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Cooperative Behavior↗
Biomedical subjects
K Ward
Publications and source records attributed to K Ward.
A new class of selective and potent inhibitors of neuronal nitric oxide synthase.
The synthesis and SAR of a series of 6-(4-(substituted)phenyl)-2-aminopyridines as inhibitors of nitric oxide synthase are described. Compound 3a from this series shows potent and selective inhibition of the human nNOS isoform, with pharmacokinetics sufficient to provide in vivo inhibition of nNOS activity.
Aminopyridines↗
Angiotensinogen Thr235 variant is associated with abnormal physiologic change of the uterine spiral arteries in first-trimester decidua.
OBJECTIVE: The angiotensinogen Thr235 polymorphism associated with preeclampsia is tightly linked to a mutation in the angiotensinogen promoter A(-6), which may lead to elevated expression in decidual spiral arteries. We hypothesize that locally elevated angiotensin II levels play a role in failed physiologic change leading to preeclampsia. Our objective was to determine whether spiral artery morphologic characteristics were different in first-trimester decidual samples from women homozygous for the angiotensinogen Thr235 allele and women homozygous for the normal angiotensinogen Met235 allele. STUDY DESIGN: We used quantitative histologic analysis to study 1266 spiral artery cross-sections in decidual samples obtained from normal pregnancies (n = 53) terminated at 8 weeks' gestation. To define vessel characteristics before pregnancy-induced remodeling, we also examined 60 arteries in nonpregnant endometrial control samples (n = 5). We measured the aspect ratio, media area, and external diameter of each cross-section with Image-Pro plus software. Maternal angiotensinogen genotypes were determined by means of mutagenically separated polymerase chain reaction. Average spiral artery morphologic measurements were compared between genotypes with the Student t test. RESULTS: The media area/external diameter ratio was lower in decidual samples than in endometrial samples (P <.0001), consistent with pregnancy-induced physiologic changes. Women homozygous for the angiotensinogen Thr235 allele (n = 11) had a greater area/diameter ratio than did women homozygous for the normal angiotensinogen Met235 allele (n = 11, P <.05). Samples from heterozygous women (n = 31) had intermediate values. CONCLUSION: Our results suggest that the angiotensinogen Thr235 allele predisposes women toward abnormal physiologic change, potentially beginning the cascade of events leading to preeclampsia.
Alleles↗
Syncytiotrophoblastic fragments in first-trimester decidual veins: evidence of placental perfusion by the maternal circulation early in pregnancy.
OBJECTIVE: To determine whether maternal placental perfusion occurs in the first trimester, this study compared veins in endometrium with those in decidua. We hypothesize that veins draining the placenta become dilated and contain syncytiotrophoblastic fragments. STUDY DESIGN: Normal late-secretory endometrial biopsy specimens (n = 10) were compared with elective abortion decidua at 7 to 11 weeks (n = 100). Tissue sections were processed by routine staining and immunohistochemical studies. The cross sections of veins and glands were counted in 25 decidual biopsy specimens, and the number of syncytiotrophoblastic fragments in veins or glands was determined. Statistical significance by chi(2) or linear regression analysis was P <.05. RESULTS: All sets of decidua had dilated veins; no secretory endometrium did. Intravenous syncytiotrophoblastic fragments were seen in 91 of 100 sets of decidua. There were more syncytial elements in veins (572/6845, 8.4%) than in glands (13/23,310, 0.06%) (P <.001). CONCLUSION: Decidual veins were distended and contained syncytiotrophoblastic fragments, consistent with maternal intervillous perfusion in the first trimester.
Decidua↗
New insights into the genetics of preeclampsia.
Preeclampsia is familial. Pedigree analyses suggest that one or more common alleles may act as "preeclampsia susceptibility genes." The authors speculate that genes involved in blood pressure control, volume regulation, placental health, vascular disease, and vascular remodeling, underlie familial susceptibility to preeclampsia. Several candidate genes have been examined. These data suggest that a common mutation in the angiotensinogen promoter, A(-6), leads to elevated expression of this gene and pleiotropic effects, including abnormal spiral artery remodeling and failed hypervolemia of pregnancy. The factor V Leiden mutation, which predisposes women to thromboembolic disorders during pregnancy, has been implicated as another preeclampsia susceptibility gene. New insights into the genetics of preeclampsia will contribute to the understanding of this disease and should ultimately lead to improved diagnosis and treatment.
Angiotensinogen↗
Transfusion of fetal cord blood cells: an improved method of hematopoietic stem cell transplantation?
Hematopoietic stem cells circulate in the fetal blood and may be isolated from the placenta through the umbilical cord after birth. These cells have been safely isolated, and transplanted into recipients to treat malignancies and marrow failure. Cord blood stem cells may be used for genetic disorders. Compared to other sources of stem cells, recipients of cord blood stem cells have fewer and less severe episodes of graft versus host disease. This may be because intrauterine graft (fetus) versus host (mother) disease is harmful to the pregnancy. Controversies persist surrounding the harvest and use of these cells.
Blood Banks↗
Genetic factors in preterm delivery.
Tens of thousands of children deliver before they are full term each year. Although many social, environmental, and medical risk factors have been suggested, the etiology of a large percentage of preterm labor cases is still unknown. It has been noted for many years that preterm delivery is a condition that runs in families. Evidence concerning its aggregation among families, the recurrent nature of preterm labor, and its differing prevalence between races has led to the suggestion of a genetic cause for preterm delivery. There have been few formal studies to investigate this hypothesis. We suggest that modern molecular biology approaches can reveal the part that genes play in preterm delivery.
Adult↗
Urinary excretion of pyridinium crosslinks in healthy 4-10 year olds.
Urinary pyridinoline and deoxypyridinoline, pyridinium crosslinks released during breakdown of mature collagen, might serve as useful markers of bone resorption. Before their role can be identified, reference values must be established. In this study, free pyridinoline (f-Pyr), free deoxypyridinoline (f-DPyr), and creatinine (Cr) were measured in first morning void urine samples from 250 girls and 265 boys between the ages of 4 and 10 years. Overall, there was a decrease in f-Pyr:Cr and f-DPyr:Cr ratios with increasing age in both sexes, but there was a wide range of values for individuals of similar ages. Further studies are required to assess whether urinary pyridinium crosslink excretion is sufficiently deranged in conditions affecting bone metabolism for the measurement of these compounds to be of clinical value.
Age Factors↗
Elements of a paracrine tubular renin-angiotensin system along the entire nephron.
The renin-angiotensin system is a major regulator of body sodium, predominantly through the actions of intrarenal angiotensin II of unclear origin. We show that polarized epithelium of the proximal tubule synthesizes and secretes angiotensinogen at its apical side and that the protein can be detected in urine as a function of dietary sodium. Furthermore, we demonstrate that renin is expressed and secreted in a restricted nephron segment, the connecting tubule, also in a sodium-dependent fashion. A paracrine renin-angiotensin system operating along the entire nephron may contribute to long-term arterial pressure regulation by integrating distant tubular sodium-reabsorbing functions.
Angiotensinogen↗
Implications of a novel cryptic splice site in the BRCA1 gene.
This study was designed to determine the significance of a single intronic base change (IVS5-12 G-->A) found in a family with a history of breast cancer. This change is predicted to form a cryptic splice site resulting in the addition of 11 nucleotides to the BRCA1 transcript. The BRCA1 gene of the relatives and control individuals was sequenced and analyzed using RT-PCR, ASO hybridization, and size fractionation. All patients showed an 11 nucleotide insert at the intron 5/exon 6 boundary. This variant is likely to form a short protein product incapable of the hypothesized tumor suppressor functions of the BRCA1 gene. This information is important for providing counseling for families with this cryptic splice site and a family history of breast cancer.
Base Sequence↗
Myotonic dystrophy is a significant cause of idiopathic polyhydramnios.
OBJECTIVE: Myotonic dystrophy, the most common form of muscular dystrophy seen in pregnant women, may be a significant cause of middle trimester polyhydramnios. Our purpose was to determine the prevalence of myotonic dystrophy in women with idiopathic polyhydramnios and to characterize the ultrasonographic findings associated with cases. STUDY DESIGN: We examined the cases of 67 patients who were delivered of infants at the University of Utah between 1992 and 1996 with a diagnosis of idiopathic polyhydramnios (amniotic fluid index >25). Women with diabetes mellitus, hydrops, or fetal anomalies known to cause polyhydramnios were excluded from the study. Amniotic fluid samples or cord blood samples were obtained from 41 patients, and polymerase chain reaction amplification and Southern blot analysis were performed to detect the presence of the myotonic dystrophy mutation. Ultrasonographic findings, prenatal course, and neonatal outcomes were reviewed in all cases. RESULTS: Four of the 41 patients tested had the myotonic dystrophy mutation, yielding a prevalence in our population of 9.7%. Three of the 4 patients reported a family history of myotonic dystrophy. Ultrasonographic findings associated with a positive result included abnormal posturing of extremities (3/4) and unilateral clubbed foot (3/4). No other structural or growth abnormalities were seen. Two of the patients were delivered before term, 1 at 26 weeks and 1 at 32 weeks. Three of the 4 infants were severely affected, necessitating admission to the intensive care unit, and 1 died on day 11 after birth. One infant, whose myotonic dystrophy mutation consisted of between 800 and 900 triplet repeats, did not require admission to the intensive care unit. CONCLUSION: Myotonic dystrophy may be seen as idiopathic polyhydramnios and should be considered as part of the differential diagnosis in these cases. Women with a familial history of myotonic dystrophy or ultrasonographic evidence of hypotonia, including positional abnormalities of the extremities, should be offered deoxyribonucleic acid testing for the myotonic dystrophy mutation.
Congenital Abnormalities↗
Angiotensinogen genotype and plasma volume in nulligravid women.
OBJECTIVE: To determine if nonpregnant plasma volume is altered in women who are homozygous for the T 235 coding angiotensinogen allele, which predisposes women to an increased risk of preeclampsia. METHODS: We measured plasma volume by Evans blue dilution and analyzed it as a function of angiotensinogen genotype in 15 nulligravid women during midfollicular phase of 26 menstrual cycles. Eleven women were evaluated during two cycles, and four women were evaluated in one cycle. Fourteen women were white, and one was Asian. No subjects had illnesses or were taking medication. The range of body mass index (BMI [kg/m2]) was 20.2-31.0. Plasma volume (mL) was reported as plasma volume divided by BMI to control for variations in body sizes. Statistical analysis was performed by analysis of variance with post hoc testing using Fisher least significant difference test for multiple comparisons (P < .05 accepted for significance). RESULTS: Angiotensinogen genotype analysis showed five women homozygous for M 235, three women homozygous for T 235, and seven women who were heterozygous (MT 235). T 235 homozygotes had significantly lower plasma volume divided by BMI compared with women who were homozygous for M 235 and women who were heterozygous for MT 235 (mean + standard deviation [SD] [71.2 + 8.8, 86.6 + 5.2, 95.8 + 15.6, respectively, P < .05]). There was a tendency toward higher plasma volume in heterozygote MT 235 compared with homozygote M 235 carriers, but it was not statistically significant. CONCLUSION: We conclude that the homozygous T 235 coding angiotensinogen genotype is associated with reduced plasma volume in nulligravid women during the follicular phase of the menstrual cycle compared with M 235 homozygotes and heterozygotes. This association of the T 235 coding genotype might contribute to fetal growth restriction in preeclampsia.
Angiotensinogen↗
Intolerance to volume expansion: a theorized mechanism for the development of preeclampsia.
We present a theorized mechanism for the development of preeclampsia, suggesting that one important underlying pathophysiologic mechanism is intolerance to volume expansion. The stage is set for this intolerance by chronic volume constriction, which leads to a requirement for increased basal peripheral vasoconstrictor tone to maintain blood pressure and allow for continued perfusion of the upright hominid head. In pregnancy, volume expansion signaled by the placenta cannot be accommodated by the constricted vascular system. The inability of the normally adaptive endothelial vasodilatory mechanisms to overcome the chronic vasoconstrictor tone leads to endothelial damage, exacerbation of vasoconstriction, and clinical hypertension. Disease resolution, characterized by diuresis, occurs with the elimination of the placenta-derived drive to retain volume. The reason preeclampsia does not recur uniformly with subsequent pregnancy is permanent restructuring of the maternal cardiovascular system with pregnancy that allows for greater plasma volume expansion in future gestations.
Female↗
Decidual spiral artery remodelling begins before cellular interaction with cytotrophoblasts.
Endometrial arteries undergo structural alterations during pregnancy to increase blood flow to the intervillous space. It is hypothesized that physiologic change in decidual arteries is similar to vascular remodelling seen in other organs. Histologic features of spiral arteries in secretory endometrial biopsies were compared blindly to decidual arteries from elective abortions. Similar sections were stained for trophoblastic and vascular antigens. Spiral arteries in endometrium from ectopic (tubal) and intrauterine pregnancies were compared also. Evidence of decidual endothelial activation was sought using antibodies to vascular cell adhesion molecule (VCAM-1). As expected, decidual arteries were significantly different than arteries in secretory endometrium: there was more endothelial basophilia, vacuolation, and arterial dilation in early pregnancy. Some vessels had disorganized or hypertrophied smooth muscle layers. Similar structural alterations were seen in endometrium of ectopic pregnancies, and in the decidua parietalis of intrauterine pregnancies. Immunohistochemical studies confirmed that these alterations occurred in the absence of cellular interaction with extravillous cytotrophoblasts. Independently of trophoblasts, decidual endothelial cells expressed VCAM-1. It is concluded that the initial stages of physiologic change are characterized by vascular remodelling, which occur in the absence of trophoblast invasion of the spiral arteries. Arterial modifications in decidua begin as a maternal response to pregnancy.
Arteries↗
A promoter mutation in the tumor necrosis factor alpha gene is not associated with preeclampsia.
Preeclampsia is associated with increased plasma concentrations of tumor necrosis factor alpha (TNF alpha) and TNF receptors. A mutation in the promoter region of the TNF alpha gene (TNF T2) has been described which is associated with increased transcription of the gene. Due to the familial predisposition of preeclampsia, we hypothesized that this promoter mutation in the TNF alpha gene may contribute to the genetic etiology of preeclampsia. Our objective was to determine the allele frequency of this mutation in a population with well-characterized preeclampsia and with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome as compared with normotensive controls. DNA was extracted from blood of 131 women with severe preeclampsia, 75 women with HELLP syndrome, and 41 normotensive gravid controls. Genotypes were determined using the polymerase chain reaction (PCR), allele-specific restriction with Nco1, and agarose gel electrophoresis. Results were analyzed with a chi 2 contingency table. No significant differences were found between patients with severe preeclampsia, HELLP syndrome, normotensive gravid controls, and previously published allele frequencies. The frequency of the TNF T2 allele is not increased in patients with preeclampsia or HELLP syndrome. Therefore, this promoter mutation is probably not a major genetic cause of preeclampsia. As more genes are cloned, sequenced and localized, this will enable investigators to take this 'candidate gene approach' to investigate potential genetic causes of preeclampsia.
Female↗
Immunological relationship between the class I epitope of streptococcal M protein and myosin.
The class I epitope of streptococcal M protein is an epidemiological marker for acute rheumatic fever (ARF)-associated serotypes of group A streptococci and is recognized by anti-M protein monoclonal antibody (MAb) 10B6. Using MAb 10B6, we determined the relationship between the class I epitope of M protein and the alpha-helical coiled-coil protein myosin. MAb 10B6 reacted by enzyme-linked immunosorbent assay and Western blotting with human cardiac myosin and rabbit skeletal myosin and its heavy meromyosin (HMM) subfragment. Overlapping synthetic peptides of M5 protein were used to identify the region of M5 protein recognized by MAb 10B6. Two C repeat peptides (C2A and C3) containing the amino acid sequence KGLRRDLDASREAK reacted with MAb 10B6. Partial sequence identity, RRDL, was found in the HMM fragment of myosin, which reacted with MAb 10B6. However, not all peptides of M5 protein and myosin containing the RRDL sequence reacted with MAb 10B6. ARF sera and sera from uncomplicated pharyngitis (UNC) reacted with C repeat region peptides of M protein, while acute glomerulonephritis sera were not as reactive. Affinity-purified human antibody to peptide C3 reacted with myosin. The data demonstrate that the class I epitope of M protein is immunologically cross-reactive with myosin and the HMM subfragment, and antibodies to peptide C3 and myosin were present in ARF and UNC sera.
Amino Acid Sequence↗
Functional differences between BHRF1, the Epstein-Barr virus-encoded Bcl-2 homologue, and Bcl-2 in human epithelial cells.
BHRF1, a component of the restricted early antigen complex of the Epstein-Barr virus lytic cycle, encodes a 17-kDa protein with both sequence and functional homology to the antiapoptotic Bcl-2 oncogene. Recent work has suggested that BHRF1 behaves like Bcl-2 in protecting cells from apoptosis induced by a range of stimuli. In this study, the effect of BHRF1 and Bcl-2 on the growth and differentiation of the SCC12F human epithelial cell line was examined. The levels of stable transfected BHRF1 expression achievable in SCC12F cells was consistently lower than that obtained with Bcl-2. While both BHRF1 and Bcl-2 inhibited epithelial differentiation, the effect of Bcl-2 was more pronounced, resulting in an almost complete blockade of differentiation in organotypic raft cultures. However, BHRF1-expressing SCC12F cells proliferated at a much higher rate than SCC12F cells expressing Bcl-2, and this effect was supported by cell cycle analysis which demonstrated that BHRF1, but not Bcl-2, promotes rapid transit through the cell cycle. These data highlight important differences between BHRF1 and Bcl-2 and suggest that BHRF1 may function to promote the survival and proliferation of lytically infected cells. The proliferative properties of BHRF1 described in this study, together with the demonstration that other oncogenic gamma herpesviruses encode Bcl-2 homologues, suggests that these proteins may serve to increase the susceptibility of virus-infected cells to oncogenic transformation, thereby contributing to the development of virus-associated tumors.
Apoptosis↗
Human spiral artery renin-angiotensin system.
Pregnancy induces uterine spiral arteries to remodel into dilated uteroplacental vessels by an unknown mechanism called "physiological change." In women who develop preeclampsia, however, many spiral arteries remain unchanged or develop medial hyperplasia and atherosis. We recently demonstrated that angiotensinogen is expressed by remodeling spiral arteries in first-trimester decidua. We hypothesize that a local spiral artery renin-angiotensin system mediates pregnancy-induced remodeling of these vessels. In this study we tested for expression of renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor genes in the first-trimester uterus using reverse-transcription polymerase chain reaction. Expression was localized by in situ hybridization and immunohistochemistry. Renin, angiotensin-converting enzyme, and the angiotensin II type 1 receptor are all expressed in and around remodeling spiral arteries. These observations suggest that a local spiral artery renin-angiotensin system may play a role in pregnancy-induced remodeling of these vessels. Elevated angiotensinogen expression in women homozygous for the A(-6) variant in the angiotensinogen promoter may promote abnormal remodeling, whereas relatively lower levels in women homozygous for G(-6) may permit enough normal remodeling to protect these women from preeclampsia.
Arteries↗