Biomedical subjects

M Longaker

Publications and source records attributed to M Longaker.

11 recordsLinked to original sources

PubMed2003

Reversed latissimus dorsi muscle flap for repair of recurrent congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Neonates with large congenital diaphragmatic hernias (CDH) require prosthetic patch closure of the defect because of the paucity of native diaphragmatic tissue. As the child grows, patch separation can occur necessitating reoperation. Use of vascularized autologous tissue may decrease the incidence of reherniation as tissue incorporation and growth may be improved. The authors report our early experience using a local muscle advancement flap with microneural anastomosis for those children in whom reherniation develops after prosthetic patch placement. METHODS: Seven patients with CDH (6 left and 1 right) whose synthetic diaphragmatic patch separated from the chest wall resulting in a clinically significant recurrent hernia were followed up with prospectively. After dissecting the ipsilateral latissimus dorsi off the chest wall and dividing the thoracodorsal neurovascular bundle (based on its lumbar blood supply), the synthetic patch was removed via an eighth intercostal incision. The muscle flap was placed into the hemithorax through the bed of the tenth rib and sutured in place over a Vicryl mesh scaffold. The thoracodorsal nerve was anastomosed to the phrenic nerve. Functional analysis of the flap was performed in 4 patients. RESULTS: Age at placement of the muscle graft ranged from 2 months to 48 months (median, 24 months). There has been no evidence of reherniation after placement of the muscle graft. Long-term outcome and functional analysis of the flap was available in 4 patients (mean, 19 months). Two infants had fluoroscopic and sonographic evidence of nonparadoxical neodiaphragmatic motion. In one of these, electromyographic evidence of function was documented with a phrenic nerve conduction velocity of 22 meters per second. The third infant showed no evidence of neodiaphragmatic motion, and the fourth infant had paradoxical motion. CONCLUSIONS: This is the first direct documentation of phrenic nerve function in an infant with CDH. An innervated reversed latissimus dorsi (RLD) flap reconstruction for recurrent CDH provides an alternative to prosthetic patch repair. This technique offers the advantages of autologous vascularized tissue with potential phrenic nerve innervation and physiologic neodiaphragmatic motion.

Female↗

PubMed2001

Retinoid signaling directs secondary lineage selection in pancreatic organogenesis.

BACKGROUND/PURPOSE: Retinoid signaling plays an important role in many differentiation pathways. Retinoid signaling has been implicated in the induction of differentiation by pancreatic ductal cancer cell lines and in patients with pancreatic cancer. The authors wished to better understand the role of retinoid signaling in pancreatic development. METHODS: Embryonic pancreas was harvested from mice at serial gestational ages and immunohistochemical analysis was performed for retinoic acid receptors (RAR-alpha, RAR-beta, RAR-gamma), and retinoid X receptors (RXR-alpha, RXR-beta, and RXR-gamma). Also, early embryonic pancreases were cultured for 7 days with exogenous 9-cis retinoic acid (9cRA) or all-trans retinoic acid (atRA) and analyzed histologically and immunohistochemically. RESULTS: Retinoid receptors were expressed in a lineage-specific distribution, with stronger expression for many in the exocrine compartment. The receptors were not often expressed until late gestation. Exogenous 9cRA induced predominantly ducts instead of acini, plus more mature endocrine (islet) architecture. Exogenous atRA induced predominantly acini instead of ducts, with no apparent endocrine effect. CONCLUSIONS: Retinoids may have an important role in pancreatic differentiation, with a particular effect on secondary lineage selection between ductal and acinar phenotype. Because the control of ductal versus acinar differentiation has been implicated strongly in the pathogenesis of pancreatic ductal carcinoma, these results may lay the groundwork for studies in the mechanism of induced differentiation of pancreatic ductal cancer by retinoids.

Animals↗

PubMed2000

In vitro characteristics of neonatal hemangioma endothelial cells: similarities and differences between normal neonatal and fetal endothelial cells.

BACKGROUND: Increased angiogenesis and eventual involution are major characteristics of neonatal hemangiomas. The mechanism to explain this transition is not completely understood. METHODS: To determine the nature of these changes, endothelial cells were isolated from eight hemangiomas and the growth characteristics and morphology of these cells were compared to cells isolated from normal fetal and neonatal skin. Three cells lines were further characterized by analyzing protein expression with immunohistochemistry and FACS analysis. RESULTS: Hemangioma endothelial cells converted to a spindle-shaped morphology similar to that of fetal endothelial cells whereas neonatal endothelial cells maintained their characteristic epithelioid morphology. While neonatal, hemangioma and fetal endothelial cells continued to express platelet-endothelial cell adhesion molecule-1 (PECAM-1) and von Willebrand factor (vWf), hemangioma and fetal cells expressed both proteins at a lower level and in a distribution distinct from normal neonatal endothelial cells. Neonatal endothelial cells continued to express epithelial specific Type IV collagen, while hemangioma and fetal endothelial cells produced interstitial Type I collagen. CONCLUSIONS: Both cell morphology and protein expression of neonatal hemangioma endothelial cells were more characteristic of embryonic microvascular endothelial cells than that of postembryonic cells demonstrating a similarity in these two cell types and suggesting a dysfunction in the normal growth and maturation of endothelial cells in this tumor.

Biomarkers, Tumor↗

PubMed1998

The in utero repair of Tessier number 7 lateral facial clefts created by amniotic band-like compression.

The purpose of this study was to determine the effectiveness of intrauterine reconstruction of lateral facial clefts caused by surgically simulated amniotic band compression. The authors hypothesized that intrauterine lysis of these bands could: 1) prevent the progression of cleft formation; 2) normalize facial development; and 3) allow for the scarless repair of these lateral atypical facial clefts. In a prospective randomized trial, eight 65-day gestational fetal lambs (term, 140 days) were exposed via a maternal hysterotomy. A Tessier 7 facial cleft was made by applying a 2.0 nylon suture as a constriction band to the growing face. The sutures were attached to the zygomatic arch and looped circumferentially into the oral commissure. Two weeks after surgery, four of eight animals were re-exposed. All four animals developed phenotypic changes consistent with Tessier 7 lateral facial clefts. These animals were treated in utero by 1) excising the synthetic constricting band, and 2) opening the epithelialized edges of the lateral facial clefts and performing a primary repair. At birth, the bands on the four untreated animals were cut. The lambs developed to 3 months of age, at which time they were evaluated anthropomorphically for changes in soft tissue measurements, and histologically using hematoxylin and eosin and Mason trichrome stain for the degree of scar at the repair site. Tessier 7 lateral facial clefts were produced in all the untreated animals. Each developed macrostomia with an average 2.3-cm lateral displacement of the oral commissure and partial maxillary clefting induced by the pressure of the restriction band. No evidence of tissue necrosis, maceration, or ulceration was noted. In contrast, animals treated in utero were phenotypically normal. There was no evidence of macrostomia and all anthropomorphic measurements were symmetrical. No bony clefts were seen on gross examination. Histologically, there was no evidence of scar formation at the site of the cleft repair. These findings suggest that like the standard cleft lip, atypical lateral facial clefts can be repaired successfully in utero without scarring. Furthermore, lysis of a restriction band in utero can prevent the progression of this facial deformity, leading to normal development of the face.

Amniotic Band Syndrome↗

PubMed1997

Wound healing is accelerated by agonists of adenosine A2 (G alpha s-linked) receptors.

The complete healing of wounds is the final step in a highly regulated response to injury. Although many of the molecular mediators and cellular events of healing are known, their manipulation for the enhancement and acceleration of wound closure has not proven practical as yet. We and others have established that adenosine is a potent regulator of the inflammatory response, which is a component of wound healing. We now report that ligation of the G alpha s-linked adenosine receptors on the cells of an artificial wound dramatically alters the kinetics of wound closure. Excisional wound closure in normal, healthy mice was significantly accelerated by topical application of the specific A2A receptor agonist CGS-21680 (50% closure by day 2 in A2 receptor antagonists. In rats rendered diabetic (streptozotocin-induced diabetes mellitus) wound healing was impaired as compared to nondiabetic rats; CGS-21680 significantly increased the rate of wound healing in both nondiabetic and diabetic rats. Indeed, the rate of wound healing in the CGS-21680-treated diabetic rats was greater than or equal to that observed in untreated normal rats. These results appear to constitute the first evidence that a small molecule, such as an adenosine receptor agonist, accelerates wound healing in both normal animals and in animals with impaired wound healing.

Adenosine↗

PubMed1996

The anti-inflammatory mechanism of sulfasalazine is related to adenosine release at inflamed sites.

The anti-inflammatory mechanism of sulfasalazine is not well understood. It has recently been shown that sulfasalazine inhibits 5-aminoimidazole-4-carboxamidoribonucleotide (AICAR) transformylase, an enzyme involved in de novo purine biosynthesis. We recently demonstrated that methotrexate promotes intracellular AICAR accumulation, thereby increasing adenosine release and diminishing inflammation, so we tested the hypothesis that sulfasalazine similarly promotes intracellular AICAR accumulation. We studied adenosine release and the state of inflammation in in vitro and in vivo models of the inflammatory process. The adhesion of stimulated neutrophils (FMLP) to endothelial cells preincubated with sulfasalazine was inhibited in a dose-dependent manner. Elimination of extracellular adenosine by addition of adenosine deaminase or inhibition of adenosine by the adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) completely reversed the anti-inflammatory effect of sulfasalazine (at concentrations <1 microM in this in vitro model. To determine whether this phenomenon was relevant to inhibition of inflammation in vivo, we studied the effect of sulfasalazine (100 mg/kg/day by gastric gavage for 3 days) on leukocyte accumulation in the murine air pouch model of inflammation. Treatment with sulfasalazine markedly decreased the number of leukocytes that accumulated in the inflamed (carrageenan, 2 mg/ml) air pouch. Injection of either adenosine deaminase or DMPX, but not the A1 receptor antagonist 8-cyclopentyl-dipropylxanthine, significantly reversed the anti-inflammatory effects of sulfasalazine treatment. Sulfasalazine increased the exudate adenosine concentration from 127 +/- 64 nM to 869 +/- 47 nM. Moreover, sulfasalazine treatment promoted a marked increase in splenocyte AICAR concentration from 35 +/- 6 to 96 +/- 3 pmols/10(6) splenocytes, which is consistent with the in vitro observation that sulfasalazine inhibits AICAR transformylase. These results indicate that sulfasalazine, like methotrexate, enhances adenosine release at an inflamed site and that adenosine diminishes inflammation via occupancy of A2 receptors on inflammatory cells. Our studies provide evidence that sulfasalazine and methotrexate may be described as a newly recognized family of anti-inflammatory agents that share the property of using adenosine as an antagonist of inflammation.

Acyltransferases↗

PubMed1992

Isolation and partial characterization of hyaluronan-protein-collagen complex (HA-PC) from fetal sheep skin of different gestational ages.

Hyaluronic acid (HA) has a positive effect on cell migration, differentiation and wound healing. Earlier work from our laboratory has shown the presence of biologically active proteins associated with HA. The protein associated with HA of fetal sheep skin varies in molecular weight depending on its gestational age. Specifically, the protein profile changes at 125 days of gestation, from a 60 KDa protein to a smaller protein of about 21 KDa. This time period coincides with the time that scarring becomes apparent in fetal sheep skin wounds. In this study, we have quantified changes in the proteins associated with HA with increasing gestational age, obtained amino acid profiles of these proteins with increasing gestational age, and proposed the existence of an HA-associated protein-collagen complex (HA-PC) which may serve as a scaffold for wound healing. Our results indicate that HA-PC content decreases from 42% of the dry weight at 75 days of gestation to 22% at 125 days of gestation. Protein content, in contrast, increases to 40% of the dry weight at 140 days of gestation. At the same time, collagen content increases from < 1% of the dry weight at 75 days to > 10% at 140 days. The increase in collagen content may account for the increase in total protein seen at 140 days. The expression of varying HA-PC's at different gestational ages may influence the kinetics of collagen fibrillogenesis and thus account for the previously noted late gestational change from "scarless" wound healing to "adult-like" wound healing in fetal sheep.

Amino Acids↗

PubMed1992

Anetoderma and human immunodeficiency virus infection.

BACKGROUND: Autoimmune disorders such as vitiligo and alopecia areata have been reported in persons infected with the human immunodeficiency virus (HIV). OBSERVATIONS: Three HIV-infected men had anetoderma develop early in the course of their HIV infection. In two patients this preceded other features of HIV disease, and in the third it occurred while the helper T-cell count exceeded 200/mm3. CONCLUSIONS: These findings suggest that anetoderma may be an early manifestation of HIV disease, perhaps autoimmune in its pathogenesis.

Adult↗

PubMed1989

Bilateral renal autotransplantation with pyelovesicostomy: a surgical treatment of refractory enteric hyperoxaluria.

A 38-year-old man, with only 3 feet of small bowel remaining after multiple resections because of chronic inflammatory bowel disease, had severe symptomatic calcium oxalate nephroureterolithiasis. Because of the refractory symptoms, he was successfully treated with bilateral autotransplantation of the kidneys, totally bypassing the ureters. Anatomically effective urinary tract continuity was reestablished by means of bilateral pyelovesicostomies with concomitant rectus muscle vesicofixation to create direct stone-dumping channels into the urinary bladder. The patient is now completely without symptoms 18 months after surgery. A description and rationale for this surgical treatment is provided. Bilateral autotransplantation of the kidneys with direct drainage into the urinary bladder may be an attractive and viable therapeutic option in complicated patients with short-gut syndrome and severe refractory calcium oxalate nephroureterolithiasis.

Abdominal Muscles↗

PubMed1989

Neonatal model of heterotopic heart transplantation in pigs.

To investigate the long-term success of heart transplantation in newborn infants who have complex congenital heart disease, we have developed a model of heterotopic heart transplantation in immature pigs. We chose the heterotopic technique because it is simple, does not require cardiopulmonary bypass or heparin, allows for significant size disparity between the recipient and donor hearts, and allows for experimental comparisons between the two hearts. Small newborn piglet hearts are harvested, prepared, and then transplanted into the left chest of larger weanling pigs to augment or substitute for the native left ventricle. Preliminary data from transplants into 49 pigs suggest that the technique is technically possible, the pigs can be immunosuppressed over the long term, and the donor heart can contribute hemodynamically. Experimentally, the model is well designed for the investigation of issues critical for the long-term success of heart transplantation in infants and children, including growth and development, optimal long-term immunosuppression, differences in immunotolerance, and the study of coronary obliterative disease. Clinically, the model has potential applicability in congenital heart anomalies if one native functioning atrium and ventricle are present.

Animals↗

PubMedDate not supplied

[Animal models for investigating the possibility of cleft lip surgery in utero].

The continuous refinement and further development of prenatal diagnostics and of anesthesiologic as well as operative techniques have rendered fetal surgery a point of major clinical interest. In view of the present clinical results of prenatal surgery in the human fetus, the question arises, if it is wise to include the correction of craniofacial malformations in the indications for intrauterine surgery and thus to allow the qualitative advantages of fetal wound healing patterns to be utilized. In the present experimental study an animal model using rabbits is presented, which allows successful intrauterine surgery of the craniofacial area.

Animals↗