients with blunt trauma. In our series, 26% of all patients with documented injuries had no free fluid visible on screening ultrasonography Attention to findings other than free fluid allowed detection in 43% of injured patients without sonographic evidence of hemoperitoneum.

Abdominal Injuries↗

PubMed2001

HIV postexposure prophylaxis after sexual assault.

Recent advances in the treatment of human immunodeficiency virus (HIV) disease have prompted health care providers to reexamine recommendations for prophylaxis of HIV infection. Parallels with occupational exposure through mucous membrane tissues spur consideration of HIV prophylaxis after sexual assault for several reasons. In both instances, exposure occurs at a single point in time and is unlikely to recur. Although the Centers for Disease Control and Prevention does not make definitive recommendations regarding postexposure prophylaxis after sexual assault, the reality is that as clinicians, we face situations in which we must consider treatment for prevention of HIV disease after sexual assault. Guidelines for treatment and how to create and implement a policy to ensure the best outcomes, and provide a high quality of patient care with the New York State guidelines as a model, are discussed.

Anti-HIV Agents↗

PubMed2000

An intron transcriptional enhancer element regulates IL-4 gene locus accessibility in mast cells.

The cell type-specific expression of a gene is dependent on developmentally regulated modifications in chromatin structure that allow accessibility of basal and inducible transcription factors. In this study, we demonstrate that a cis-acting element in the second intron of the murine IL-4 gene has a dual function in regulating transcription in mast cells as well as chromatin accessibility of the IL-4 gene locus through its influence on the methylation state of the gene. Previous studies have shown that mast cell-restricted transcription factors GATA-1/2 and PU.1 associate with the intron element and regulate its activity. In this study, we use DNase I footprinting and mutational analyses to identify two additional sites that contribute to the element's ability to enhance transcription. One of these sites associates preferentially with STAT5a and STAT5b. We also demonstrate that deletion of the element or mutation of the GATA binding site in the context of a stably integrated IL-4 genomic construct prevents maintenance of a demethylated locus in IL-4-producing mast cells. These data indicate that, analogous to Ig and TCR intron regulatory elements, the intron enhancer has an essential role in maintaining developmentally regulated demethylation at the IL-4 gene locus. In addition, they indicate that members of the GATA family of transcription factors likely play an important role in these processes.

Animals↗

PubMed2000

Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice.

We have generated transgenic mice that harbor a 140 kb genomic fragment of the human BRCA1 locus (TgN x BRCA1GEN). We find that the transgene directs appropriate expression of human BRCA1 transcripts in multiple mouse tissues, and that human BRCA1 protein is expressed and stabilized following exposure to DNA damage. Such mice are completely normal, with no overt signs of BRCA1 toxicity commonly observed when BRCA1 is expressed from heterologous promoters. Most importantly, however, the transgene rescues the otherwise lethal phenotype associated with the targeted hypomorphic allele (Brca1DeltaexllSA). Brca1-/-; TgN x BRCA1GEN bigenic animals develop normally and can be maintained as a distinct line. These results show that a 140 kb fragment of chromosome 17 contains all elements necessary for the correct expression, localization, and function of the BRCA1 protein. Further, the model provides evidence that function and regulation of the human BRCA1 gene can be studied and manipulated in a genetically tractable mammalian system. Oncogene (2000) 19, 4085 - 4090

Animals↗

PubMed2000

Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis.

Ankylosing spondylitis (AS) is a common and highly familial rheumatic disorder. The sibling recurrence risk ratio for the disease is 63 and heritability assessed in twins >90%. Although MHC genes, including HLA-B27, contribute only 20-50% of the genetic risk for the disease, no non-MHC gene has yet been convincingly demonstrated to influence either susceptibility to the disease or its phenotypic expression. Previous linkage and association studies have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) located at chromosome 22q13.1. We performed a linkage study of chromosome 22 in 200 families with AS affected sibling-pairs. Association of alleles of the CYP2D6 gene was examined by both case-control and within-family means. For case-control studies, 617 unrelated individuals with AS (361 probands from sibling-pair and parent-case trio families and 256 unrelated non-familial sporadic cases) and 402 healthy ethnically matched controls were employed. For within-family association studies, 361 families including 161 parent-case trios and 200 affected sibling-pair families were employed. Homozygosity for poor metabolizer alleles was found to be associated with AS. Heterozygosity for the most frequent poor metabolizer allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. We postulate that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.

Alleles↗

PubMed2000

Identification and purification of vitamin K-dependent proteins and peptides with monoclonal antibodies specific for gamma -carboxyglutamyl (Gla) residues.

Novel monoclonal antibodies that specifically recognize gamma-carboxyglutamyl (Gla) residues in proteins and peptides have been produced. As demonstrated by Western blot and time-resolved immunofluorescence assays the antibodies are pan-specific for most or all of the Gla-containing proteins tested (factors VII, IX, and X, prothrombin, protein C, protein S, growth arrest-specific protein 6, bone Gla protein, conantokin G from a cone snail, and factor Xa-like proteins from snake venom). Only the Gla-containing light chain of the two-chain proteins was bound. Decarboxylation destroyed the epitope(s) on prothrombin fragment 1, and Ca(2+) strongly inhibited binding to prothrombin. In Western blot, immunofluorescence, and surface plasmon resonance assays the antibodies bound peptides conjugated to bovine serum albumin that contained either a single Gla or a tandem pair of Gla residues. Binding was maintained when the sequence surrounding the Gla residue(s) was altered. Replacement of Gla with glutamic acid resulted in a complete loss of the epitope. The utility of the antibodies was demonstrated in immunochemical methods for detecting Gla-containing proteins and in the immunopurification of a factor Xa-like protein from tiger snake venom. The amino acid sequences of the Gla domain and portions of the heavy chain of the snake protein were determined.

1-Carboxyglutamic Acid↗

PubMed2000

Protein-degrading enediynes: library screening of Bergman cycloaromatization products.

[structure: see text] A screening method based on Bergman cycloaromatization products was applied to a compact library of estrogenic-enediyne hybrids. An enediyne candidate identified from the screen was subsequently synthesized, and it induced temperature- and concentration-dependent degradation of human estrogen receptor alpha upon cycloaromatization.

Antibiotics, Antineoplastic↗

PubMed2000

Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis.

In addition to their well characterized role in allergic inflammation, recent data confirm that mast cells play a more extensive role in a variety of immune responses. However, their contribution to autoimmune and neurologic disease processes has not been investigated. Experimental allergic encephalomyelitis (EAE) and its human disease counterpart, multiple sclerosis, are considered to be CD4(+) T cell-mediated autoimmune diseases affecting the central nervous system. Several lines of indirect evidence suggest that mast cells could also play a role in the pathogenesis of both the human and murine disease. Using a myelin oligodendrocyte glycoprotein (MOG)-induced model of acute EAE, we show that mast cell-deficient W/W(v) mice exhibit significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores when compared with their wild-type congenic littermates. No differences were observed in MOG-specific T and B cell responses between the two groups, indicating that a global T or B cell defect is not present in W/W(v) animals. Reconstitution of the mast cell population in W/W(v) mice restores induction of early and severe disease to wild-type levels, suggesting that mast cells are critical for the full manifestation of disease. These data provide a new mechanism for immune destruction in EAE and indicate that mast cells play a broader role in neurologic inflammation.

Age of Onset↗