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Biomedical subjects

K Ward

Publications and source records attributed to K Ward.

At least 37 records · Page 2Linked to original sources
PubMed2001

The tension-free vaginal tape procedure in women with previous failed stress incontinence surgery.

PURPOSE: The tension-free vaginal tape procedure is an increasingly popular choice for treating female urinary stress incontinence. This ongoing, prospective, open label study presents the results of tension-free vaginal tape surgery at 1 year in women who have previously undergone unsuccessful stress incontinence surgery. MATERIALS AND METHODS: A total of 67 women with previous failed surgery for stress urinary incontinence underwent the tension-free vaginal tape procedure. Treatment outcome was categorized as cure, significant improvement or failure based on cystometry findings and urinary pad loss results at 3 months of followup, and on subjective questioning at 3 months and 1 year of followup. RESULTS: At 12 months 54 women (81%) were cured, 4 (6%) were significantly improved and 9 (13%) were no better. No serious morbidity was noted after the procedure. CONCLUSIONS: The tension-free vaginal tape procedure provides the prospect of a success rate similar to that of a conventional sling procedure in patients with previous failed surgery. It has a low rate of operative complications and postoperative morbidity.

Adult↗
PubMed2000

Control of gammaherpesvirus latency by latent antigen-specific CD8(+) T cells.

The contribution of the latent antigen-specific CD8(+) T cell response to the control of gammaherpesvirus latency is currently obscure. Some latent antigens induce potent T cell responses, but little is known about their induction or the role they play during the establishment of latency. Here we used the murine gammaherpesvirus system to examine the expression of the latency-associated M2 gene during latency and the induction of the CD8(+) T cell response to this protein. M2, in contrast to the M3 latency-associated antigen, was expressed at day 14 after infection but was undetectable during long-term latency. The induction of the M2(91-99)/K(d) CD8(+) T cell response was B cell dependent, transient, and apparently induced by the rapid increase in latently infected cells around day 14 after intranasal infection. These kinetics were consistent with a role in controlling the initial "burst" of latently infected cells. In support of this hypothesis, adoptive transfer of an M2-specific CD8(+) T cell line reduced the initial load of latently infected cells, although not the long-term load. These data represent the first description of a latent antigen-specific immune response in this model, and suggest that vaccination with latent antigens such as M2 may be capable of modulating latent gammaherpesvirus infection.

Animals↗
PubMed2000

Influence of hydrophilicity of cationic polymers on the biophysical properties of polyelectrolyte complexes formed by self-assembly with DNA.

To investigate the possibility of producing charge-neutral gene delivery complexes with extended, non-particulate structures, DNA was allowed to self-assemble with a series of hydrophilic cationic polymers containing quaternary charged trimethylammonio ethylmethacrylate (TMAEM, 5, 15, 50, 100 mol%) copolymerised with hydrophilic N-(2-hydroxypropyl)methacrylamide (HPMA, 95, 85, 50, 0 mol%, respectively). Copolymers were all able to bind DNA, assessed using ethidium bromide fluorescence, although copolymers with low TMAEM content did not expel ethidium bromide. Increasing TMAEM content of the copolymers changed the morphology of the complexes from extended (5-15 mol% TMAEM), through partially condensed particles (50 mol%) to discrete nanoparticles (100 mol% TMAEM). Complexes based on copolymers with low TMAEM content (5-50 mol%) showed less resistance to degradation by nucleases and lower surface charge (21.2+/-5.9-45.1+/-3.9 mV) than those formed using 100 mol% TMAEM (57.8+/-8.2 mV). They also showed significantly less association with phagocytic cells in vitro (human leucocytes, uptake decreased by up to 92.3%; murine peritoneal macrophages, uptake decreased by up to 69.6%), although in vivo their hepatic accumulation was only slightly decreased (maximum decrease 27.6%). Finding the appropriate balance of hydrophilicity and stability is key to development of effective vectors for gene delivery.

Animals↗
PubMed2000

Direct visualization and quantitation of cytomegalovirus-specific CD8+ cytotoxic T-lymphocytes in liver transplant patients.

BACKGROUND: CMV infection remains a significant clinical problem in the context of LT. Changes in the magnitude of the CMV-specific CTL response after LT have not previously been assessed but may be important in determining the outcome of CMV infection. METHOD: We used a fluorescent HLA-B*0702-CMV peptide tetrameric complex to directly visualize and quantitate CMV-specific CD8+ CTL both in immunosuppressed patients after LT and in immunocompetent controls. RESULTS: CMV-specific CD8+ CTL, at a frequency ranging from 0.1 to 5.8% of CD8+, were detected in the peripheral blood of 22 of 25 B*0702, CMV immunoglobulin G seropositive individuals, with no difference observed between immunocompetent controls and patients >3 years after LT. In CMV seropositive LT recipients who did not have symptomatic CMV infection during the first 3 months after LT, CMV-specific CD8+ CTL magnitude initially decreased, then increased up to 5 times higher than pre-LT levels within 3 months. Two CMV seronegative recipients of seropositive donors had symptomatic CMV infection in association with high viral load. In both patients, no CD8+ CTL response was detected before the onset of symptoms, and a reduction in viral load was observed during antiviral therapy. However, polymerase chain reaction negativity was achieved only when a demonstrable CMV-specific CD8+ CTL response was generated. Responses were never observed in asymptomatic CMV seronegative patients. CONCLUSIONS: We suggest that the generation of CMV-specific CD8+ CTL may be driven by, and seems to coincide with the suppression of, viral reactivation. Direct monitoring of CMV-specific CD8+ CTL using an HLA-peptide tetramer may prove to be of value in the management of patients after LT.

Blood↗
PubMed2000

Whole-body metabolic rate appears to determine the rate of DNA oxidative damage and glycation involved in aging.

While aging has been found to be a multifactorial process, it seems logical that different aging parameters which reflect the deleterious effects of normal basal metabolism should be directly related. Three such putative aging parameters were therefore measured in adult male Fischer 344 rats on three different long-term diets which have been shown to yield different lifespans. It was found that the daily caloric intake per unit organ weight, a measure of whole-body metabolic rate, was directly proportional to: (1) the level of 8-hydroxydeoxyguanosine in skin dermal cells, used as a measure of the rate of DNA oxidative damage; (2) the proportion of hemoglobin that was glycated, used as a measure of the rate of glycation. This appears to be the first evidence suggesting that whole-body metabolic rate plays a role in determining both the rate of DNA oxidative damage and the rate of glycation involved in aging, because whole-body metabolic rate was the only one of these three variables manipulated in the study. The study also found that there were no significant between-group differences in brain, kidney and liver 8-hydroxydeoxyguanosine, suggesting that DNA oxidative damage in non-mitotic and slow-dividing cells is not a reliable linear biomarker of aging.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Fetal endothelial cells express vascular cell adhesion molecule in the setting of chorioamnionitis.

PROBLEM: In intrauterine infection, inflammatory mediators may be released into the fetal circulation prior to fetal infection. We hypothesize that, in chorioamnionitis, inflammation alters fetal blood vessels. To test this, fetal endothelial cells were examined for vascular cell adhesion molecule (VCAM). METHOD OF STUDY: Umbilical cords (n = 9) from placentas with chorioamnionitis were immunostained for VCAM. Controls from preterm preeclamptic pregnancies (n = 7) without histologic inflammation were selected, and matched for gestational age and method of delivery. VCAM sections were reviewed by a pathologist blinded to clinical diagnoses. RESULTS: All endothelial cells from each of the nine cords from placentas with chorioamnionitis had strong VCAM staining. Two of nine samples also had acute cord vasculitis. No cord endothelial cells from preeclamptic placentas demonstrated similar VCAM staining (p < 0.01). CONCLUSION: Histologic chorioamnionitis was associated with VCAM expression of the umbilical cord vessels. In chorioamnionitis, inflammatory mediators may have entered the fetal circulation to activate endothelial cells. Intrauterine inflammation was not restricted to the chorioamnion, but also involved the fetal circulation.

Chorioamnionitis↗
PubMed2000

Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family.

BACKGROUND: Primary pulmonary hypertension (PPH), resulting from occlusion of small pulmonary arteries, is a devastating condition. Mutations of the bone morphogenetic protein receptor type II gene (BMPR2), a component of the transforming growth factor beta (TGF-beta) family which plays a key role in cell growth, have recently been identified as causing familial PPH. We have searched for BMPR2 gene mutations in sporadic PPH patients to determine whether the same genetic defect underlies the more common form of the disorder. METHODS: We investigated 50 unrelated patients, with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension, by direct sequencing of the entire coding region and intron/exon boundaries of the BMPR2 gene. DNA from available parent pairs (n=5) was used to assess the occurrence of spontaneous (de novo) mutations contributing to sporadic PPH. RESULTS: We found a total of 11 different heterozygous germline mutations of the BMPR2 gene in 13 of the 50 PPH patients studied, including missense (n=3), nonsense (n=3), and frameshift (n=5) mutations each predicted to alter the cell signalling response to specific ligands. Parental analysis showed three occurrences of paternal transmission and two of de novo mutation of the BMPR2 gene in sporadic PPH. CONCLUSION: The sporadic form of PPH is associated with germline mutations of the gene encoding the receptor protein BMPR-II in at least 26% of cases. A molecular classification of PPH, based upon the presence or absence of BMPR2 mutations, has important implications for patient management and screening of relatives.

Adolescent↗
PubMed2000

Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin.

Anti-streptococcal antibodies cross-reactive with N-acetyl-betaD-glucosamine (GlcNAc) and myosin are present in the sera of patients with rheumatic fever (RF). However, their role in tissue injury is not clear. In this study, we show that anti-GlcNAc/anti-myosin mAb 3.B6 from a rheumatic carditis patient was cytotoxic for human endothelial cell lines and reacted with human valvular endothelium and underlying basement membrane. Reactivity of mAb 3.B6 with the valve was inhibited by human cardiac myosin > laminin > GlcNAc. The mAb 3.B6 epitopes were localized in fragments of human cardiac myosin, including heavy meromyosin (HMM), the S1 subfragment, and two light meromyosin (LMM) peptides containing amino acid sequences KEALISSLTRGKLTYTQQ (LMM 1) and SERVQLLHSQNTSLINQK (LMM 33). A novel feature of mAb 3.B6 was its reactivity with the extracellular matrix protein laminin, which may explain its reactivity with the valve surface. A laminin A-chain peptide (HTQNT) that includes homology to LMM33 inhibited the reactivity of mAb 3.B6 with human valve. These data support the hypothesis that cross-reactive antibodies in rheumatic carditis cause injury at the endothelium and underlying matrix of the valve.

Acetylglucosamine↗
PubMed2000

Synergistic interaction between anti-p185HER-2 ricin A chain immunotoxins and radionuclide conjugates for inhibiting growth of ovarian and breast cancer cells that overexpress HER-2.

Radionuclide conjugates or ricin A chain (RTA) immunotoxins that target pl85HER-2 have partially inhibited the growth of human ovarian cancer xenografts in athymic mice but generally have not cured mice bearing human tumor transplants. The present study was undertaken to explore whether a combination of ionizing radiation and an immunotoxin could exert additive or synergistic cytotoxicity in culture and in vivo against cancer cells that overexpress p185HER-2. In cell culture, treatment with 200-2000 cGy external beam irradiation followed by incubation with TA1-anti-pl85mHER2-RTA immunotoxin (TA1-RTA) produced synergistic inhibition of clonogenic growth of ovarian and breast cancer cells that expressed > 10(6) pl85HER-2 receptors/cell. The effect on cell survival correlated with an inhibition of DNA repair. A prior study (F. J. Xu et al, Nucl. Med. Biol., 24: 451-460, 1997) compared the biodistribution of radionuclide conjugates prepared with monoclonal antibodies that bind to different epitopes on the extracellular domain of pl85HER-2 and found optimal tumor uptake with the 520C9 antibody, which did not compete with TA1 for binding to the receptor. In this report, the TA1-RTA immunotoxin and the 131I-labeled 520C9 radionuclide conjugate could each inhibit the growth of clone-9002-18 xenografts in athymic mice but did not yield long-term survivors using maximally tolerated doses of each agent. When TA1-RTA and 131I-labeled 520C9 were used in combination, a greater inhibition of tumor growth was obtained than with either single agent. Similarly, survival with the combined treatment was significantly prolonged (P = 0.004) relative to treatment with immunotoxin or radionuclide conjugate alone. After treatment with an optimal combination of immunotoxin and radionuclide conjugate, 50% of mice survived >300 days, whereas controls succumbed with a median survival of 36 days. These results suggest that combinations of immunotoxins and radionuclide conjugates deserve further evaluation for the treatment of cancers that overexpress pl85HER-2.

Animals↗
PubMed2000

Prayer in medicine: a survey of primary care physicians.

Prayer and spirituality have been shown to have a significant impact on several health variables. Additionally, studies have shown that patients think prayer is important to their health. Very little research, however, has been done to determine primary care physicians' opinions regarding prayer and spirituality as it pertains to healthcare. We surveyed primary care physicians in Mississippi to assess their use of prayer in medical practice. Ninety-one percent of respondents considered prayer an important treatment modality, but 50.6% rarely or never discussed prayer with patients. Most who excluded prayer from clinical practice did so to avoid imposing their beliefs upon patients. A majority of primary care physicians in Mississippi recognize prayer as an important psychosocial variable in assessing and treating patients, but many are hesitant to incorporate this variable into the doctor-patient encounter.

Attitude of Health Personnel↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗