Biomedical subjects

M T Longaker

Publications and source records attributed to M T Longaker.

At least 199 records · Page 11Linked to original sources

PubMed1994

Induction of keratinocyte growth factor expression is reduced and delayed during wound healing in the genetically diabetic mouse.

We have recently demonstrated induction of expression of several members of the fibroblast growth factor family during wound healing, particularly for keratinocyte growth factor, which was more than 150-fold induced within 24 h after injury. To assess whether wound-healing disorders are associated with a defect in fibroblast growth factor regulation, we have now investigated the expression of these mitogens as well as their receptors in normal and wounded skin of genetically diabetic db/db mice, which are characterized by their impaired wound healing. We demonstrate that induction of keratinocyte growth factor expression in these mice is significantly reduced and delayed compared to normal mice. Induction of acidic fibroblast growth factor (FGF) and basic FGF expression was earlier in diabetic mice than in normal mice, but by 3 d after injury expression of these mitogens had already returned to the basal levels. In contrast, elevated levels of acidic FGF and basic FGF transcripts were detected within the first 5 d in wounds from normal mice. Thus, FGFs seem to be expressed in a limited fashion in the wound tissue of db/db mice during the period when re-epithelialization and granulation tissue formation normally occur. These findings provide an explanation for the beneficial effect of exogenous FGF in the treatment of impaired wound healing in these animals and suggest that induction of KGF early in repair may be critical for the rapid re-epithelialization in normal wound healing.

Animals↗

PubMed1993

Are patients with neoplasia at an increased risk for cardiac myxomas?

A case-control study was undertaken to assess whether a significant association exists between the presence of a neoplasm or malignancy and the presence of a cardiac myxoma. We identified 13 patients seen at our institution between 1935 and 1990 whose autopsies revealed a cardiac myxoma that was undetected during the patient's lifetime. For each patient four control subjects were selected among the autopsied patients who had never had a cardiac myxoma; these were matched for age at death, gender, and year of autopsy. The institutional medical records and autopsy reports revealed that 46% of the patients and 65% of their controls had a neoplasm diagnosed prior to or at autopsy. The estimated odds ratio was 0.34 (95% confidence interval, 0.05 to 1.84). There was insufficient evidence to conclude that an association exists between the presence of a neoplasm and the presence of a cardiac myxoma (P = .2722).

Adult↗

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 cleft lip repair in lambs: histologic characteristics of the healing wound.

Sequential surgical procedures in cleft lip/palate (CL/P) patients result in scar formation that is believed to be associated with midface growth retardation. By use of a previously developed fetal lamb model, wound healing characteristics were investigated after in utero CL repair. It is hypothesized that scarless healing after fetal CL repair occurs without inflammation and scar formation. CL wounds were created in mid-second-trimester fetal lambs and either repaired in three layers (mucosa, muscle, and skin) or left unrepaired. Fetuses were then harvested at 7, 14, and 21 days postoperatively, and the wound site was examined microscopically. When created at 75 days' gestation (term = 145 days), fetal lamb CL wounds heal rapidly without inflammation and scar formation. By day 21 postoperatively, there was complete regeneration of skin, muscle, and mucosa, as well as epidermal appendages. With this model, it will be possible to compare the effects of scarless fetal CL repair with those of postnatal repair on midface growth.

Animals↗

PubMed1993

Fetal wound healing. The ontogeny of scar formation in the non-human primate.

OBJECTIVE: This study determined how scar formation develops in a non-human primate model of fetal skin repair. SUMMARY BACKGROUND DATA: A transition from healing scarlessly to healing with scar formation characterizes skin repair in rat and sheep fetuses. New knowledge of the regulatory processes occurring in the fetal wound at the initial stages of scar formation may provide insights into the early mechanisms of scar formation. METHODS: Full-thickness wounds were made in fetal rhesus monkey lips from 75 through 114 days gestation (n = 6, term = 165 days). Wounds were harvested at 14 days postwounding and processed for histology (hematoxylin & eosin, Masson's trichrome) as well as immunohistochemistry (human type I or type III collagen). RESULTS: Wounds healed with complete restoration of normal tissue architecture in the 75-day gestation fetus. However in the 85-100 day gestation fetuses, wounds healed with an absence of hair follicles and sebaceous glands, but the dermal collagen pattern remained reticular and similar to that in unwounded dermis. At 107 days, a thin scar was present in the wound, thereby demonstrating a transition to scar formation between 100 and 107 days gestation (early 3rd trimester) in the non-human primate. CONCLUSIONS: In the non-human primate fetus, a transition from scarless repair to adult-type repair with scar formation occurs in the early third trimester. These data provide insight into the transition process; the ontogeny of scar formation is characterized initially by wounds healing without the presence of epidermal appendages but with a normal reticular dermal collagen pattern, which we term the "transition wound."

Animals↗

PubMed1993

Fetal cleft lip repair in rabbits: long-term clinical and cephalometric results.

We have developed a model for fetal cleft lip (CL) repair in rabbits. To date, the in utero CL procedure has been performed on 174 fetuses in 98 pregnant does. Details of the model, wound healing characteristics, and early growth results have been published previously. In this study, we report long-term clinical and cephalometric findings in 23 fetuses who underwent the fetal CL procedure, were born alive, and survived until completion of growth. The surgically created and repaired CL in fetal rabbits described here resulted in healing without scar formation. The deformity varies from an incomplete to a severe complete cleft, resembling the clinical spectrum of spontaneous clefts in humans. Cephalometric studies indicate that there were no statistically significant differences in premaxillary width, anterior maxillary length, or anterior and posterior maxillary width among control, unrepaired, and repaired animals. Documentation of this phenomenon in higher animals is necessary before the technique can be applied to humans with cleft lip.

Animals↗

PubMed1993

Radiotelemetric fetal monitoring during and after open fetal operation.

Diagnosis and treatment of fetal disease processes has advanced dramatically, but the ability to monitor the fetus in utero remains rudimentary. Open fetal operation provides a unique opportunity to correct life-threatening fetal abnormalities, but it also places the fetus at risk. Continuous intraoperative and post-operative fetal electrocardiographic monitoring may decrease the risk by optimizing fetal and maternal perioperative management. We tested an implantable radiotelemetry device that allowed continuous intraoperative and postoperative fetal electrocardiographic and temperature monitoring. The radiotelemetry device was placed subcutaneously in four fetal sheep at 100 to 112 days' gestation (term equals 145 days). During and after the fetal operation, the monitor reliably and continuously transmitted the analog fetal electrocardiogram and temperature. We then tested a similar device during human fetal operations on both an acute and a chronic basis. The radiotelemetry device permits continuous and reliable fetal monitoring during and after fetal operation and we now consider it essential to the operation. Its use should facilitate optimal fetal and maternal management and improve survival of the fetus.

Animals↗

PubMed1993

Serial quantitation of hyaluronan and sulfated glycosaminoglycans in fetal sheep skin.

Fetal wounds are abundant in hyaluronic acid (HA), but little is known as to the total HA content of fetal tissues as a function of gestational age. Previous studies demonstrated scarless healing prior to approximately 130 days gestation, after which disorganized collagen deposition became prevalent. Glycosaminoglycans (GAGs) have been shown to play an important role in wound healing, cytodifferentiation, and morphogenesis. In this study, we examined the HA and GAG content of fetal sheep skin of increasing gestational age. We found that the total amount of HA and GAGs declined from a high at 80 days gestation (528 +/- 9 micrograms/gm) to a low at 130 days (174 +/- 11). Analysis of the various GAG species revealed that HA comprised the largest fraction (75-96%). The sulfated GAGs, Heparan Sulfate (HS) and Dermatan Sulfate (DS), were not present in the extracellular matrix until 120 days gestation. Both the trough of HA content and the appearance of sulfated GAGs in the extracellular fraction correspond to the appearance of scarring in fetal sheep wound repair.

Animals↗

PubMed1992

Large induction of keratinocyte growth factor expression in the dermis during wound healing.

Recent studies have shown that application of basic fibroblast growth factor (basic FGF) to a wound has a beneficial effect. However, it has not been assessed whether endogenous FGF also plays a role in tissue repair. In this study we found a 160-fold induction of mRNA encoding keratinocyte growth factor (KGF) 1 day after skin injury. This large induction was unique within the family of FGFs, since mRNA levels of acidic FGF, basic FGF, and FGF-5 were only slightly induced (2- to 10-fold) during wound healing, and there was no expression of FGF-3, FGF-4, and FGF-6 detected in normal and wounded skin. High levels of FGF receptor 1 and FGF receptor 2 mRNA and low levels of FGF receptor 3 mRNA were found in both normal and wounded skin. No change in the levels of these transcripts was detected during wound healing. In situ hybridization studies revealed highest levels of KGF mRNA expression in the dermis at the wound edge and in the hypodermis below the wound. In contrast, mRNA encoding the receptor of this growth factor (a splice variant of FGF receptor 2) was predominantly expressed in the epidermis. These results suggest that basal keratinocytes are stimulated by dermally derived KGF during wound healing and implicate a unique role of this member of the FGF family in wound repair.

Animals↗

PubMed1992

New techniques in fetal surgery.

Optimal fetal management during and after fetal surgery has been limited by an inability to reliably monitor the fetal heart rate and temperature, and by a lack of access to the fetal circulation. In order to solve these problems, we used early third trimester fetal sheep to develop: (1) an implantable radiotelemetry device that transmits the fetal electrocardiogram and temperature, and (2) an intraosseous access technique. A miniaturized radiotelemeter was implanted subcutaneously in the axilla of four fetal sheep. Safe implantation of the radiotelemeter was technically feasible and the device reliably recorded the fetal electrocardiogram and temperature both intraoperatively and postoperatively. Although many possible routes for access to the fetal circulation have been tried experimentally and clinically for both resuscitation and blood sampling, none have proven satisfactory. We assessed the use of intraosseous access in fetal sheep (n = 6) for both infusion and blood sampling. Access with an intraosseous needle was obtained in both sheep fetuses and human fetal cadavers. Blood gas values (pH, PCO2, and PO2) obtained from the medullary cavity of fetal sheep accurately reflected peripheral venous values. Resuscitation drugs reached the fetal circulation via the intraosseous route: sodium bicarbonate elevated venous bicarbonate levels from 28.4 +/- 1.7 to 31.8 +/- 2.1 mEq/dL (P < .05); injected glucose increased venous glucose levels by 520 +/- 108 mg/dL (P < .01); and injection of calcium chloride elevated venous calcium levels from 11.8 +/- 0.7 to 15.2 +/- 2.2 mEq/dL (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Necrotizing fasciitis in two children with acute lymphoblastic leukemia.

Necrotizing fasciitis is a severe, soft tissue infection, and is an unusual condition in children. The cornerstone of therapy is prompt, aggressive surgical treatment. Despite vigorous treatment, mortality rates are high. We report the occurrence of necrotizing fasciitis in two children during the granulocytopenic phase of induction chemotherapy for acute lymphoblastic leukemia. The diagnosis and treatment of necrotizing fasciitis in these two children was made more difficult by their underlying disease and its chemotherapy. The successful treatment of their infections relied on a multimodality approach. Aggressive surgical debridement was the mainstay of therapy. Adjuvant therapy was vital to the successful outcomes and included meticulous wound care, intravenous hyperalimentation, appropriate antibiotics, and granulocyte transfusions.

Agranulocytosis↗

PubMed1992

The effect of tissue expansion on dermal fibroblast contraction.

Tissue expansion alters the function of skin cells. We studied the effects of expansion on the contractile function of dermal fibroblasts using an in vitro model, the fibroblast-populated collagen lattice (FPCL). Spherical expanders were placed dorsally in 30 Sprague-Dawley rats; one-half were serially inflated. One, 2, and 4 weeks later, 5 rats from each group were killed. Fibroblasts were cultured from dermis overlying the expanders and mixed with collagen, medium, and serum in petri dishes to form FPCL. Fibroblasts from 5 rats that had not undergone surgery were cultured to make control FPCL. Contraction was assessed by measuring the areas of the FPCL. At 48 hours, FPCL containing expanded fibroblasts had contracted significantly less than those containing unexpanded or control fibroblasts. Four weeks of expansion resulted in less contraction than 1 or 2 weeks. Tissue expansion inhibits the in vitro contractile function of dermal fibroblasts in the rat in a time-related fashion.

Animals↗

PubMed1992

Scarless fetal healing. Therapeutic implications.

The purpose of this report is to call attention to the fetal wound healing process as a blueprint for ideal tissue repair. Wound healing in the fetus is fundamentally different from healing in the adult. Fetal tissue repair occurs rapidly and in the absence of scar formation. Because scarring and fibrosis dominate some diseases in every area of medicine, an understanding of fetal wound healing should help develop therapeutic strategies to avert the devastating consequences of excessive scar formation.

Adult↗

PubMed1992

An in utero model of craniosynostosis.

To define better the pathophysiology of craniosynostosis, we developed an in utero model in rabbits. Premature fusion of the sutures was achieved by osteoinduction using demineralized bone matrix (DBM). Thirty-six fetuses from 18 time-dated pregnant rabbits underwent coronal strip craniectomies and implantation of DBM at 25 days of gestation (term = 31 days). Seventeen (47%) survived vaginal delivery and 10 (28%) survived for long-term follow-up. Surviving, operated animals demonstrated bony fusion across the coronal sutures presumably due to osteoinduction by the DBM. Coronal computed tomographic scans with sagittal reconstructions revealed that experimental animals had taller and wider skulls than nonoperated control animals. We conclude that employing DBM to create craniosynostosis in the fetal rabbit is technically feasible. Such a model may be used to more clearly define the pathophysiology of craniosynostosis and to evaluate methods of treatment.

Animals↗

PubMed1992

A model for fetal cleft lip repair in lambs.

Fetal wounds heal without inflammation and scar formation. This phenomenon may, in the future, be applicable to human cleft lip and palate repair. However, extensive experimental work must first be done to document the benefits of in utero repair. We developed a large animal model for creation and repair of a complete cleft lip and alveolus using fetal lambs. The cleft lip and alveolus deformity was created in eight 75-day-gestation fetuses (term = 145 days) and either repaired in three layers or left unrepaired. There were four sham-operated fetuses, and all animals were alive at harvest. Repaired, unrepaired, and control fetuses were harvested at 7, 14, 21, and 70 days following surgery. The unrepaired fetuses demonstrated a complete cleft lip and alveolus with an oronasal fistula. The maxilla was asymmetrical, with the greater segment deviated toward the cleft and with decreased anterior maxillary width. In contrast, repaired cleft lip and alveolus animals showed no scar, normal thickness of the lip, and a symmetrical maxilla. Histologic analysis of the repaired wounds showed evidence of tissue regeneration without scar formation. The results of this preliminary study indicate that the fetal lamb cleft lip and alveolus model is technically feasible with an excellent survival rate. Healing occurs without scar formation. In the repaired animals, the maxilla was symmetrical. This model will be used to document facial growth following in utero repair of a cleft lip and alveolus.

Alveolar Process↗

PubMed1992

Scarless wound repair: a human fetal skin model.

Animal studies demonstrate that the fetus heals cutaneous wounds by reformation of normal tissue architecture without scar formation. We have developed a new model to study human fetal skin wound healing. Grafts of human fetal skin placed onto athymic mice retain the morphologic features of normal development, although they differentiate at an accelerated rate when placed cutaneously compared to subcutaneously. Full-thickness skin grafts from human fetuses at 15 (n = 12), 17 (n = 11), 18 (n = 25), 19 (n = 20) and 22 (n = 13) weeks gestational age were placed onto athymic (nu/nu) mice in 2 locations: (1) cutaneously onto a fascial bed and thereby exposed to air or (2) subcutaneously in a pocket under the murine panniculus carnosus. Linear incisions were made in each graft 7 days after transplantation. Grafts were harvested at 7, 14 and 21 days postwounding and analyzed histologically for scar formation. By hematoxylin & eosin and Mallory's trichrome stains, complete epidermal and dermal graft wound healing without scar formation was demonstrated in the subcutaneous grafts at each gestational age studied. In contrast, scar was seen at all time points in the cutaneous grafts in both the incisional wound and at the interface of the fetal human skin graft and adult mouse skin, regardless of fetal skin gestational age.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1992

Endoscopic creation and repair of fetal cleft lip.

In utero repair of several life-threatening malformations in the human fetus is now a clinical reality, yet fetal surgery still poses significant risks to both the mother and the unborn child. Preterm labor is a major problem and is directly related to the large hysterotomy required for fetal exposure. Endoscopic surgical manipulation of the fetus, through small uterine "ports," solves this problem and may eventually permit fetal intervention for non-life-threatening malformations. In this pilot study we demonstrated the feasibility of performing endoscopic surgery on the fetus in situ. A lip incision was created and repaired using endoscopic microsurgical techniques in midgestation fetal lambs. This represents the first application of this technique for in utero fetal intervention.

Animals↗

PubMed1992

Fetal fracture healing in a lamb model.

A large animal model to assess fetal fracture repair and the ability to close excisional bony defects is presented. Incisional and excisional ulnar fractures were made in 14 midgestation fetal lambs, harvested at serial time points, and subjected to high-resolution low-kilovolt magnification radiographs, magnetic resonance imaging scans, and histologic analysis. Fetal fracture healing was characterized by early closure of excisional defects and rapid fracture healing with minimal or no soft-tissue inflammation or callus formation. Magnetic resonance imaging scans of the fractures revealed a characteristic pattern compatible with the histologic findings, namely, minimal inflammation in soft tissue adjacent to the fracture site. Histologic and magnification radiographic findings indicated that complete bony repair occurred within 21 days in incisional defects and within 40 days in excisional defects. In both cases, healed fetal bone resembled normal bone matrix. Excisional defects, including periosteum, of greater than three times the width of the bony cortex closed rapidly with virtually normal-appearing bony matrix and with minimal or no callus formation.

Animals↗