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Biomedical subjects

M R Harrison

Publications and source records attributed to M R Harrison.

At least 145 records · Page 8Linked to original sources
PubMed1994

Congenital cystic adenomatoid malformation: a sheep model of fetal hydrops.

Congenital cystic adenomatoid malformation (CCAM) can be diagnosed in utero. Nonimmune hydrops associated with CCAM is a predictor of fetal demise. Fetuses with prenatally diagnosed large CCAM tumors and hydrops have undergone successful in utero resection. An animal model is needed to understand the pathophysiology of CCAM and hydrops. To create a model of CCAM and hydrops, the authors implanted an intrathoracic tissue expander in six fetal sheep at 120 days' gestation. The inflatable tissue expander was implanted in the right side of the chest, and arterial, venous, intrathoracic, and intraamniotic pressure catheters were placed. Each day, the expander was inflated with 25 to 50 mL of saline (maximum, 150 mL), ultrasound examination was performed, and all pressure measurements were taken. In all six fetuses, hydrops developed after expander inflation. Expander inflation correlated with an increase in central venous pressure (CVP) (4 +/- 2 mm Hg v 16 +/- 2 mm Hg [mean +/- SD]; P < .05). To simulate in utero CCAM resection, the expander was deflated in four hydropic sheep, resulting in return of the CVP to near baseline and resolution of hydrops. Silicone vascular casts of two postmortem sheep demonstrated lateral displacement and compression of the vena cavae by the expander. The authors successfully created a model of CCAM and hydrops by inflating an intrathoracic tissue expander in fetal sheep. Based on this model, hydrops associated with CCAM results from obstruction of cardiac venous return and central venous hypertension. This pathophysiology is reversed by expander deflation, which simulates in utero CCAM resection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Pharmacokinetics and pharmacodynamics of a new cardiotonic vasodilator agent, 349U85, in normal subjects.

OBJECTIVE: To assess the pharmacodynamics and pharmacokinetics of single oral doses of a new vasodilator-cardiotonic agent, 349U85 hydrochloride [6-piperidino-2(1H)-quinolinone hydrochloride], in healthy male subjects. METHODS: This randomized, parallel, double-blind, placebo-controlled, dose escalation trial was conducted at a university-based clinical research center among 27 healthy male subjects. Data measurements used in the study included cardiac index, supine and standing blood pressure, 24-hour ambulatory electrocardiography, and 12-lead electrocardiography. RESULTS: Doses from 2 mg to 250 mg were well tolerated. Cardiac index, supine heart rate, and orthostatic hypotension, indicators of inotropic, chronotropic, and vasodilator effects, respectively, correlated to plasma concentrations of 349U85 and of its metabolite, 661U88. Results suggest that 349U85 may be more responsible for inotropic effects, whereas 661U88 may be more responsible for vasodilatory and chronotropic effects. These results are consistent with the preclinical pharmacologic profile for these two compounds. Headache, orthostatic dizziness, and hypotension tended to occur more frequently at higher doses and were temporally related to drug administration. Pharmacokinetic analyses indicate nonlinearity of 349U85 and 661U88, suggestive of saturation of metabolism and large interindividual variability in maximum plasma drug concentration and area under the plasma concentration-time curve. The source of the variability is not known. The time to maximum distribution was approximately 0.7 hours for both 349U85 and 661U88; the terminal elimination half-life was 1 hour for 349U85 and 3 hours for 661U88. Holter monitoring revealed asymptomatic increases in ventricular and supraventricular ectopic activity in some volunteers; ectopy appeared to be related to the dose of 349U85 and generally occurred at higher doses.

Adult↗
PubMed1994

Fetal fibroblast contraction of collagen matrices in vitro: the effects of epidermal growth factor and transforming growth factor-beta.

Wound contraction is an important component of healing but, in the extreme, may lead to excessive scar formation and pathological wound contracture. Fetal rabbit wounds heal without contraction or scarring, whereas excisional fetal sheep wounds have been shown to contract, but no scarring or pathological wound contracture is noted. We used an in vitro model, the fibroblast-populated collagen lattice, to study the ability of fetal fibroblasts to coordinate contraction of a collagen matrix and the modulating effects of epidermal growth factor and transforming growth factor-beta 1 on this contraction. With increasing gestational age, fibroblasts increased the degree of collagen lattice contraction. Epidermal growth factor inhibited contraction by fetal fibroblasts, whereas transforming growth factor-beta 1 stimulated it. These findings suggest that while intrinsic differences between fetal and adult fibroblasts exist, polypeptide growth factors may operate at the site of tissue repair to alter cell phenotype. Further work is underway to delineate the role of soluble protein factors responsible for the absence of scarring and contracture seen in the fetal wound.

Animals↗
PubMed1994

Adult skin wounds in the fetal environment heal with scar formation.

OBJECTIVE: This study investigated the influence of the fetal environment on the healing characteristics of adult skin. SUMMARY BACKGROUND DATA: The remarkable ability of the fetus to heal without scarring is poorly understood. The unique qualities of fetal wound healing may be caused by the fetal environment, the fetal tissues, or a combination of both. There are numerous differences between the prenatal and postnatal environments that may play a role in the unique fetal response to injury. METHODS: Full-thickness adult sheep skin was transplanted onto the backs of 60-day-gestation fetal lambs (term, 145 days of gestation). The adult skin grafts were thus perfused by fetal blood and bathed in amniotic fluid. Previous work has demonstrated that, before midgestation, fetal lambs do not reject allogenic skin grafts. Forty days later (100 days of gestation), incisional wounds were made on both the adult skin graft and the adjacent fetal skin. The wounds were harvested 14 days postwounding and analyzed by both light microscopy and immunohistochemical testing using antibodies to collagen types I, III, and VI. RESULTS: The wounds in the adult skin grafts healed with scar formation. This observation contrasts strongly with the scarless healing of the incisional fetal skin wounds. CONCLUSIONS: This study suggests that scarless fetal skin healing properties are intrinsic to fetal skin and are not primarily the result of the fetal environment.

Amniotic Fluid↗
PubMed1994

Gastroschisis: can sonography of the fetal bowel accurately predict postnatal outcome?

To determine whether prenatal sonographic features of the small bowel can accurately predict postnatal outcome in fetuses with gastroschisis, the sonograms of 24 fetuses with prenatally detected gastroschisis were retrospectively reviewed for fetal bowel features including small bowel dilatation and bowel wall thickening. To identify a relationship between the sonographic features and neonatal outcome, each feature was analyzed against eight adverse clinical outcome measures including bowel obstruction or atresia, necrosis, and need for bowel resection, using chi-square analysis and Kendall's taub correlation. When a relationship was identified, the sensitivity and specificity of the sonographic feature for predicting adverse outcome were determined. Only maximum small bowel diameter was related to postnatal bowel complications. Significantly more fetuses with a maximum small bowel diameter of greater than 11 mm (7/12) had bowel complications than did fetuses with MBD 11 mm or less (2/12) P < 0.05). Using a cutoff point of greater than 11 mm for maximum small bowel diameter, the sensitivity was 78%, specificity 66%, and positive predictive value 71% for predicting postnatal bowel complications. However, in only seven of 24 cases did the two observers make the same maximum small bowel diameter measurement, and in 14 of 24 cases their measurements differed by 2 mm or more. The observers varied sufficiently in their measurements to shift three fetuses (13%) between categories (< or = 11 mm or > 11 mm). Although a maximum small bowel diameter of 11 mm stratified our fetuses, this measurement may not be clinically meaningful.

Abdominal Muscles↗
PubMed1994

Nitric oxide synthase is deficient in the aganglionic colon of patients with Hirschsprung's disease.

OBJECTIVES: The cause of Hirschsprung's disease is unknown but defects in nonadrenergic, non-cholinergic innervation could prevent relaxation of aganglionic colon in patients with this disease. Nonadrenergic, noncholinergic nerves induce relaxation by using nitric oxide synthase to produce the smooth muscle relaxant nitric oxide (NO). In this study we asked whether aganglionic colon in patients with Hirschsprung's disease is deficient in NO synthase-containing nerves. METHODOLOGY: Using the tetrazolium blue dye method of demonstrating nicotinamide adenine dinucleotide phosphate-diaphorase enzymes, we examined eight colon specimens (four aganglionic and four ganglionic) from patients with Hirschsprung's disease for the presence of NO synthase. We further quantified NO synthase enzyme activity in these eight specimens by using the [3H]arginine-to-[3H]citrulline conversion assay. RESULTS: The nicotinamide adenine dinucleotide phosphate-diaphorase staining showed that aganglionic colon contained less NO synthase than ganglionic colon. This NO synthase deficiency was located primarily in the nerves of the circular muscle layer of the colon. In addition, there was a striking difference in the NO synthase enzyme activity between aganglionic and ganglionic colon as measured by the [3H]arginine-to-[3H]citrulline conversion assay. Total NO synthase activity, as measured by this assay, was found to be less in aganglionic than in ganglionic colon. When the total activity was divided into its four known isoforms, aganglionic colon was noted to be striking deficient in the isoform derived primarily from nerves. CONCLUSION: We conclude that aganglionic colon is deficient in NO synthase-containing nerves. This deficiency could prevent smooth muscle relaxation in the aganglionic colon of patients with Hirschsprung's disease.

Amino Acid Oxidoreductases↗
PubMed1994

An effective strategy for decontamination, ex vivo expansion, and storage of human fetal liver hematopoietic stem cells.

The transplantation of human fetal tissue has the potential to cure a variety of life-threatening diseases. The strategy for procurement, quality control, and functional assessment of human fetal liver HSC may prove useful for the transplantation of other fetal tissues. In addition to technical limitations, there are ethical and legal issues which need to be resolved before widespread use of fetal tissue. Further development of regulatory standards for the acquisition and distribution of fetal tissues will foster the application of this novel technology.

Abortion, Induced↗
PubMed1994

Fetal therapy--1994.

Treatment of fetal anomalies has allowed the intact survival of increasing numbers of fetuses with previously fatal or very likely fatal disorders. Percutaneous in-utero surgery for obstructed bladders and thoracic effusions, and open surgery for diaphragmatic hernias and lung malformations has become increasingly successful. Medical and gene therapy approaches are likewise expanding and will continue to become more available.

Congenital Abnormalities↗
PubMed1993

Prenatal diagnosis of congenital diaphragmatic hernia not amenable to prenatal or neonatal repair: Brachmann-de Lange syndrome.

Brachmann-de Lange syndrome (BDLS) is a variable multiple congenital anomaly syndrome that occasionally includes congenital diaphragmatic hernia (CDH). CDH per se is commonly diagnosed antenatally and has been corrected with increasing success in utero and by neonatal repair with extracorporeal membrane oxygenation (ECMO). In utero repair requires normal karyotype as well as the absence of other lethal anomalies. Postnatal repair in combination with ECMO has resulted in improved neonatal outcome and has been recommended in all cases not having in utero repair. We describe a fetus diagnosed with a diaphragmatic hernia at 18 weeks of gestation in a woman whose only other pregnancy has been a 16 week abortus diagnosed with Fryns syndrome (FS). FS is a lethal, variable congenital anomaly syndrome that includes CDH, which is thought to contribute to the lethality of the syndrome. In utero repair was considered, but rejected because of the position of the liver and suspected FS. The patient elected to carry the pregnancy to term. Postnatal repair with ECMO was considered; however, the infant died at several hours of age because of severe pulmonary hypoplasia, being considered ineligible for ECMO. The diagnosis of BDLS was made at autopsy and suggests that the first case may, in fact, have been BDLS. In spite of recent success in the repair of CDH both in et ex utero, CDH in association with BDLS is likely lethal, and women with fetuses diagnosed antenatally with CDH and BDLS should be counseled as such.

Adult↗
PubMed1993

Selective erythroid replacement in murine beta-thalassemia using fetal hematopoietic stem cells.

We have explored the application of fetal hematopoietic stem cell (HSC) transplants for cellular replacement in a murine model of beta-thalassemia. Liver-derived HSCs from nonthalassemic syngeneic murine fetal donors were transplanted into nonirradiated neonatal beta-thalassemic recipients. Significant erythrocyte chimerism (9-27%) was demonstrated in the majority of recipients at 1 month and remained stable or increased (up to 55%) during long-term follow-up in almost all cases. Chimeras had improved phenotypes, as evidenced by decreased reticulocyte counts, increased mean erythrocyte deformability, and decreased iron deposits in comparison to controls. To investigate whether the high degree of peripheral blood chimerism was predominantly a feature of erythroid elements or was a general feature of all hematopoietic elements, chimeras were created using donor HSCs "tagged" with a DNA transgene. Whereas donor hemoglobin comprised > 30% of total hemoglobin, nucleated tagged nonerythroid donor cells comprised < 1% of peripheral blood elements. Explanations for the observed selective increase in erythroid chimerism include longer survival of normal donor red cells compared to that of thalassemic red cells and the effective maturation of the donor erythroid elements in the bone marrow in chimeric animals. The latter explanation bears consideration because it is consistent with the process of ineffective erythropoiesis, well documented to occur in thalassemia, in which the majority of thalassemic erythroid cells are destroyed during erythropoiesis prior to release from the bone marrow. Overall, these data demonstrate the potential for significant erythroid chimerism and suggest that fetal HSC transplantation may play a significant role in future treatment.

Animals↗
PubMed1993

Chronic fetal vascular access.

Intensive management of the fetus is limited by our inability to achieve access to the fetal circulation. Using laparoscopic surgery, we can maintain long-term access to the fetal circulation by extra-amniotic catheterisation of chorionic vessels in third-trimester monkeys and early-gestation sheep. We can sample fetal blood, continuously measure blood pressure, and infuse drugs without complications. Safe vascular access will permit assessment of fetal status during fetal surgical procedures and improve postoperative monitoring.

Animals↗
PubMed1993

Effect of xenogeneic chimerism in a human/sheep model on natural antibody.

Xenogeneic transplantation is a potential solution to the severe shortage of donor organs for clinical transplantation. The primary limitation to xenogeneic transplantation between widely disparate species is hyperacute rejection, which is triggered by the recipient's natural antibodies reacting against the donor's endothelial cells. Natural antibodies react between widely disparate species but do not react between closely related species. Specific tolerance for xenogeneic transplantation between closely related species can be induced by creating hematopoietic chimerism between donor and recipient. However, whether specific xenograft tolerance can be induced by the creation of chimerism between widely disparate species, where natural antibody reacts, is unknown. We previously have established a model of hematopoietic chimerism between widely disparate species by the in utero transplantation of human fetal hematopoietic stem cells into early gestation fetal lambs. In the present study, we determined whether long-standing hematopoietic chimerism in this human/sheep model reduces the level of natural antibody directed against human endothelial cells. To answer this question, we measured the reactivity of serum from five chimeric sheep, five sheep controls, and five human controls in an in vitro enzyme-linked immunoabsorbance assay directed against human umbilical vein endothelial cells. Unexpectedly, we found that long-standing hematopoietic chimerism in the human/sheep model did not reduce the reactivity of serum against human endothelial cells compared to age-matched sheep controls. These results suggest that the induction of hematopoietic chimerism between widely disparate species will not control the problem of natural antibody and hyperacute rejection.

Animals↗
PubMed1993

Fetal surgery for cystic adenomatoid malformation of the lung.

We reviewed our experience with fetal therapy for congenital cystic adenomatoid malformation of the lung (CCAM) at the University of California, San Francisco Fetal Treatment Center. Fetuses with life-threatening CCAM were selected for prenatal treatment according to predetermined guidelines, including the gestational age of the fetus, the size of the intrathoracic lesion, maternal health, and the development of fetal hydrops. The knowledge that fetuses with hydrops are at high risk for fetal or neonatal death led to fetal surgical resection of the massively enlarged pulmonary lobe (fetal lobectomy) in six cases. In the first case, resection was too late, since preoperative labor and maternal preeclampsia could not be reversed, leading to premature delivery of a nonviable infant. In the next four cases, CCAM resection led to resolution of the hydrops, impressive in utero lung growth, and neonatal survival. Right middle and lower lobe resection in the sixth fetus at 21 weeks was successful, but subsequent inexplicable fetal death highlights the need for better postoperative fetal monitoring and treatment. Three other fetuses with a single predominant cyst underwent thoracoamniotic shunt placement alone; two survived after delivery and prompt neonatal surgery with the assistance of high-frequency ventilation or extracorporeal membrane oxygenation. Fetal therapy can now be considered for otherwise fatal space-occupying intrathoracic lesions in the fetus.

Adult↗
PubMed1993

The CDH two-step: a dance of necessity.

Repair of fetal diaphragmatic hernia has proven technically difficult especially when the left lobe of the fetal liver is incarcerated in the chest. A step-wise approach from both above and below the diaphragm solves several frustrating technical problems.

Fetal Diseases↗
PubMed1993

Hyaluronate metabolism undergoes an ontogenic transition during fetal development: implications for scar-free wound healing.

Wound healing in the fetus occurs by a different process from that in the adult. Instead of healing with scar formation, fetal cutaneous wounds heal by regeneration that results in complete restoration of normal skin architecture. The mechanisms responsible for this remarkable phenomenon involve factors in the fetal environment and properties intrinsic to fetal cells. Hyaluronic acid (HA) is a major component of the fetal extracellular matrix (ECM) and is believed to play an important role in this process. In this study, HA and HA-stimulating activity (HASA) in fetal and adult wound fluid were examined using sensitive, newly developed assays. In an ovine model, higher levels of HA and HASA were observed in fetal as compared with adult wound fluid. This difference was most prominent in wound fluid from fetal lambs at 75 and 100 days gestation (term = 145 days); these samples contained persistently elevated HA and HASA levels for up to 2 weeks after wounding (HA peak levels 145 micrograms/mL and 110 micrograms/mL, respectively). In contrast, wound fluid from 120-day-gestation fetuses had significantly lower levels (P < .001) that were transient and similar to that in the adult (HA peak levels 70 micrograms/mL and 10 micrograms/mL, respectively). These observations confirm an ontogenic transition in wound HA metabolism from a fetal to an adult-like phenotype. Levels of HASA as a function of time after wounding correlated with levels of HA, suggesting a role for HASA in controlling HA deposition during tissue repair. Two patterns of HASA and HA synthesis were noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Fetal hematopoietic stem cell transplantation into beta-thalassemic mice.

The transplantation of fetal-derived hematopoietic stem cells (HSCs) may potentially be used to treat hemoglobinopathies, immunodeficiencies, and storage diseases. The levels of donor cell engraftment needed to reconstitute the recipient's hematopoietic system are disease-dependent and remain unknown for most deficiencies. We have explored the application of fetal hematopoietic stem cell transplants for the amelioration of hemolytic disease in a murine model of beta-thalassemia. Nonirradiated neonatal homozygous beta-thalassemic mice were transplanted intraperitoneally (IP) with 10(6) fetal liver cells from syngeneic nonthalassemic murine fetal donors (14 to 16 days gestation). Donor hemoglobin was demonstrated in the peripheral blood of 9 of 14 transplant recipients at levels ranging from 8.8% to 27.1% at 30 days. The levels of engraftment in 6 of these 9 transplant chimeras remained stable or increased up to 150 days after transplantation, with levels ranging from 13.6% to 54.6% at 280 days. Three chimeras have demonstrated gradually decreasing engraftment after 200 days. The degree of engraftment correlated with clinically relevant improvement: decreased reticulocyte counts (8.4% to 15.7% in chimeras [n = 9] v 17.1% to 19.1% in controls [n = 8], P = .01), increased mean RBC deformability, and the significant reduction in extramedullary hematopoiesis and iron deposits seen on histological examination of chimeric liver and spleen. These data demonstrate that fetal HSC transplants results in significant long-term chimerism with favorable alterations in red cell characteristics, and decreased hemolytic anemia in beta-thalassemia.

Animals↗