Biomedical subjects

K Ward

Publications and source records attributed to K Ward.

At least 55 records · Page 3Linked to original sources

PubMed1999

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↗

PubMed1998

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↗

PubMed1998

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↗

PubMed1998

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↗

PubMed1998

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↗

PubMed1998

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↗

PubMed1998

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↗

PubMed1998

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↗

PubMed1998

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↗

PubMed1998

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↗

PubMed1998

Factor V Leiden is not common in patients diagnosed with primary pulmonary hypertension.

Substantial evidence suggests that thrombosis contributes to the pathogenesis of primary pulmonary hypertension (PPH). An abnormal factor V (factor V Leiden) may contribute to thrombosis in the pulmonary microcirculation of PPH patients. A point mutation in which adenine is substituted for guanine at nucleotide 1691 (1691A) alters factor V so that it resists cleavage by activated protein C. Heterozygosity for the 1691A mutation is more common (2-8%) in Caucasian Europeans and Americans than in Africans (1%) and Asians (<1%). The aim of the study was to examine the prevalence of the mutation that codes for factor V Leiden in individuals with PPH. We identified 42 Caucasians diagnosed with PPH. We extracted deoxyribonucleic acid (DNA) from whole blood and assayed DNA samples for the point mutation (1691 A) that codes for factor V Leiden. One out of 42 (2.4%; 95% confidence interval=0.1-12.6) Caucasians diagnosed with PPH was heterozygous for the normal 1691G and mutant 1691A allele. All 10 individuals with familial PPH were homozygous for the normal 1691G allele. The prevalence of heterozygosity for the 1691A allele and the normal 1691G allele does not differ from that observed in reference (control) populations. The low prevalence of the 1691A mutation among individuals diagnosed with primary pulmonary hypertension provides evidence that factor V Leiden does not contribute to the pathogenesis of the disease in most patients.

Adult↗

PubMed1998

Comparison of salicylic acid and urea versus ammonium lactate for the treatment of foot xerosis. A randomized, double-blind, clinical study.

Xerosis is defined as dehydration of skin characterized by redness, dry scaling, and fine crackling that may resemble the crackling of porcelain. The present double-blind trial was a randomized paired comparison study evaluating the keratolytic effect of 5% salicylic acid and 10% urea ointment (Kerasal) on one foot and 12% ammonium lactate lotion (Lac-Hydrin) on the other foot in mild-to-moderate xerosis. Seventy patients were initially enrolled in the trial. Fifty-four patients were evaluated after 2 weeks of treatment; of those 54 patients, 39 were evaluated after 4 weeks of treatment. Although there was significant improvement in severity of xerosis after 2 and 4 weeks of treatment, there was no statistically significant difference between treatment groups. Irrespective of the mechanism of action, this study shows that both Kerasal and Lac-Hydrin 12% lotion result in reduction in the severity of xerosis after 4 weeks of therapy.

Administration, Topical↗

PubMed1998

Massive lymphadenopathy and airway obstruction in a child with Kawasaki disease: success with pulse steroid therapy.

Kawasaki disease (KD) is an acute, febrile, self-limited, multisystem vasculitis that almost exclusively affects young children. We describe a 4-year-old girl with intravenous immunoglobulin (IVIG) resistant KD who developed massive cervical lymphadenopathy and severe respiratory distress. Treatment with intravenous pulse methylprednisolone led to dramatic resolution of her symptoms. We conclude that pulse steroid therapy should be considered in patients with KD complicated by massive lymphadenopathy with life threatening airway obstruction and/or IVIG resistant disease.

Airway Obstruction↗

PubMed1998

Lower extremity manifestations of vascular disease.

All podiatrists are required to know the anatomy and pathophysiology of vascular pathology because it is the leading cause of morbidity and mortality in the western world and a frequent complaint of podiatry patients. Podiatrists have a unique opportunity to reduce the risk of lower extremity vascular pathology, specifically PVD, by encouraging proper diet and exercise in the podiatric patient. Because the next century will bring a population explosion of older people, particular attention must be paid to the multiple and complex disorders that impair functional independence and compromise quality of life--one of the most important disorders being vascular disease. Successful treatment depends on recognition of lower extremity pathology (whether it be arterial, venous, or lymphatic) and the possible suprastructural causes and timely referrals to a vascular specialist when indicated.

Arterial Occlusive Diseases↗

PubMed1998

The foot and systemic disease. Differential diagnoses.

The discipline of medicine is truly a combination of both science and art, and nowhere is this more true than in the practice of differential diagnosis. From the initial clinic visit, when the patient presents with a nonspecific symptom, until the final treatment is rendered, the clinician must constantly and critically evaluate his or her diagnosis. This process can be expedited by using a consistent and comprehensive methodology that reminds the clinician to entertain the full spectrum of causes. Two such methodologies have been presented in this article. It is important, however, to note that the systems presented here are by no means the sole, or even best, methods. The clinician should experiment and discover what works best for him or her. Any system is ideal if it allows the clinician to consistently derive the correct diagnosis in a short amount of time. After all, the most important part of any treatment is the proper diagnosis.

Diagnosis, Differential↗

PubMed1997

Xq28-linked noncompaction of the left ventricular myocardium: prenatal diagnosis and pathologic analysis of affected individuals.

Isolated noncompaction of the left ventricular myocardium (INVM) is characterized by the presence of numerous prominent trabeculations and deep intertrabecular recesses within the left ventricle, sometimes also affecting the right ventricle and interventricular septum. Familial occurrence of this disorder was described previously. We present a family in which 6 affected individuals demonstrated X-linked recessive inheritance of this trait. Affected relatives presented postnatally with left ventricular failure and arrhythmias, associated with the pathognomonic echocardiographic findings of INVM. The usual findings of Barth syndrome (neutropenia, growth retardation, elevated urinary organic acids, low carnitine levels, and mitochondrial abnormalities) were either absent or found inconsistently. Fetal echocardiograms obtained between 24-30 weeks of gestation in 3 of the affected males showed a dilated left ventricle in one heart, but were not otherwise diagnostic of INVM in any of the cases. Four of the affected individuals died during infancy, one is in cardiac failure at age 8 months, and one is alive following cardiac transplant at age 9 months. The hearts from infants who died or underwent transplantation appeared, on gross examination, to be enlarged, with coarse, deep ventricular trabeculations and prominent endocardial fibroelastosis. Histologically, there were loosely organized fascicles of myocytes in subepicardial and midmyocardial zones of both ventricles, and the myocytes showed thin, often angulated fibers with prominent central clearing and reduced numbers of filaments. Markedly elongated mitochondria were present in some ventricular myocytes from one specimen, but this finding was not reproducible. Genetic linkage analysis has localized INVM to the Xq28 region, where other myopathies with cardiac involvement have been located.

Adolescent↗

PubMed1997

Angiotensinogen T235 expression is elevated in decidual spiral arteries.

Preeclampsia is associated with a common molecular variant of angiotensinogen (Met235Thr). This variant is in tight linkage disequilibrium with a mutation in the angiotensinogen promoter, G(-6)A, which leads to elevated expression in vitro. Since angiotensin II levels could play a role in atherotic changes of the uterine spiral arteries associated with preeclampsia, we investigated angiotensinogen expression in the first trimester uterus. We localized angiotensinogen transcription in uterine decidua using in situ reverse transcription PCR. We then compared decidual T235 expression levels to M235 levels in heterozygous women using an allele-specific ligation assay and a single nucleotide primer extension assay. In human decidua, angiotensinogen is expressed only in spiral artery smooth muscle cells. Heterozygous women have significantly elevated expression of the T235 allele compared to the M235 allele (P < 0.0001). These observations suggest that elevated expression of the T235 allele in decidual spiral arteries may cause first trimester atherotic changes leading to preeclampsia.

Alleles↗

PubMed1997

Umbilical cord agenesis in limb body wall defect.

The term "Limb Body Wall Defect" (LBWD) refers to a variable group of congenital defects having in common abdomino- or thoraco-schisis and limb deficiency. Three general pathogenic mechanisms have been proposed for this disorder: amnion rupture, vascular disruption, and embryonic malformation. We hypothesize that there are subsets of "Limb Body Wall Defect," which have similar structural abnormalities and a common pathogenesis. We report on five cases of LBWD that were selected by using more restrictive criteria. An infant or fetus was included if it had abdominoschisis with a broad attachment of skin to amnion at the site of the abdominal wall defect, limb defects, and umbilical cord agenesis. Autopsy detected additional common structural defects. All had evisceration of the gastrointestinal structures into the extra-embryonic coelomic space with structural abnormalities of the intestines. All had scoliosis, thoracic deformities, pulmonary hypoplasia, and structural abnormalities of the cloaca and urogenital ridge. Four of five had meningomyelocele. Three had exstrophy of the cloaca. The four females all had ovarian agenesis and incomplete Mullerian fusion. None had normal development of the external genitalia. We propose that the pathogenesis was a primary malformation of body wall closure, with abnormal fusion of the amnion, which had occurred in the first month of development.

Abdominal Muscles↗