Warren Garner

Heparin-binding ligands mediate autocrine epidermal growth factor receptor activation In skin organ culture.

Exogenous EGF and TGF-alpha accelerate wound healing, but treatment effects are often modest. Using short-term human skin organ culture, we found that autocrine EGF receptor activation could account for this observation. Amphiregulin and heparin-binding EGF-like growth factor (HB-EGF) transcripts were rapidly and markedly induced, whereas EGF and TGF-alpha mRNAs were undetectable or only slightly increased. Vascular permeability factor and keratin 6 transcripts were also strongly induced, albeit with a >/= 3 h delay relative to HB-EGF and amphiregulin. All four transcripts were upregulated in actual healing skin wounds, HB-EGF and keratin 6 being the most prominent. The highly EGF receptor-specific tyrosine kinase inhibitor PD153035 strongly inhibited induction of all four transcripts in organ culture, as well as release of immunoreactive HB-EGF into the medium. These effects were confirmed using the anti-EGF receptor mAb 225 IgG. Neither PD153035 nor 225 IgG was toxic to keratinocytes, as judged by calcein-AM uptake. PD153035 completely abrogated the proliferative phase of keratinocyte outgrowth in skin explant cultures, whereas it had no effect on the antecedent migratory phase. Based on these results, we conclude that EGF receptor activation by highly inducible, keratinocyte-derived heparin-binding ligands is an important mechanism for amplification and transmission of the cutaneous wound healing signal.

Interleukin‐8 levels and activity in delayed‐healing human thermal wounds

There are numerous causes for slow or delayed wound healing. Because slowly healing wounds are often inflamed, we quantitated the inflammatory chemokine, interleukin‐8, produced by slowly healing human burn wounds and compared this to interleukin‐8 from healed wounds and normal intact skin. Interleukin‐8 levels were increased significantly in unhealed wounds (19.7 ng/ml) compared to healed wounds (7.7 ng/ml) or normal skin (5.7 ng/ml). Interleukin‐8 in these ranges was added to adult human keratinocytes and fibroblasts. Interleukin‐8 significantly decreased keratinocyte replication but had no effect on fibroblast replication. The rate or final degree of fibroblast populated collagen lattice contraction was inhibited at interleukin‐8 concentrations between 10 and 30 ng/ml, but not altered at concentrations below 10 ng/ml and above 100 ng/ml. The concurrent application of indomethacin at 10 μg/ml reversed this interleukin‐8 induced inhibition. Interleukin‐8 inhibited myosin ATPase activity, apparently by reducing the phosphorylation of nonmuscle myosin light chain. We conclude that elevated levels of interleukin‐8 may be found during delayed healing, and these elevated interleukin‐8 levels may directly contribute to retarded wound closure.

Excessive scarring as a consequence of healing

Synthesis and degradation of collagen is an essential component of wound healing. In most persons, this deposition of collagen results in the formation of a fine line scar which restores much of the tensile strength to the injured tissue and is cosmetically acceptable. However, in certain individuals, the result of wound healing is the excessive accumulation of collagen, resulting in a hypertrophic scar or keloid. The precise origin of this abnormal collagen deposition is unknown, but recent studies have begun to identify potential mechanisms for these disfiguring and painful lesions. This article will review the clinical and laboratory findings pertinent to understanding the origin and treatment of excessive scarring.

Local reactions after injection of iodinated contrast material: Detection, management, and outcome

RATIONALE AND OBJECTIVES The authors assessed the frequency, sequelae, and risk factors of extravasation of intravenously administered iodinated contrast media. MATERIALS AND METHODS All patients with local reactions after intravenous injection of contrast media between November 1994 and December 1996 were studied. Comparison was made with data obtained from a control group of 100 patients with no local reactions who underwent contrast material-enhanced computed tomography (CT). RESULTS Local reactions were reported in 56 (0.25%) of 22,254 patients who received intravenous injections of iodinated contrast media. Fifty-one patients experienced extravasation, and five patients experienced local irritation in the absence of clinically detectable extravasation. Extravasation occurred during CT (n = 46), urography (n = 4), and venography (n = 1). Contrast material was nonionic in 37 cases and conventional ionic in 14 cases of extravasation. Extravasated volumes exceeded 30 mL in 22 patients and 100 mL in six patients. Forty-five (80%) of 56 patients with local reactions had complete resolution of symptoms within 24 hours. Only four patients had symptoms for more than 48 hours. No surgery was required. Compared with the control group, patients with extravasation were significantly more likely to have been injected with small-bore catheters (21 or 22 gauge) and to have been injected at low or high rates. CONCLUSION Symptoms of contrast medium extravasation usually resolve quickly. In patients with extravasation, injections are more likely to have been performed with techniques that vary from normal practice.

The effects of burn blister fluid on keratinocyte replication and differentiation

The optimal clinical care of burn blisters has not been determined. The effects of burn blister fluid and control serum on epidermal cell proliferation and differentiation were determined. Both burn blister fluid and serum decreased the cell responses necessary for healing of the burn wound by approximately 40%. The degree of suppression varied from 81% to 28% dependency on the specific burn blister fluid and cell tested. These data suggest that reepithelialization may be inhibited beneath burn blisters. We conclude that in most cases burn blisters should be debrided.

Burn wounds: Infection and healing☆

Early wound closure is the ultimate goal of burn care. While excisional therapy is necessary in the treatment of both large, full-thickness and deep, partial skin-thickness burns, the majority of burns are superficial partial skin-thickness injuries requiring a different clinical approach. In superficial wounds, cosmetic and functional restoration in conjunction with relief from pain and prevention of infection is as important as rapid wound closure. The moist wound healing associated with hydrocolloid dressings may provide an alternative treatment modality for certain partial-thickness injuries. In comparable wounds, these dressings produce good functional and cosmetic results, rapid reepithelialization, and improved patient comfort.

Donor site repair.

Delayed healing of skin donor sites may be costly and life threatening, especially in patients with large body-surface area burns. A donor site dressing should maximize the ability of the wound to heal without increasing the risk of local infection, systemic infection, or both. Specifically, the possibility of a secondary infection may either slow the healing process or ultimately convert the donor site to a full-thickness wound. A number of materials, ranging from gauze to biological agents, have been investigated for use as donor site dressings. The use of hydrocolloids for donor sites has been studied extensively, and, compared with conventional dressings, improved healing rates are reported. Our recent study using a hydrocolloid dressing confirmed earlier research showing fewer infections and more rapid donor site healing.

Effect of triglycyl-lysine-vasopressin on skin blood flow and blood loss during wound excision in patients with burns.

Excisional therapy often results in large-volume blood loss. Triglycyl-lysine-vasopressin selectively decreases dermal blood flow and therefore was tested for efficacy in limiting intraoperative blood loss in a series of patients undergoing excisional therapy. Ten patients with symmetric injuries were treated with intravenous triglycyl-lysine-vasopressin after excision of half of their burn wound. Blood loss, which was quantified by weighing sponges used to absorb shed blood, was significantly decreased after treatment. Triglycyl-lysine-vasopressin treatment was safe and effective and should be considered in cases when large-volume blood loss is expected.

The effect of essential fatty acid supplementation on keratinocyte replication

Epidermal cell growth in culture, using the low calcium, low serum technique described by Boyce, is thought to induce rapid expansion by inducing an essential fatty acid (EFA) deficiency state. To determine the mechanisms whereby EFA deficiency induces increased epidermal cell growth, keratinocytes were passaged into medium without or with the addition of EFAs, 18:2(n-6), 20:4(n-6). The resulting populations were assayed for replication rate, differentiation, and plating efficiency. Supplemental EFAs significantly decrease keratinocyte culture expansion. This is evidenced by an increase in generation time, a decrease in thymidine incorporation, and a decrease in modeled replication rate. EFA supplementation also increased the expression of cornified cell envelopes. Serum-free medium induces EFA deficient keratinocytes that demonstrate increased replication and decreased differentiation. Restoration of EFAs reverses these changes. It may be possible to manipulate keratinocyte physiology using fatty acid modifications.

Cholescintigraphy in the critically III

Summary Critical review of cholescintigraphy in critically ill patients suggests the examination will not conclusively prove or disprove the diagnosis of acute cholecystitis. Of 17 scans performed in critically ill patients with clinical evidence of acute cholecystitis, 7 were true-negative, 1 was false-negative, 6 were false-positive, and 3 were nondiagnostic. Cholestasis and hepatocyte dysfunction, common in the critically ill, result in abnormal clearance of hepatobiliary radionuclide imaging agents, decreasing the usefulness of cholescintigraphy in this patient population. diagnosing acute cholecystitis in a critically ill patient remains difficult.