Enhancement of wound healing by growth factors.
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Growth Substances↗
Biomedical subjects
T K Hunt
Publications and source records attributed to T K Hunt.
Inhibition of prolyl hydroxylase by poly(ADP-ribose) and phosphoribosyl-AMP. Possible role of ADP-ribosylation in intracellular prolyl hydroxylase regulation.
Poly(ADP-ribose) prepared by incubating NAD+ with rat liver nuclei inhibited the hydroxylation reaction catalyzed by purified prolyl hydroxylase (proline,2-oxoglutarate dioxygenase, EC 1.14.11.2) in vitro. Near complete inhibition of the enzyme was seen in the presence of 6 nM (ADP-Rib)18 with a Ki(app) of 1.5 nM. The monomer unit of poly(ADP-ribose), adenosine diphosphoribose (ADP-Rib), was found to be a weak inhibitor. On the other hand, poly(ADP-ribose)-derived phosphoribosyl-AMP (PRib-AMP) and its dephosphorylated product, ribosyl-ribosyl-adenine (Rib-RibA), inhibited the enzyme in nanomolar concentrations (Ki(app) 16.25 nM). The order of inhibition was (ADP-Rib)18 greater than PRib-AMP, Rib-RibA much greater than ADP-Rib. These results suggested that the 1"----2' ribosyl-ribosyl moiety in these compounds was involved in the inhibition of the enzyme. The possibility that intracellular prolyl hydroxylase is regulated by the involvement of ADP-ribosylation reactions was examined in confluent cultures of skin fibroblast treated with 20 mM lactate. The activity of prolyl hydroxylase was stimulated by 145% over that of untreated cultures. In the lactate-treated cells, the level of NAD+ was lowered and the total ADP-ribosylation of cellular proteins reduced by 40%. These observations imply that the lactate-induced activation of cellular prolyl hydroxylase is mediated by a reduction in ADP-ribosylation and that the synthesis and degradation of ADP-ribose moiety(ies) may possibly regulate prolyl hydroxylase activity in vivo.
Adenosine↗
Medullary thyroid carcinoma. The need for early diagnosis and total thyroidectomy.
Forty patients with medullary thyroid carcinoma and 3 patients with C-cell hyperplasia were studied. Seventeen (40%) cases were sporadic and 26 (60%) were hereditary. Eight patients had type lla multiple endocrine neoplasia, 7 patients had type llb multiple endocrine neoplasia, and 11 patients had familial nonmultiple endocrine neoplasia medullary thyroid carcinoma. Mean follow-up was 6.3 years, with actuarial survival of 88% and 78% at 5 and 10 years (22 and 13 patients), respectively. Seven patients died 1.5 to 10 years after the initial operation; all had advanced disease at presentation (6 with distant, 1 with lymph node metastasis). No deaths occurred in patients with familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, C-cell hyperplasia, or medullary thyroid carcinoma limited to the thyroid gland. Nineteen (68%) of 28 patients diagnosed without screening had regional or distant metastases, whereas only 6 (40%) of 15 patients diagnosed by screening had metastases. Twenty-six patients treated initially with total thyroidectomy and central neck clearance required an average of one reoperation, whereas those with lesser initial procedures required an average of two reoperations. We concluded that (1) familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, early medullary thyroid carcinoma or C-cell hyperplasia, and asymptomatic patients have a good prognosis; (2) screening for medullary thyroid carcinoma by measuring serum calcitonin levels results in earlier diagnosis; and (3) total thyroidectomy and central neck clearance is the procedure of choice for medullary thyroid carcinoma.
Adult↗
MHC antigens persist on human fetal pancreatic islet cells even after culture and transplantation into nude mice.
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Animals↗
Selective effects of tumor necrosis factor-alpha on wound healing in rats.
Many growth factors are believed to act simultaneously in wounds. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine released by activated macrophages. In various concentrations it has inflammatory, cytolytic, mitogenic, antitumor, and possibly angiogenic or antiangiogenic effects; therefore it is likely to affect wound healing. With stainless steel wire mesh wound cylinders implanted in rats, we tested topical TNF-alpha in wounds, alone and in combination with platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta). The cylinders were injected daily for a total of 12 days, after which we measured the accumulation of protein, DNA, and hydroxyproline in each cylinder. TNF-alpha had little effect by itself; it inhibited the growth-promoting effects of TGF-beta, but it did not influence the effects of PDGF. These results agree with the in vitro studies showing synergism of TNF-alpha and PDGF and antagonism between TGF-beta and TNF-alpha. They also suggest that TGF-beta may have a negligible role in normal healing and emphasize that interaction of growth factors must be understood before appropriate clinical use can be planned.
Animals↗
The cost of hospitalization for firearm injuries.
The hospital records for all patients (N = 131) admitted during 1984 to San Francisco General Hospital because of firearm injuries were studied to determine the hospital costs and sources of payment for these injuries. Because San Francisco General Hospital is the regional trauma center, the sample is population based, representing all firearm victims hospitalized in San Francisco during 1984. Only hospital costs (excluding professional fees) for the first hospitalization were studied. The total costs for the year were $905,809, an average cost per patient of $6915. Public sources paid 85.6% of this cost, while private sources paid only 14.4%. These findings have important implications for legislators considering bills to restrict the availability of firearms. These legislators must be aware that the issue is not simply one of individual rights, since taxpayers pay most of the costs (estimated to be more than $1 billion per year for the United States) associated with firearm injuries.
Adult↗
Biologic priming of neutrophils in subcutaneous wounds.
Migration of neutrophils from blood into tissue is a complex response by circulating cells to chemotactic stimulation. Previous studies of the functional changes induced by this process have produced variable results. We compared neutrophils isolated from blood and from subcutaneous wounds in rabbits using established assays for adherence, chemotaxis, superoxide anion production, and hydrogen peroxide production. No differences in adherence to biologic surfaces or chemotaxis toward activated plasma were found. However, our results confirm the observation that wound neutrophils are "primed" for increased production of oxygen radicals. Primed responses were observed for both soluble (formyl methionyl leucylphenylalanine, phorbol myristate acetate) and particulate (opsonized zymosan) stimulants. Priming was also observed for peritoneal exudate neutrophils. The data suggest that the process of extravascular migration includes priming of the superoxide generating system.
Animals↗
Oxygen tension measurements using an oxygen polarographic electrode sealed in an implantable silastic tonometer: a new technique.
Our new method is comparable to the standard, "open-end" tonometer system and incorporates all its abilities to monitor oxygen tension and perfusion. The new device has the advantage of being completely sealed, providing a true, continuous direct measurement over several days, with freedom of movement for the patient without operator attention and with improved stability of the electrode, which minimizes the drift artifacts previously encountered. These improvements will facilitate routine clinical monitoring of tissue oxygen tension.
Animals↗
The physiology of wound healing.
Many of the biochemical events of wound healing are prisoners of the victim's physiologic state. Although the initial local events of inflammation occur normally in any viable tissue, the subsequent reparative capacities of macrophages, fibroblasts, and endothelial cells are seriously impaired by any compromise of local perfusion and oxygenation. In particular, the bacteriocidal capacities of granulocytes are heavily dependent on local oxygenation/perfusion, nutrition, and endocrine status. This article depicts the local mechanisms of repair with special attention to the means by which physiologic and nutritional support at the clinical level influence repair, even to a point at which wound healing may exceed contemporary expectations. Without appropriate physiologic, nutritional, and endocrine support, wound healing often fails totally. It is now possible, although not always easy, to achieve optimal physiologic support.
Humans↗
Oxygen as an isolated variable influences resistance to infection.
The relative importance of oxygen in relation to resistance to infection was assessed in 24 mongrel dogs. Rectus abdominis musculocutaneous (MC) and corresponding cutaneous random pattern (RP) flaps based at the level of the xiphoid were elevated, replaced, and sutured. Immediately after the surgical procedure, 0.1 ml saline containing 10(8) Staphylococcus aureus/ml was injected intradermally into six fields of each flap. After the operation, the dogs were caged in controlled environments with different oxygen concentrations at 12%, 21%, and 45% for 3 days. After 24, 48, and 72 hours, lesion size was measured. Different lesion size was noted between the hypoxic and the hyperoxic groups in the MC flaps from the first day on and in the RP flaps from the second day on (p less than 0.05). Resistance to infection with S. aureus is oxygen dependent, particularly when tissue PO2 is below 40 mmHg.
Animals↗
Tissue oxygen measurements in delayed skin flaps: a reconsideration of the mechanisms of the delay phenomenon.
The delay phenomenon was studied by measuring tissue oxygen tension (PsqO2) for 3 weeks in delayed flaps and normal adjacent contralateral skin in seven mongrel dogs. The PsqO2 fell after elevation of a bipedicle flap and rose again to normal by day 14. Delivery of oxygen to this flap was improved by surgical delay, so that when the bipedicle flap was reelevated on day 14 and its distal pedicle divided, minimal changes in PsqO2 occurred. When the control area was elevated on day 14 as a random-pattern flap, it had higher PsqO2 values than measured in the bipedicle flap on day 0, and therefore, it too had participated in the delay phenomenon, even though only its midline edge had been incised. An anatomic explanation for the findings was sought in wounds made in 10 rabbit ear chambers. After injury, blood flow was seen to be rerouted parallel to the incision line and was increased first by vasodilation and then also by angiogenesis until about day 14. Rerouting of blood by injury, inflammation, and angiogenesis due to repair appears to account for a significant portion of the delay phenomenon.
Animals↗
P & T Committee interview: Promoting rational drug use.
In this exclusive Hospital Formulary interview, Thomas K. Hunt, MD, and Eric T. Herfindal, PharmD, chairman and secretary of the P & T Committee at the University of California San Francisco Medical Center, discuss how their Committee has evolved over the years. In a highly specialized medical center like UCSF, the P & T Committee has become the liaison between quality assurance and the medical staff. A diverse patient population necessitates a broad spectrum of agents, although restriction policies are common in order to minimize the spread of resistance or inappropriate use of drugs. Because of ongoing investigational drug research--including AIDS-related treatments--use of expensive, genetically-derived agents is often justified by the P & T Committee, in what Drs. Hunt and Herfindal describe as "million-dollar decisions."
Drug Utilization↗
Metabolic regulation of prolyl hydroxylase activation.
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Animals↗
Rock-climbing injuries in Yosemite National Park.
This study was presented in part at the annual meeting of the Wilderness Medical Society at Aspen, Colorado, in August 1986 and at "Mountain Medicine 1987," Leavenworth, Washington, in November 1987. We questioned 220 injured rock climbers or their partners seen consecutively at the Yosemite (California) Medical Clinic over 3 (1/2) years regarding details of their accidents. Injury type and location were extracted from medical records and severity quantified. The National Park Service rescued 27% of the climbers. Injured climbers were characteristically male (88%) and experienced (mean 5.9 years) and typically fell while leading climbs (66%). Among 451 injuries, 50% were to the skin or subcutaneous tissues, while 28% involved the lower extremity and were predominantly fractures. In terms of each climber's most severe injury (n = 220), 45% involved the lower extremities (30% from the ankle alone). Head injury or hypothermia caused 12 of 13 fatalities, showing the lowest case-fatality rate reported to date among injured climbers (6%). Rescue personnel successfully managed airways in victims of head injuries, anticipated and treated complications of hypothermia, and stabilized fractures. Victims requiring immediate extensive surgical intervention or blood transfusion usually died before rescue could be effected.
Accidental Falls↗
Wound healing: a foundation for future surgeons.
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Growth Substances↗
Prospective: a retrospective perspective on the nature of wounds.
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Growth Substances↗
Somatomedins: do they play a pivotal role in wound healing?
Somatomedin-C is present in human and other animal wound fluids. Somatomedin-C has previously been shown to be synthesized by fibroblasts. Our data shows that at least part of the wound fluid somatomedin-C comes from local wound synthesis. This somatomedin-C has the capability of acting as an autocrine in further stimulating the proliferation of fibroblasts. In addition, somatomedin-C has been shown to stimulate collagen synthesis by fibroblasts. Wound fluid also contains a somatomedin carrier protein; however, our evidence is that association between the carrier protein and somatomedin-C is much weaker than normal and, thus, wound fluid somatomedin that is bound to carrier protein is much more "available" for biologic action. An understanding of the role of somatomedins in normal wound healing might be able to help us understand abnormalities of the repair process such as keloid formation.
Animals↗