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Biomedical subjects

J L McCullough

Publications and source records attributed to J L McCullough.

At least 37 records · Page 2Linked to original sources
PubMed1989

Vasoactive pharmacologic responses of human skin xenografts in ciclosporin-treated rats.

Human skin xenografts in ciclosporin-treated rats have been reported to preserve many of the characteristics of normal human skin. This model was used to study the cutaneous responses of human skin xenografts and host rat skin to intradermal injections of vasoactive agents. The xenograft responses to corticosteroids (blanching), nicotinic acid (erythema), histamine HCl (urticaria), and privine (blanching) all paralleled those of the host rat skin. However, when quantitatively compared to the responses reported for human skin in vivo, the xenografts were less sensitive to these compounds. The large variability seen in the xenograft responses may be due to variable graft revascularization and to structural irregularities in the dermis from the recent grafting procedure. It is concluded that the lower sensitivity and variable responsiveness of the xenografts limit the potential usefulness of this pharmacologic model for evaluating vasoactive agents.

Animals↗
PubMed1989

Topical methotrexate therapy for psoriasis.

In vitro percutaneous penetration of methotrexate is enhanced with 1-dodecylazacycloheptan-2-one (laurocapram [Azone]). Laurocapram-containing methotrexate formulations provide effective local inhibition of epidermal DNA synthesis in the in vivo hairless mouse and minipig models, providing the biochemical rationale for topical use in the treatment of psoriasis. Topical methotrexate (0.1%, 0.5%, and 1%) in a laurocapram-containing formulation was tested in a two-center double-blind pilot clinical study of 42 patients with plaque psoriasis. Drugs were applied twice a day for six weeks, and lesions were scored weekly for erythema, scale, and elevation. An overall improvement of 50% or more in the combined scores for erythema, scale, and elevation was obtained with 0.1% methotrexate (64% of patients), 0.5% methotrexate (59%), and 1% methotrexate (56%) vs the vehicle alone (25%). These preliminary findings suggest that methotrexate preparations that provide adequate percutaneous absorption may have a beneficial effect in the treatment of psoriasis.

Administration, Topical↗
PubMed1988

Photodynamic therapy of human malignant melanoma xenografts in athymic nude mice.

While photodynamic therapy (PDT) for cutaneous malignancies including dermal recurrences of breast cancer and basal cell carcinomas has shown great promise, PDT of malignant melanoma has remained incompletely understood. A comparison study of the effects of PDT on human xenograft amelanotic and melanotic malignant melanoma in the athymic nude mouse model was performed. Twenty-four hours after ip administration of Photofrin II, the responses to total laser light doses of 25-300 J/cm2 were evaluated by histologic examination. Animals were also sacrificed 24 hours after administration of Photofrin II without light, and their uptake and localization of hematoporphyrin derivative (HpD) for each tumor were measured and compared. The results indicate that human xenograft melanotic melanoma, despite the fact that it contains more HpD than does amelanotic melanoma, is far less responsive to PDT. This result appears to be due to the competing chromophore melanin, which may inhibit the photochemical reaction at several key points.

Animals↗
PubMed1988

Identification of differentiation-specific antigens in psoriatic versus normal skin using monoclonal antibodies.

Human cell hybrids derived from fusions between carcinoma (HeLa) and normal epidermal keratinocytes can be used as immunogens to generate monoclonal antibodies against keratinocyte differentiation-specific antigens. We examined the immunofluorescent staining patterns of these monoclonals in normal human and psoriatic (lesional and uninvolved) skin tissue sections. The immunofluorescent staining patterns indicate that the monoclonal antibodies are recognizing a number of different keratinocyte antigens. Three monoclonals (HLK7, HLK3, and HLK20) displayed different immunofluorescent reactivity in these tissues. These new monoclonal antibodies will be useful tools to study the differentiation abnormalities in psoriasis and may serve as a marker of the psoriatic diathesis.

Antibodies, Monoclonal↗
PubMed1988

Paraplegia after thoracic aortic occlusion: influence of cerebrospinal fluid drainage. Experimental and early clinical results.

Paraplegia occurs in 6.5% to 40% of patients after repair of extensive thoracoabdominal aortic aneurysms requiring aortic clamping. This study aimed to determine whether drainage of cerebrospinal fluid (CSF) done before aortic cross-clamping could decrease the incidence of paraplegia in dogs. The descending thoracic aorta was clamped distal to the left subclavian artery for either 40 minutes (group I) or 60 minutes (group II). All control animals in group I (10) and group II (10) showed evidence of spinal cord injury with paraparesis or paraplegia. In contrast, 9 of 10 animals (90%) in group I and 7 of 10 animals (70%) in group II that had CSF drainage before aortic cross-clamping were neurologically normal (p less than 0.001 and p less than 0.01, respectively). Aortic pressure distal to the aortic cross clamp was the same in all groups; however, spinal cord perfusion pressure (distal aortic pressure minus CSF pressure) was significantly higher in neurologically normal animals (34 +/- 5 mm Hg, n = 15) compared with those with paraparesis (26 +/- 4 mm Hg, n = 8) or paraplegia (19 +/- 5 mm Hg, n = 8) (r = 0.871, p less than 0.001). This study demonstrates that drainage of CSF before thoracic aortic occlusion significantly increases spinal cord perfusion pressure and decreases the incidence of paraplegia. Limited early clinical experience suggests that CSF drainage may be a useful adjunct to prevent paraplegia in patients who are having repair of thoracoabdominal aortic aneurysms.

Animals↗
PubMed1987

Dietary influences of evening primrose and fish oil on the skin of essential fatty acid-deficient guinea pigs.

There have been reports that certain dietary lipids are capable of regulating cellular inflammation and hyperproliferation. To investigate further the role of dietary manipulation involving gamma-linolenic acid (18:3n-6) and eicosapentaenoic acid (20:5n-3) on hyperproliferative cellular components, the effects of orally administered primrose oil (containing 18:3n-6) and menhaden fish oil (containing 20:5n-3) were tested in a cutaneous system using the essential fatty acid (EFA)-deficient guinea pig fed a hydrogenated coconut oil (HCO) diet. The effects of the dietary crossover regimen were determined on epidermal 1) morphology, 2) DNA synthesis, 3) delta 6- and delta 5-desaturase activities and 4) fatty acid composition of skin and liver lipids. Our results demonstrated that dietary fish oil lacked the capacity to reverse the signs of epidermal hyperproliferation, acanthosis and hypergranulosis that are characteristic of EFA deficiency. In contrast, primrose oil feeding reversed the histological and biochemical signs of hyperproliferation. These results suggest that dietary fish oil, which contains largely the 20:5n-3 fatty acid, lacks EFA-functional properties in the skin. In addition, substitution of HCO with primrose or fish oil after 6 wk revealed incorporation of 18:3n-6 and 20:5n-3 into epidermal lipids, respectively. The significance of these altered epidermal fatty acid profiles is discussed.

Animals↗
PubMed1987

A model of human melanoma in cyclosporine-immunosuppressed rats.

A human malignant melanoma maintained in athymic nude mice has been successfully implanted and grown in cyclosporine (Cys)-immunosuppressed Lewis rats. Suspended melanoma cells (10(6)) or solid tumor sections measuring 2-4 mm in diameter were implanted s.c. in rats receiving parenteral Cys doses of 15-50 mg/kg each day for 1 week, and 3 times per week thereafter. Eighty-five percent of solid tumor sections implanted in animals receiving 25 mg/kg resulted in tumor growth, whereas no tumors grew from cell suspension injection sites. The average maximum tumor growth rate was 2 cm3/day, with a doubling time of 8 days. Tumors retained pretransplant gross and microscopic morphology, karyotype, and labeling index. Possible advantages of this model over the athymic nude mouse include greater longevity, larger animal and tumor size, and less stringent aseptic environmental requirements. This model may prove useful for further study of the pathophysiology of melanoma and for testing of new antimelanoma therapies.

Animals↗
PubMed1987

Photosensitizers in dermatology.

Systemic injection of hematoporphyrin derivative (HpD) in contribution with visible light (red or blue-green) delivered by laser was used to treat a patient with psoriasis. The psoriatic lesions responded vigorously to laser treatments, forming eschars by 1 week post irradiation. In contrast, only minimal erythema was observed in the noninvolved, clinically normal appearing skin. Two approaches for localized HpD administration were investigated in the guinea-pig and minipig models as a means of achieving local photodynamic effects. Intracutaneous injection of HpD produced localized cutaneous photosensitization with either UVA or red light. Azone increased percutaneous penetration of HpD in human skin in vitro. Topical application of HpD and irradiation with UVA produced localized cutaneous photosensitivity and inhibition of epidermal DNA synthesis.

Animals↗
PubMed1987

The treatment of severe psoriasis. A national survey.

In 1974, we conducted a randomized survey of dermatologists to determine trends in the use of chemotherapeutic agents for psoriasis. The present survey updates and extends the earlier one to include phototherapy, photochemotherapy, and other modalities being used in the treatment of psoriasis too extensive or severe for topical agents alone. Questionnaires were sent to approximately 20% of dermatologists nationwide and also to all training/research programs. Results of the survey include: (1) approximately 523,000 patients with psoriasis were treated by dermatologists in 1984, and 30% of these were severe enough to require more than topical care; (2) the majority of dermatologists use ultraviolet B (71%) and methotrexate (58%), while 36% use psoralen and ultraviolet A; (3) creatinine clearance rates and liver biopsy specimens are being obtained for approximately half of methotrexate-treated patients; and (4) of those physicians using methotrexate, most (74%) use weekly divided orally administered methotrexate doses.

Adult↗
PubMed1986

Prolonged viability of human skin xenografts in rats by cyclosporine.

The immunosuppressant cyclosporine (CSA) has shown usefulness in both animal and human transplantation. The present study investigated the effect of CSA in human to rat skin xenografts. Recipient rats received either a fresh split-thickness (0.020 in.) or full-thickness graft obtained from plastic surgery, or frozen cadaver skin. The graft bed of recipient Lewis rats was prepared by full-thickness excision. Animals were maintained on CSA 25 mg/kg/day X 50 days, followed by 12.5 mg/kg 2 X/week. Control animals received an equivalent volume of vehicle. All animals receiving split-thickness grafts and treated with CSA maintained their grafts significantly longer (up to 255 days) than controls. The 2 CSA-treated full-thickness grafts and the 10 vehicle-treated controls showed clinical and microscopic signs of rejection at a mean of 6.4 days. Histologic examination of successful grafts showed areas of viable epidermis with a negligible inflammatory infiltrate. There was some loss of normal polarity and occasional apoptotic pigmented basal cells. The dermis revealed moderate fibrosis, probably secondary to the surgical procedure. Graft viability was confirmed by autoradiography. Immunohistochemical staining for S-100 protein revealed morphologic alteration of suprabasilar dendritic (Langerhans-indeterminate) cells, as well as their existence in xenografts at 12 weeks posttransplantation. Toxicities reflected by weight loss and blood chemistries were felt to be dose-dependent. This in vivo model may provide a means for testing percutaneous drug penetration and pharmacokinetics in human skin, and for observing the immune component of explanted cutaneous neoplasms and dermatoses.

Animals↗
PubMed1986

Topical tritiated thymidine for epidermal growth fraction determination.

Direct autoradiographic identification of the epidermal growth fraction (GF) requires the delivery of tritiated thymidine ([3H]dThd) to the skin during the time interval of an entire cell cycle. The GF in normal human epidermis has not been directly measured using this technique because the systemic infusion of radioactive [3H]dThd in benign skin conditions is precluded by ethical considerations. Studies were undertaken to assess the feasibility of measuring the epidermal GF in vivo by the topical delivery of [3H]dThd. The percutaneous penetration of [3H]dThd in various vehicles was evaluated to select an effective topical delivery system. A vehicle consisting of Azone, isopropanol, and water (2:49:49) was the best of 4 different vehicles tested. The optimal penetration of [3H]dThd, with respect to the concentration of Azone over a range of 0-4%, was achieved at 2%. During the initial 24 h following a single topical application of [3H]dThd to hairless mice the labeling increased linearly with time. In vivo studies in hairless mice produced a GF of 95% by both continuous systemic [3H]dThd infusion, and by twice daily topical [3H]dThd. Azone vehicles induced epidermal hyperplasia which was minimized by lowering the Azone concentration and by decreasing the frequency of applications from 24 to 48 h. These studies establish the rationale for using topical delivery of [3H]dThd for the in vivo measurement of epidermal GF.

1-Propanol↗
PubMed1986

Growth kinetics of primary versus metastatic human melanoma xenografts in nude mice.

Primary and metastatic tumors from a single patient with fatal malignant melanoma were heterotransplanted and maintained in BALBc/Nu mice. Kinetic parameters were determined using tritiated thymidine as a single injection for percent labeled mitoses studies and continuous infusion for growth fraction studies. Tumor growth characteristics in mice were also examined. Karyotyping and ouabain studies showed that the human chromosomes were maintained in serial transplantation and did not form hybrid cells with the mice. Results suggest that while the metastatic cells have longer cell cycle and duration of S phase, they possess other characteristics which permit faster growth and easier transplantation. The possible role of an "angiogenesis factor" in this situation is discussed.

Animals↗
PubMed1986

Characterization of cutaneous phototoxicity induced by topical alpha-terthienyl and ultraviolet A radiation.

Alpha-terthienyl (alpha-T), a phototoxic thiophene compound isolated from marigolds (Tagetes species), affects cell membranes and does not appear to induce cytogenetic damage. This study was undertaken to investigate topical delivery of alpha-T and characterize its cutaneous phototoxicity in combination with long-wave UV radiation (UVA) in comparison with locally (intradermal) administered alpha-T. Percutaneous penetration (PC) of 0.1% and 1% alpha-T in a 3% Azone gel vehicle was studied in guinea pig skin in vitro and quantitated by UV fluorescence microscopy. Dose-dependent PC of epidermis, adnexae, and superficial dermis was demonstrated in vitro. Alpha-terthienyl (0.1% and 1%) in this vehicle was applied topically in vivo and irradiated with 30 J/cm2 UVA at intervals of 10 min-24 h. Maximum sensitization was achieved with irradiation 1 h following drug application. The clinical response was dose-dependent consisting of erythema, edema, crusting, erosion, and inhibition of hair growth and was observed 72 h to 7 days postirradiation. A comparable dose-dependent phototoxic response was observed when 5-500 micrograms alpha-T were injected intradermally and irradiated with UVA. These results indicated that low-dose topical alpha-T in a nonirritating vehicle can rapidly produce cutaneous photosensitization. Topical alpha-T/UVA may provide a selective and safer alternative approach for the photochemotherapy of psoriasis and other cutaneous diseases.

Administration, Oral↗
PubMed1986

The costs of surgery for limb-threatening ischemia.

The clinical courses of 106 patients with limb-threatening ischemia were traced for as long as 5 years to determine the cost of their care. Seventy-eight patients initially treated with vascular reconstruction accrued an average of $40,769 +/- $3726 in costs over a mean follow-up period of 805 +/- 57 days, during which they had an average of 2.4 +/- 0.2 hospitalizations or 67 +/- 6 inpatient days. Twenty-eight high-risk patients treated with primary amputation accrued $40,563 +/- $4729 in costs over a mean follow-up period of 663 +/- 97 days, during which they had an average of 2.2 +/- 0.3 hospitalizations or 85 +/- 10 inpatient days. Successful revascularization resulted in lower costs ($28,374) than did primary amputation ($40,563) or failed reconstruction ($56,809). Patients with ischemic tissue loss accrued costs more rapidly than did patients with rest pain only. The high cost of providing care for these patients and the advent of diagnosis related group reimbursement mandate that proposed treatment protocols be evaluated not only for their effectiveness but also for their cost-effectiveness.

Actuarial Analysis↗
PubMed1985

Evaluation of arterial prostheses in a baboon ex vivo shunt: the effect of graft material and flow on platelet deposition.

Surface thrombogenicity is recognized as an important factor in the failure of small caliber vascular prostheses. The baboon ex vivo shunt was developed to study small caliber grafts under controlled conditions at different flow rates. The shunt was created by percutaneous insertion of catheters into the baboon femoral artery and vein. Platelet-graft interactions were studied using autogenous indium 111 labeled platelets. Two graft materials were placed in series and exposed to blood flow for 2 1/2 hours at flow rates of 25 and 200 ml/min. At the end of this period, the grafts were removed for morphologic examination. Platelet adhesion to the grafts, especially with the less thrombogenic materials (PTFE and HUV), was found to be independent of flow rate. PTFE was found to be the least platelet-reactive material, HUV was intermediate, and knitted Dacron was the most thrombogenic surface. Platelet deposition on the flow surface was confirmed by light microscopy and scanning electron microscopy.

Animals↗
PubMed1985

Regulation of epidermal proliferation in mouse epidermis by combination of difluoromethyl ornithine (DFMO) and methylglyoxal bis(guanylhydrazone) (MGBG).

Topical methylglyoxal bis(guanylhydrazone) (MGBG) and alpha-difluoromethylornithine (DFMO) individually have been shown to produce partial clinical improvement in psoriasis. In an effort to further enhance therapeutic activity, studies were designed to optimize percutaneous penetraton of DFMO in vitro and to determine the effects of the combination of DFMO and MGBG on DNA synthesis and polyamine levels in hairless mouse skin. MGBG was shown to be more effective than DFMO in inhibiting DNA synthesis in vitro and in vivo. Maximum in vitro percutaneous penetration of DFMO (5%) was obtained in Vehicle N containing 10% Azone (297 micrograms/h/cm2). Topical administration of the combination of 5% DFMO and 0.1% MGBG in this vehicle produced a greater inhibition of DNA synthesis and depletion of polyamine levels than either drug individually. The simultaneous topical administration of DFMO and MGBG, allowing the use of lower concentrations of the more toxic MGBG, may be useful for therapy of psoriasis and other cutaneous disorders associated with abnormalities in polyamine metabolism.

Animals↗
PubMed1985

Cell kinetic basis for pathophysiology of psoriasis.

Studies on the cell proliferation kinetics of psoriatic epidermal cells are presented and the results compared to similar studies for normal epidermis. The short 36-h duration of the psoriatic cell cycle (Tc) is confirmed with the first double-peaked fraction of labeled mitoses (FLM) curve in human subjects. The growth fraction of psoriasis using two experimental techniques approximates 100% within 36 h, confirming the rapid Tc found by the FLM method. The cell kinetic basis for the pathophysiology of psoriasis consists of at least 3 proliferative abnormalities in comparison to normal epidermis. By far the largest alteration is the shortening of the Tc from 311 to 36 h. There is also a doubling of the proliferative cell population in psoriasis from 27,000 to 52,000 cells/mm and an increase in the growth fraction from 60% to 100%. As a consequence of these abnormalities the psoriatic epidermis produces 35,000 cells/day from a proliferative compartment of 52,000 cells/mm2 surface area. This is a 28-fold greater production of cells than the 1,246 cells/day produced in normal epidermis. The biochemical or control factors leading to these kinetic differences continue to remain elusive.

Cell Division↗