Biomedical subjects

T M Crombleholme

Publications and source records attributed to T M Crombleholme.

At least 91 records · Page 5Linked to original sources

PubMed1990

Pulmonary vascular resistance in neonatal swine: response to right pulmonary artery occlusion, isoproterenol, and prostaglandin E1.

The pulmonary physiological response of adults to unilateral pulmonary artery (PA) occlusion has been well-characterized as resulting in a decrease in the pulmonary vascular resistance (PVR), in order to maintain the same PA pressure and accommodate the entire cardiac output (CO). We evaluated the response of the neonate to unilateral PA occlusion and how this response is altered by infusions of Isoproterenol (Isuprel) and prostaglandin E1 (PGE1) in the neonatal swine model. Twenty farm piglets (five at 1 day, three at 5 days, seven at 14 days, and five at 60 days as controls) underwent left lateral thoracotomy and measurement of PA and left atrial (LA) pressures, CO, and PVR with the right PA open and occluded. To determine if neonatal PVR could be influenced by a vasodilator (indicating the vascular capacity is not fixed) or by an inotrope (indicating the lung is not maximally recruited) this experiment was then repeated with infusions of PGE1 (a vasodilator) at doses of 0.1, 0.5, and 1.0 micrograms/kg/min and subsequently with Isuprel (an inotrope and vasodilator) at doses of 0.1, 0.5, 1.0 micrograms/kg/min. Control measurements taken without unilateral PA occlusion showed that PVR is high at 1 day of age but progressively decreases to a level 89% lower by 60 days of age. The vascular capacity of the neonatal lung is fixed and responds to unilateral PA occlusion with a dramatic increase in PVR. This response cannot be altered by either a vasodilator (PGE1) or an inotrope (Isuprel) thereby limiting the utility of these drugs in treating neonatal pulmonary hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗

PubMed1990

In utero transplantation of hematopoietic stem cells in sheep: the role of T cells in engraftment and graft-versus-host disease.

Transplantation of hematopoietic stem cells (HSC) from adult sheep into fetal lambs results in hematopoietic chimerism and graft-versus-host disease (GVHD). To evaluate the role of T cells in HSC engraftment and GVHD we depleted adult marrow HSC of T cells and observed the incidence of chimerism and GVHD in the fetal recipients. Using a naturally occurring polymorphism of the beta-globin locus to detect engraftment, bone marrow obtained from homozygous type A hemoglobin adult sheep were transplanted (2 x 10(9) cells/kg fetal weight) into 90 days' gestation fetal lambs homozygous for type B hemoglobin. Donor HSC were T-cell depleted by treatment with antisera (raised in rabbits against sheep thymocytes) in the presence of complement. T-cell depletion resulted in significant decrease in hematopoietic colony formation by donor HSC in vitro (305 +/- 49 v 134 +/- 21 colonies/10(5) cells) that normalized by the addition of autologous T cells (433 +/- 32 colonies/10(5) cells). Marrow depleted of T cells exhibited reduced engraftment in the recipient fetuses. When T cells were added back to donor HSC (depleted of T cells) at near-normal concentrations, engraftment improved but the lambs also developed GVHD. The addition of T cells to donor HSC (depleted of T cells) at concentrations below that present in unprocessed bone marrow resulted in significant engraftment but not GVHD. T cells play an important role in both the engraftment of adult HSC in fetal recipients and the development of GVHD in chimeric newborns. The elimination of T cells prevents GVHD but markedly reduces engraftment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Complete heart block in fetal lambs. I. Technique and acute physiological response.

Prenatally diagnosed complete heart block (CHB), without associated cardiac anomalies, is often refractory to attempts to increase heart rate and cardiac output by medical therapy, and results in fetal death. We developed a model of CHB in fetal lambs in order to evaluate the acute physiological consequences of CHB and to assess the feasibility of fetal cardiac ventricular (V) and atrioventricular (AV) pacing. After hysterotomy and fetal sternotomy AV-sequential pacing leads were placed on the right atrium and ventricle (RV). Electromagnetic flow transducers were placed around the pulmonary artery and the ascending aorta to measure combined ventricular output (CVO) in normal sinus rhythm (NSR), CHB, AV, and V pacing. CHB block was successfully induced in 19 of 21 (90%) fetal lambs at 100 to 110 days' gestation by injection of formalin into the interventricular septum. Two fetuses were refractory to CHB despite multiple injections. The mean ventricular escape rate was 52 +/- 3 (+/- SEM) beats/min (range, 45 to 60 beats/min). CHB lasted for the period of study (1 to 8 hours), and spontaneously reverted to NSR in one fetus after 3 hours. Combined ventricular output in NSR was 470 +/- 31 mL/min (+/- SEM), which fell to 213 +/- 13 mL/min in CHB, 45% of normal CVO (P less than .0001). CVO during AV-sequential and V pacing was 77% (P = .02) and 62% (P less than .001), respectively, of combined ventricular output in NSR. Both RV (27%) and left ventricles (LV) (37%) showed compensatory increase in stroke volume during CHB.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Nephron-sparing approach to bilateral Wilms' tumor: in situ or ex vivo surgery and radiation therapy.

Bilateral Wilms' tumor patients, who experience local recurrence after maximal multimodality therapy, present a difficult surgical problem. The role of surgery in the management of these patients has changed from ablation to preservation of renal tissue, with bilateral nephrectomy as a last resort. Two children who had recurrent tumors in the remaining kidney underwent nephron-sparing surgery and focal intraoperative radiation therapy. In one case, this nephron-sparing surgery and intraoperative radiation therapy were performed in situ, in the other kidney was removed and reimplanted (ex vivo bench surgery and irradiation). These techniques may allow complete obliteration of gross and microscopic disease, while maximizing residual renal function.

Child↗

PubMed1990

Studies in fetal wound healing, VII. Fetal wound healing may be modulated by hyaluronic acid stimulating activity in amniotic fluid.

Fetal wound healing occurs rapidly and without inflammation, fibrosis, or scar formation. It is a process fundamentally different from adult wound healing. The mechanisms that underlie such unique healing properties are unknown. However, hyaluronic acid, a glycosaminoglycan component of the extracellular matrix, is prominent throughout the course of fetal wound healing, and is thought to play a major role in the healing process. Amniotic fluid contains high levels of hyaluronic acid. Amniotic fluid also contains a number of potent growth factors that are critical for fetal development. In this report, a new factor in amniotic fluid that stimulates deposition of hyaluronic acid is described. This activity is measured in an in vitro assay system in which cultured fibrosarcoma cells are used as indicator cells. Amniotic fluid thus provides two separate mechanisms for the deposition of hyaluronic acid. One is by exogenous application directly onto fetal skin wounds; the second is by providing a factor to increase the production of hyaluronic acid endogenously, by stimulating cells around the wound site. The resulting hyaluronic acid-rich area may support the ability of the fetal wound to heal with its unique properties.

Amniotic Fluid↗

PubMed1990

Etiology of intestinal damage in gastroschisis, II. Timing and reversibility of histological changes, mucosal function, and contractility.

Previous work in the fetal lamb examined the relative effects of amniotic fluid and bowel constriction in the etiology of bowel damage in gastroschisis. The present study used the same model to assess the timing and reversibility of these changes during gestation. Gastroschisis was created at 80 days' gestation, and a tape was placed around the bowel to cause gradual constriction with growth. Lambs were killed at 100 days, 120 days, and term. Bowel damage was assessed using histology, mucosal enzyme activity, and in vitro motility. In an additional "repaired" group, the constrictor was removed at 120 days, a silastic pouch placed over the bowel, and bowel damage assessed at term. Normal fetuses at each gestational age were used as controls. A fibrous peel was observed at all gestational ages. Mucosal villous atrophy and mesenteric venous and lymphatic dilation were mild at 100 and 120 days, but severe at term. These changes were present but mild in repaired animals at term. Mucosal enzyme activity decreased gradually with gestational age; inhibition of maltase activity was maximal at term, and was significantly reversed by repair, whereas inhibition of aminooligopeptidase activity was maximal at 120 days, and was not affected by repair. Protein/DNA, DNA/weight, and protein/weight ratios showed that repaired mucosal cells were significantly more proliferative, smaller, and less mature than control or gastroschisis cells. In vitro motility studies demonstrated a mild decrease in contractility at 100 and 120 days, and a large decrease at term. This deleterious effect at the end of gestation was only partially reversed by repair in utero.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdominal Muscles↗

PubMed1990

Fetal trauma: relation to maternal injury.

Conventional surgical wisdom is that fetal death is a predictable consequence of severe maternal injury. In order to define the natural history of maternal-fetal trauma and better formulate management strategies, we reviewed our recent experience with 32 cases of maternal trauma at a major trauma center. There were three cases of fetal death; two were associated with severe maternal injury, but one had no significant injury to the mother. All cases had placental injury. Conversely, there were five cases of severe maternal trauma but only two unsuccessful pregnancy outcomes. We conclude that the extent of maternal injury does not necessarily correlate with the degree of fetal injury. Lethal placental or direct fetal injury can occur even in the absence of significant maternal injury. In selected cases, fetal salvage after maternal-fetal trauma may be achieved by early delivery and prompt pediatric surgical intervention.

Adult↗

PubMed1990

The modified Puestow procedure for chronic relapsing pancreatitis in children.

Chronic relapsing pancreatitis in children is an unusual condition that often goes undiagnosed and untreated for years. In light of recent reports in adults that endocrine and exocrine function may be preserved by early pancreaticojejunostomy, we reviewed our experience with this procedure (one Duval, 10 Puestows) in 10 children between 1969 and 1989. The underlying etiology was familial pancreatitis in four patients, one case of unknown etiology, congenital ductal anomalies in four (one pancreas divisum, one annular pancreas, one choledochal cyst, and one ductal stenosis), and posttraumatic in one. All 10 had intractable recurrent abdominal pain. Preoperatively, only three patients evidenced exocrine insufficiency and none had endocrine insufficiency. There was complete resolution of pain in eight patients and improvement in two during a mean observation period of 4 years (range, 7 months to 19.75 years). Exocrine insufficiency resolved in two patients but has persisted in the third patient now on Viokase. Endocrine insufficiency has developed during follow-up in one patient. Pancreaticojejunostomy provides excellent relief of recurrent pain in chronic relapsing pancreatitis in children. Endoscopic retrograde cholangiopancreatography (ERCP) is indicated when the diagnosis of chronic relapsing pancreatitis is suspected to define the ductal anatomy. Pancreaticojejunostomy may prevent the progression of exocrine and endocrine insufficiency if performed early in the course of the disease.

Abdominal Pain↗

PubMed1990

Pulmonary lobar transplantation in neonatal swine: a model for treatment of congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) babies born with severe pulmonary hypoplasia are unsalvageable despite maximal therapy including extracorporeal membrane oxygenation (ECMO). Lung transplantation is a potential treatment for these otherwise doomed infants using ECMO as a bridge to transplantation. Cadaveric, or living related donation of a more mature reduced size lung (pulmonary lobe or segment) may help solve the critical donor shortage problem. We evaluated the physiological response of mature left lower lobe (LLL) transplants in neonatal swine with the hemodynamic conditions of CDH simulated by occlusion of the right pulmonary artery (PA), and also studied the pulmonary function of the mature lobar graft compared with the neonatal lung. LLL transplantation was well tolerated and resulted in minimal alteration in hemodynamic parameters. The response to right PA occlusion was similar pre- and posttransplantation with a fall in cardiac output and a significant rise in pulmonary vascular resistance. Compared with the contralateral native lung, the lobar graft was preferentially ventilated with resultant higher pH (7.65 +/- 0.17 v 7.41 +/- 0.08, P less than .01) and lower pCO2 (17 +/- 6 v 36 +/- 5, P less than .001). The more mature lobar graft was preferentially ventilated due to the increased compliance compared with the neonatal right lung (8.16 +/- 1.28 v 5.48 +/- 0.82 mL/cm, P less than .0001). Reduced size lung transplantation is technically feasible and may help solve the donor problem for severe CDH neonates for whom no effective therapy is currently available.

Animals↗

PubMed1990

Studies in fetal wound healing, VI. Second and early third trimester fetal wounds demonstrate rapid collagen deposition without scar formation.

The mechanisms that underlie the lack of scarring in fetal wounds are unknown, but probably relate to the control of collagen fibrillogenesis. The role of collagen in the fetal wound matrix is controversial, and several wound implant models have been used to evaluate collagen deposition in fetal wounds. Unfortunately, these models create an artificial wound environment and may thereby affect the results. In order to study fetal wound collagen deposition in linear wounds without artificially altering the wound environment, we applied a highly sensitive immunohistochemical technique that uses antibodies to collagen types I, III, IV, and VI. We found that collagen was deposited in fetal wounds much more rapidly than in adult wounds. Wound collagen deposition occurred in a normal dermal and mesenchymal pattern in second and early third trimester fetal lambs. These findings are consistent with the observation that the fetus heals rapidly and without scar formation. In contrast, wounds in late gestation fetal lambs showed some evidence of scar formation. Further studies may suggest ways to alter the adult wound so that it heals in a fetal manner.

Animals↗

PubMed1989

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.

Age Factors↗

PubMed1989

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.

Adult↗

PubMed1989

Systemic-to-pulmonary artery shunt using the internal mammary artery.

Systemic-to-pulmonary artery shunts may be useful for palliation of cyanotic congenital heart disease. We report the case of a 5-year-old boy in whom the internal mammary artery was used to create a systemic-to-pulmonary artery shunt after failure of a previous Blalock-Taussig shunt. This technique may have distinct advantages in selected cases and should be considered as an alternative during investigation of the older child who requires a systemic-to-pulmonary artery shunt.

Anastomosis, Surgical↗

PubMed1989

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)

Abdominal Muscles↗

PubMed1989

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.

Female↗

PubMed1989

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.

Animals↗

PubMed1989

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.

Animals↗

PubMed1989

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.

Animals↗