Biomedical subjects
M R Harrison
Publications and source records attributed to M R Harrison.
In-utero transplantation of fetal liver haemopoietic stem cells in monkeys.
To evaluate the potential of in-utero transplantation of fetal haemopoietic stem cells (HSCs) for permanent engraftment as a treatment of congenital haemoglobinopathies, fetal rhesus monkeys were transplanted with HSCs derived from fetal livers. Five pregnant monkeys (60-62 days' gestation) were given an in-utero intraperitoneal injection of fetal liver cells (10(8)-10(9) cells/kg estimated fetal recipient body weight) derived from opposite sex donors at 59-68 days' gestation. Engraftment was confirmed by karyotype analysis of peripheral blood leucocytes and bone marrow; cells of donor sex were found among the recipient cells. Donor cell engraftment was apparent in four of five in-utero HSC transplant recipients at birth. Engraftment involved lymphoid (2.9-8.0% donor cells), erythroid (5.3-12.5%), and myeloid (8.5-15.4%) lineages and has persisted for up to 2 years without evidence of graft-versus-host disease.
Effect of blood pressure and afterload on Doppler echocardiographic measurements of left ventricular systolic function in normal subjects.
Doppler echocardiographic measurements of blood flow velocity and acceleration in the ascending aorta have been shown to be useful descriptors of left ventricular (LV) systolic function. Few data exist, however, regarding the influence of loading conditions, particularly afterload, on these Doppler measurements in human subjects. Therefore, 14 normal volunteers (mean age 28 years) were studied using continuous wave Doppler echocardiography performed from the suprasternal notch both at baseline and during a controlled infusion of methoxamine. LV peak systolic (delta pk) and end-systolic (delta ES) wall stresses were calculated noninvasively using blood pressure and echocardiographic dimensions. Heart rate was kept constant by transesophageal atrial pacing. Methoxamine resulted in significant increases in mean systolic (163 +/- 8 vs 129 +/- 10 mm Hg) and diastolic (93 +/- 7 vs 71 +/- 12 mm Hg) blood pressure, as well as delta pk (277 +/- 25 vs 222 +/- 40 g/cm2 x 10(3] and delta ES (97 +/- 26 vs 77 +/- 19 g/cm2 x 10(3] (p less than or equal to 0.0004 for all). Conversely, peak velocity decreased from 0.91 +/- 0.18 m/s at baseline to 0.8 +/- 0.18 m/s (p less than or equal to 0.002) and peak acceleration decreased from 22 +/- 5 m/s2 at baseline to 19 +/- 5 m/s2 (p less than or equal to 0.006) during methoxamine infusion. Flow velocity integral and LV end-diastolic dimension remained unchanged. Thus, aortic flow velocity and peak acceleration are inversely related to afterload. This relation should be considered when using serial determinations of these Doppler parameters for patients in whom changing levels of afterload might occur.
Usefulness of color Doppler flow imaging to distinguish ventricular septal defect from acute mitral regurgitation complicating acute myocardial infarction.
Several studies have found 2-dimensional echocardiography and conventional spectral Doppler ultrasound useful in the assessment of ventricular septal defect (VSD), but few data exist regarding the usefulness of color Doppler flow imaging in evaluating this problem. Thus, the results of color flow imaging performed in 14 patients who presented with a recent acute myocardial infarction (AMI), hemodynamic instability and a new systolic murmur were evaluated. All patients underwent cardiac catheterization for definitive diagnosis, which proved to be VSD in 7 and acute mitral regurgitation in 7. VSD, identified by turbulent flow traversing the ventricular septum during ventricular systole, was correctly identified in all 7 patients with septal rupture. In the remaining 7 patients with a new murmur after AMI, mitral regurgitation was demonstrated as turbulent systolic flow in the left atrium by both color flow imaging and cine ventriculography. In all 14 patients with new murmurs, color flow imaging was 100% accurate for the presence or absence of VSD. Color flow imaging localized the septal defect to the apical septum (3), inferior septum (3) or both inferior and apical septal regions (1), and was 100% concordant for location compared with cineangiography, surgery and conventional Doppler echocardiographic techniques. Color flow imaging was accurate in identifying the presence and location of VSD complicating AMI, and accurately differentiated VSD from mitral regurgitation. Color flow imaging provides safe, rapid diagnosis of VSD complicating AMI, and may alleviate the need for diagnostic right-sided heart catheterization and preoperative cine ventriculography in these seriously ill patients.
Resolution of spontaneous contrast with platelet disaggregatory therapy (trifluoperazine).
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Gastrointestinal tract obstruction in the fetus.
Surgical advice is often sought when a prenatal diagnosis of gastrointestinal tract obstruction is made. We reviewed our experience with 17 such cases during a 4-year period. Eight fetuses had complete proximal obstruction. Seven of the 8 did well after maternal transport to a perinatal center and prompt neonatal surgery. Six fetuses had distal obstruction with dilated bowel and increased peristalsis. Two died after birth (1 with severe associated anomalies and 1 with short-bowel syndrome), and the other 4 did well. Three fetuses had a false-positive diagnosis of in utero meconium peritonitis. Two died and the other had no postnatal evidence of obstruction. Our data suggest (1) polyhydramnios may not be present early in gestation or with distal obstruction; (2) other anomalies, including a family history of cystic fibrosis, should be sought; (3) dilated bowel with increased peristalsis is diagnostic of fetal gastrointestinal tract obstruction, whereas intra-abdominal calcification and ascites are nonspecific findings; (4) late development of ascites in a fetus with documented obstruction may be an indication for early delivery; and (5) prenatal diagnosis permits appropriate counseling, planned delivery, and prompt postnatal resuscitation and surgery with a good prognosis in most cases.
Fetal hydrops and death from sacrococcygeal teratoma: rationale for fetal surgery.
Most sacrococcygeal teratomas diagnosed before birth can be managed by planned delivery and postnatal surgery. However, large tumors early in gestation may result in placentomegaly, hydrops, and fetal death and a preeclampsia-like syndrome in the mother. This chain of events may result from high output cardiac failure in the fetus caused by arteriovenous shunting through the tumor. We recently encountered this situation in a fetus at 21 weeks' gestation and performed fetal surgery in an attempt to reverse the process. Excision of the teratoma resulted in reversal of hydrops, diminution of descending aortic flow on Doppler echocardiography, and decrease in placental thickness. Despite these changes, uterine irritability after hysterotomy resulted in labor and delivery of a nonviable premature infant. This case demonstrates that when fetal sacrococcygeal teratoma becomes very large early in gestation, high output cardiac failure can endanger both fetus and mother. In the future, use of Doppler echocardiography may allow appropriate selection of high-risk fetuses. Intervention to prevent arteriovenous shunting through the tumor may offer these fetuses an improved chance for survival.
Clinical significance of in vitro and in vivo experimental findings regarding Doppler flow velocity recordings.
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Effect of heart rate on Doppler indexes of systolic function in humans.
Recent investigations have shown Doppler echocardiography to be useful in the noninvasive assessment of left ventricular systolic function. No data exist, however, regarding the influence of heart rate on Doppler measurements of aortic blood flow velocity and acceleration in humans. Thus, 12 normal volunteers underwent continuous wave Doppler ultrasound recording from the suprasternal notch at baseline and during progressive transesophageal atrial pacing at intervals of 10 beats/min between 90 and 140 beats/min while 100% atrial capture and 1:1 atrioventricular conduction were maintained. Subjects were studied both upright (n = 12) and supine (n = 10). With the subject upright at baseline (mean heart rate 77.8 +/- 10.6 beats/min), peak acceleration averaged to 16.8 +/- 3.4 m/s2, and peak modal velocity and flow velocity integral averaged 0.72 +/- 0.14 m/s and 8.4 +/- 2.1 cm, respectively. With pacing at 90 beats/min, peak acceleration decreased to 15.6 +/- 3.6 m/s2, a significant decline from baseline values (p less than 0.005). Similar declines were seen during pacing at 90 beats/min for peak modal velocity and flow velocity integral (0.64 +/- 0.16 m/s and 7.1 +/- 1.9 cm, respectively; both p less than 0.005 versus baseline values). At the peak pacing rate of 140 beats/min, average peak acceleration decreased to 12.8 +/- 3.1 m/s2, and peak modal velocity and flow velocity integral decreased to 0.52 +/- 0.11 m/s and 5.02 +/- 1.25 cm, respectively. A significant linear correlation (r greater than or equal to 0.97, p less than 0.0001) was obtained for the relation between heart rate and peak acceleration, peak modal velocity and flow velocity integral.(ABSTRACT TRUNCATED AT 250 WORDS)
Etiology of intestinal damage in gastroschisis. I: Effects of amniotic fluid exposure and bowel constriction in a fetal lamb model.
Gastroschisis is often complicated by damage to the herniated small bowel, resulting in motility and absorption disturbances and occasional intestinal necrosis and atresia. To study the pathophysiology of this process, a model of gastroschisis was developed in fetal lambs. At 80 days' gestation, the anterior abdominal wall was partially excised to create a small peritoneal cavity, and the small bowel was extruded through a Silastic ring to create a defect of uniform size. In one experimental group, a tie was placed around the herniated bowel at the level of the abdominal wall to provide gradual constriction as the fetus grew. In a second group, no tie was placed. Control animals had a simple laparotomy and no abdominal wall defect; some also had a constrictor placed around the base of the bowel. The animals were delivered near term, and the bowel was evaluated histologically and by an in-vitro bowel motility assay. Histologic examination showed normal ganglion cells in all groups and no evidence of ischemic injury. A fibrous peel was seen only in bowel exposed to amniotic fluid, with or without a constrictor. Lymphatic and venous dilation, smooth-muscle thickening, and focal mucosal blunting were seen in bowel subjected to chronic obstruction by a constrictor, regardless of whether it was exposed to amniotic fluid. Both constriction of the bowel and amniotic fluid exposure were associated with a decrease in motility; these two effects were independent and additive.(ABSTRACT TRUNCATED AT 250 WORDS)
Primary fetal hydrothorax: natural history and management.
Primary fetal hydrothorax presents a wide spectrum of severity ranging from small, harmless effusions, to life-threatening thoracic compression. To define natural history and management, we reviewed 32 cases seen at two large perinatal centers from 1980 to 1987. Spontaneous resolution of the effusions was seen in three fetuses, all of whom survived. Three fetuses were electively terminated. The overall mortality was 53%. In the 24 untreated fetuses, sex and the presence of polyhydramnios did not influence mortality, but hydrops, gestational age less than 35 weeks at delivery, and bilateral effusions were associated with a poor prognosis. Five fetuses underwent in utero decompression. In four, thoracentesis was performed, with rapid reaccumulation of the effusion. All four died from pulmonary insufficiency. In the fifth fetus, a thoracoamniotic shunt permanently decompressed the effusion, with resolution of the hydrops, and delivery of a normal viable infant. We conclude that (1) primary fetal hydrothorax may resolve or progress to hydrops, necessitating close follow-up with ultrasound; (2) pulmonary hypoplasia as a result of undrained large pleural effusions may result in neonatal mortality; (3) the gestational age at both diagnosis and delivery, the development of hydrops, and bilaterality of effusions are important prognostic predictors; and (4) the fetus with large effusions and hydrops has a poor prognosis, and thoracic decompression with a thoracoamniotic shunt may prove life saving.
Studies in fetal wound healing: I. A factor in fetal serum that stimulates deposition of hyaluronic acid.
Fetal wound healing without scar formations, fibrosis, or contracture might be accompanied by major differences in the wound extracellular matrix. The matrix of fetal wounds is rich in hyaluronic acid, a glycosaminoglycan found in high concentrations whenever there is tissue proliferation, regeneration, and repair. Although hyaluronic acid is a critical molecule for both embryonic development and wound healing, no factor has yet been identified that modulates hyaluronic acid in a consistent manner. We describe here a substance present in fetal sheep serum that stimulates hyaluronic acid synthesis by cultured fibroblasts. This glycoprotein factor appears to be ubiquitous, present in fetal sheep and bovine serum, reaching a peak in each at 40% of the way through gestation. This factor is also present in amniotic fluid. It might control hyaluronic acid deposition. In turn, hyaluronic acid, by creating an extracellular environment permissive for cell motility and proliferation, might be critical for fetal development. We suggest that the same sequence of events underlie the unique properties observed in fetal wound healing.
Studies in fetal wound healing: II. A fetal environment accelerates fibroblast migration in vitro.
We have used an in vitro model of wound healing using scratches made in a confluent monolayer of fibroblasts. The effects of fetal calf and postnatal calf serum on the migration of fibroblasts were compared. Differences between fetal and calf serum-incubated fibroblasts grown on coverslips were observed within 15 minutes of exposure. Cells in fetal serum began to change both shape and orientation and to move into the trough created by the scratch. The fibroblasts incubated in fetal calf serum completely filled in the trough within 16 hours while those incubated in calf serum did not do so even after 24 hours. We estimate that, at any point, there was a 50% lag time in the migration of the fibroblasts in the presence of postnatal calf serum. This difference in migration and filling was not a function of mitogenesis; the mitogenicity of the two sera were comparable. The results suggest that fibroblast migration in vitro is accelerated by the fetal serum. A similar mechanism may occur in vivo and may underlie the ability of the fetal wound to heal more rapidly.
Studies in fetal wound healing: III. Early deposition of fibronectin distinguishes fetal from adult wound healing.
Wound healing in the fetus proceeds through a series of steps that differ in the fetus and the adult. At each phase of this complex process, there is signaling between the tissue cells and the wound microenvironment, signals that are mediated by and through the extracellular matrix. We postulate that these signals occur earlier in fetal wounds, resulting in more rapid repair. To investigate this, we compared the first 24 hours of wound healing in the rabbit fetus and adult, using antibodies against key extracellular matrix macromolecular components: laminin, fibronectin, and type-specific collagens I, III, IV, and V. Fibronectin was the first matrix component to be deposited, and was visualized as early as four hours after fetal wounding and 12 hours after adult wounding. There was no evidence of new laminin or collagen deposition in either the fetal or adult wounds at any time point examined. The early deposition of fibronectin, a matrix adhesion molecule that provides a scaffolding for epithelial migration, may underlie the rapid reepithelialization observed in fetal wounds.
Appendicovesicostomy: a new technique for bladder diversion during reconstruction of cloacal exstrophy.
Urinary tract diversion in the reconstruction of cloacal exstrophy presents a difficult problem. Many methods have been used, but none has been found to be ideal. We describe a simple technique that incorporates the ileocecal plate in the bladder augmentation, and uses the appendix as a conduit for urinary diversion. This technique offers the advantages of primary closure, effective urinary drainage without tubes, and simplicity of bowel reconstruction with preservation of maximal absorptive surface.
Biliary appendico-duodenostomy: a nonrefluxing conduit for biliary reconstruction.
Biliary conduits constructed during operations for choledochal cysts or biliary atresia are frequently complicated by reflux of gastrointestinal contents, stasis, and obstruction with resulting cholangitis. We have used the appendix as a biliary conduit for cases of biliary atresia and choledochal cyst, adapting the urologic technique of a tunneled, nonrefluxing anastomosis for reconstruction of the biliary tree--biliary appendico-duodenostomy (BAD). From our preliminary experience with this technique, it appears promising.