Electron microscopic features in psoriatic patients with alpha 1-antitrypsin deficiency.

We studied the electron microscopic features of 7 psoriatic patients with alpha 1-antitrypsin deficiency and 14 psoriatic controls. We found a statistically significant difference in frequency of basal keratinocyte herniations (BKH) as well as of BKH with abnormal configuration (broad-based BKH, herniating through wide gaps in the basal lamina; and multipolypoid BKH) in the alpha 1-antitrypsin deficient group. The differences were more marked in the MZ phenotype than in the MS/SS phenotypes. These findings may reflect the changes resulting from defective inhibition of proteolytic enzyme activity in the psoriatic patients with alpha 1-antitrypsin deficiency, and support the concept that proteolytic enzyme release and activity may play a role in BKH formation.

Electron microscopic features in generalized pustular psoriasis.

Basal keratinocyte herniations (BKH) have been used as markers of psoriatic activity. Abnormal multipolypoid forms herniating through large gaps in the basal lamina have been found to characterize biopsies from psoriatic patients with concomitant alpha 1-antitrypsin deficiency, and appear to be a marker of excessive proteolytic activity. The finding of similar multipolypoid BKH in patients with generalized pustular psoriasis of the von Zumbusch variety (but not in patients with psoriasis vulgaris), in the absence of concomitant alpha 1-antitrypsin deficiency, would support the concept of the presence of large amounts of proteolytic enzymes in the dermis of patients with this syndrome. The large proportion of BKH directly associated with dermal neutrophils, and the presence of clusters of high-density BKH overlying collections of dermal neutrophils, suggests that neutrophilic proteases are largely responsible for BKH formation in patients with this syndrome.

Significance and pathogenesis of basal keratinocyte herniations in psoriasis.

Using transmission electron microscopy, we studied, quantitatively, basal keratinocyte herniations (BKH) in relation to the other basement membrane zone changes in psoriatic lesions of varying clinical activity, and in psoriasiform skin diseases. BKH appears to correlate with disease activity. They do not occur passively as a result of the formation of gaps in the basal lamina. BKH in active psoriasis are associated with electron-lucent areas suggestive of proteolytic enzyme release. Their apparent association with Langerhans cells, neutrophils, macrophages, and endothelial cells may point to these cells as the source of proteolytic enzymes in psoriasis. BKH may prove to be a useful marker for clinical psoriasis.

Expression of the L-fucose moiety on infrainfundibular follicular keratinocytes of terminal follicles, its decreased expression on vellus and indeterminate follicles of androgenetic alopecia, and re-expression in drug-induced hair regrowth.

The distribution of various glycoprotein molecules on the surface of follicular keratinocytes was studied with a panel of lectins with specificity for various sugar moieties on biopsy specimens from both bald/balding scalp and normal occipital scalp, of 23 patients with androgenetic alopecia as well as on biopsies of normal forearm skin of four patients. The most significant differences between bald and normal scalp biopsy were noted with Ulex europaeus agglutinin I (UEA I). We noted an increased (91.8% +/- 3.1; mean +/- SE) expression of UEA I binding sites on the infra-infundibular follicular keratinocytes in anagen terminal scalp hairs, compared to 28.5% +/- 5.2 in the indeterminate (anagen) hairs of balding scalps, and 23.2% +/- 6.3 in the anagen follicles of vellus fore-arm hairs. By contrast, the telogen hairs demonstrated minimal UEA I staining: 4.0% +/- 0.8, mean +/- SE in telogen scalp hairs, 1.8% +/- 0.5 in telogen hairs of balding scalps (0% in completely bald scalps, in which all the hairs were in the telogen phase), and 1.9% +/- 0.2 in telogen forearm hairs. The percentage of UEA I staining correlated with the length of the infra-infundibular follicles in all cases studied. In three cases of hair regrowth after hair growth promotors, the UEA I staining increased to 80.6% +/- 6.1 in anagen hairs and correlated with increased length of infra-infundibular follicles. Our data indicate that there are 1) marked differences between anagen and telogen follicles in UEA I binding to infra-infundibular follicular keratinocytes; 2) the percentage of UEA I staining reflects the size (length) of the infra-infundibular hair follicle; and 3) the anagen follicles of balding scalps (indeterminate hairs) show UEA I staining resembling that exhibited by anagen follicles of vellus hairs.

Lithium carbonate toxicity. Acneform eruption and other manifestation.

Manifestations of lithium carbonate toxicity include acneform eruptions, sinus node dysfunction, hyperparathyroidism, hypothyroidism, thyrotoxicosis, extrapyramidal side effects, and renal toxicity, which may present as nephrogenous diabetes insipidus. This report concerns a patient with a toxic reaction to lithium carbonate. The patient initially had acneform lesions, hypoglycemia, hypothyroidism, and nephrogenous diabetes insipidus. Features of lithium carbonate-induced acneform eruptions are emphasized. Renal toxicity from a lithium carbonate overdose is common, and the hazards of prescribing potentially nephrotoxic drugs to such a patient are stressed.

Cell interactions in psoriasis.

Products of the HLA-D gene, the la or DR antigens, have been shown to control interactions between certain cells with immune functions. Three HLA-D alleles have been reported to be associated with a markedly increased relative risk in psoriatic individuals. We report the existence of apparently unique anatomic interactions between lymphocytes and basal keratinocytes, between Langerhans' cells and basal keratinocytes, and between Langerhans' cells and lymphocytes, deduced on the basis of (1) characteristic cytoplasmic processes extending from one cell into the cytoplasm of adjacent cells, with frequent absence of the intervening plasma membrane at the apexes of these processes, and (2) intimate apposition of the plasma membranes between the interaction cells over a large surface area. These interactions were noted in five of ten untreated psoriatic patients (three of four patients with Koebner's phenomenon) and in one of six treated psoriatic patients, but in none of 17 controls. Intercellular space abnormalities, probably secondary to excessive proteolytic enzyme release, and basal keratinocyte herniations in psoriasis may result from these anatomic interactions.

A simplified hyperbaric oxygen technique for leg ulcers.

A modified technique for administering hyperbaric oxygen with the use of disposable polyethylene bags was evaluated for the treatment of arterial leg ulcers. The potential advantages of the method include fairly low expense, lack of cross-infection, and simplicity in the administration of oxygen. Six men with 27 chronic arterial ulcers were treated with this technique, and five men (ten ulcers) served as controls. In the treated group, 18 of 27 ulcers (5/6 patients) were healed within six to 21 days, with 50% to 90% reduction in size of seven of nine of the remaining ulcers after a three-week period. None were healed in the control group. The treated ulcers healed by 7.8% +/- 1.15% per day compared with -0.5% +/- 0.37% in the control patients. The results indicate that our technique of administering hyperbaric oxygen for the treatment of leg ulcers is simple and effective. It can be adapted for either inpatient or outpatient treatment.

Pathogenesis of the acquired immune deficiency syndrome (AIDS).

The pathogenesis of the acquired immune deficiency syndrome (AIDS) is still unknown. However, it appears to develop in the milieu of prolonged immunodeficiency. Recently, the disease has reached almost epidemic proportions among homosexuals. Patients with AIDS present primarily with disseminated Kaposi's sarcoma and/or a host of opportunistic infections. A hypothesis is submitted incriminating induced tolerance leading to multiple viral infections and reinfections with cytomegalovirus and others, with or without additional immunosuppression by drugs and chemicals, as the cause of prolonged immunosuppression necessary for the development of AIDS. These viruses, behaving as both tumor inducers and promotors in turn, could result in tumors like Kaposi's sarcoma.

Local necrosis and interstitial nephritis due to topical methyl salicylate and menthol.

Excessive percutaneous absorption of potentially toxic substances such as menthol and methyl salicylate may occur through local application of heat, such as the use of a heating pad. Menthol and methyl salicylate are found in nonprescription items and used for muscular and arthritic pains. This patient experienced full-thickness skin and muscle necrosis as well as persistent interstitial nephritis as a result of topical application of methyl salicylate and menthol followed by use of a heating pad, despite the manufacturer's warning against the use of heating pads.

Enhanced healing and cost-effectiveness of low-pressure oxygen therapy in healing necrotic wounds: a feasibility study of technology transfer.

Recent advances in topical hyperbaric oxygen technology identified the use of low-pressure topical hyperbaric oxygen therapy in enhancing wound healing. This study prospectively examined the feasibility of technology transfer from university to Health Maintenance Organization personnel, using topical hyperbaric oxygen therapy to heal necrotic wounds. Fifteen patients with 24 gangrenous and/or necrotic wounds that did not improve or worsened after at least 6 weeks of standard wound care were treated with topical hyperbaric oxygen therapy by trained HMO personnel. Four patients underwent digital amputation for osteomyelitis and/or gangrene followed by topical hyperbaric oxygen therapy. Assessment parameters included wound healing and cost of wound care before and after topical hyperbaric oxygen therapy. Six of the six Level 2 wounds healed within 2 to 4 weeks, nine of the ten Level 3 wounds healed within 4 to 10 weeks, and seven of the eight Level 4 wounds healed within 4 to 12 weeks. The ulcers improved by a mean of 0.829 cm2 per day. T test (SSPS 7.5) showed significant improvement per day after topical hyperbaric oxygen therapy, t = 5.217, df = 24, P < 0.0001 (95% CI = 1.13-0.49). Wound healing with topical hyperbaric oxygen therapy was associated with decreased costs. The results of this support the feasibility of transfer of new wound healing technology from research to HMO personnel.

Angiogenesis in necrotic ulcers treated with hyperbaric oxygen.

Necrotic/gangrenous wounds lack adequate blood supply and develop further vascular damage from either reperfusion injury or oxygen toxicity when exposed to oxygen at the wrong pressures. A prospective randomized study was performed to confirm the efficacy of topical hyperbaric oxygen at 1.004 to 1.013 atmospheres (THOT) in stimulating angiogenesis and healing of necrotic/gangrenous wounds. Participants included 40 inpatients (79 ulcers) recruited over 12 months who were assigned to treatment by either THOT or standard wound care (SWC). The results showed that 90% of the wounds healed in the THOT group compared to 22% in the SWC controls. Repeated measures ANOVA on log (ulcer size at 4 weeks) showed a significant group by time interaction, F(1,55) = 68.2, P < 0.0001. The size of ulcers (at 4 weeks) was significantly smaller with THOT, but larger with SWC. Capillary density/hpf (high power field) was significantly higher in THOT wounds than in SWC wounds (P < 0.001). It was concluded that THOT is effective in stimulating angiogenesis with enhanced healing of necrotic wounds.

Hyperbaric oxygen therapy for pyoderma gangrenosum.

Hyperbaric oxygen administered systemically has been advocated in the treatment of pyoderma gangrenosum. Owing to the serious potential risks of oxygen toxicity with systemic administration, we have devised a simplified technique for the administration of hyperbaric oxygen topically, and have used this method successfully to treat two patients with pyoderma gangrenosum, in whom the underlying etiology was not apparent, and specific therapy, therefore, not possible. The abundant formation of granulation tissue and the ability of the hyperbaric oxygen to arrest further extension of the ulceration suggests that this form of therapy might become the treatment of choice for all ulcers of the pyoderma gangrenosum type.

Topical hyperbaric therapy for problem skin wounds.

BACKGROUND: Hyperbaric oxygen remains the sole treatment capable of inducing growth of new blood vessels. However, systemic hyperbaric oxygen therapy risks central nervous system and pulmonary toxicity. OBJECTIVE: To describe topical hyperbaric oxygen therapy for the treatment of recalcitrant open wounds. METHODS: Topical and systemic hyperbaric oxygen treatments are described and contrasted from one another. Applications of topical hyperbaric oxygen therapy are described. CONCLUSION: Topical hyperbaric oxygen therapy is useful only for open wounds. The advantages of topical hyperbaric oxygen therapy include low cost, the lack of systemic oxygen toxicity, and effectiveness, allowing this treatment to be prescribed for many patients early in the course of their disease rather than as a last resort.

Thrombotic phenomena associated with intravenous cocaine.

A patient with infarctive skin lesions and associated involvement of the kidney and liver caused by an intravenous overdose of cocaine is described. The thrombotic tendency may possibly be related to endothelial cell damage from prolonged vasoconstriction or cocaine toxicity, with disturbance of prostacyclin-thromboxane balance and enhancement of platelet aggregation and thrombotic tendency.

Endothelial cell toxicity in leg ulcers treated with topical hyperbaric oxygen.

We report the clinical and electron-microscopic features of endothelial cell toxicity in patients treated with hyperbaric oxygen for prolonged periods for leg ulcers. The clinical manifestations include the appearance of depressed white areas within the bed of granulation tissue, which correlated with decreased vascularity under light microscopy. Electron-microscopic findings include endothelial cells with serrated nuclear membranes and degenerate mitochondria in the cytoplasm. These changes occurred in all patients subjected to at least 8 weeks of hyperbaric oxygen, even though an intermittent regimen was adopted. The changes reversed after 1-2 weeks of cessation of hyperbaric oxygen.

Predominance of CD8 subset in id eruption of poison oak-induced dermatitis.

The pathophysiology and immune mechanisms involved in the clinical syndrome of autoeczematization remain a mystery. In this study of nickel dermatitis without autoeczematization and poison oak dermatitis with autoeczematization, it was noted that the process of autoeczematization was associated with the presence of CD8+ lymphocytes within the epidermis and the expression of HLA-DR antigens on epidermal keratinocytes. It is surmised that since CD8+ clones are induced by poison oak antigen but not by nickel, the inability of nickel to induce CD8+ lymphocytes may explain why uncomplicated nickel dermatitis does not autoeczematize. Since the selective adherence of CD8+ lymphocytes to keratinocytes, probably via the expression of adhesion molecules such as ICAM-1, the generation of antigens on endothelial cells of high endothelial venules involved in lymphocyte trafficking, and the expression of HLA-DR antigens on epidermal keratinocytes are all due to the activity of interferon-8, it is deduced that this lymphokine may play a key role in id eruptions induced by contact allergens.

Efficacy of cyclophosphamide in toxic epidermal necrolysis. Clinical and pathophysiologic aspects.

In this article we describe the immunocytochemical and electron microscopic findings in five patients with toxic epidermal necrolysis. They indicate the occurrence of necrotic keratinocytes with nuclear disintegration associated with apposed dendritic cells with the nuclear chromatin configuration of T lymphocytes. These findings, including the presence of blebbing of the keratinocytes and membrane defects associated with cytoplasmic processes from these apposed lymphoid cells, fit known electron microscopic criteria that suggest the involvement of T lymphocyte-mediated cytolysis of drug-altered target keratinocytes in toxic epidermal necrolysis. The effector cell appears to be a dendritic subset, with the phenotypic characteristics (CD3+, CD4-, CD8+, CD2+, DR+) of a T cell subset. There is some evidence that tumor necrosis factor alpha, secreted by activated macrophages, may play a role in necrolysis of the epidermis. The dramatic response of our patients to cyclophosphamide, which is known to inhibit cell-mediated cytotoxicity by inhibiting both the recognition and lethal hit stages, together with the rapid regrowth of the epidermis within 4 days to a week in patients who received adequate dosage of the drug, supports the preceding concepts.

Heat-shock protein 65 and activated gamma/delta T cells in injured arteries.

Because immune mechanisms are implicated in atherogenesis, we investigated the T-lymphocyte subset and factors related to its activation after acute arterial ligation (22 ligated and 13 non-ligated specimens). Ligated arteries produced heat-shock protein 65 (hsp65) and were infiltrated with activated T cells (mostly dendritic, CD3+, CD4-, CD8-, and gamma/delta T-cell-receptor bearing). The protein was found with dendritic T cells, with immunogold-labelled hsp65 beside the dendritic processes. Thus, the immune reaction after acute arterial injury may be associated with binding and recognition of in-situ hsp65 by dendritic gamma/delta T-cells.

Beta-adrenoceptor antagonist-induced psoriasiform eruption. Clinical and pathogenetic aspects.

A number of beta-adrenoceptor blocking drugs have been reported to induce a papulosquamous eruption which resembles psoriasis. We report distinctive clinical, histopathologic, immunocytochemical, and electron microscopic features in beta-blocker-induced psoriasiform eruptions that differentiate this syndrome from psoriasis. Preliminary data suggest that biopsy specimens from eruptions caused by beta 1-selective adrenoceptor blocking agents (metoprolol and atenolol) were characterized by excessive degranulation of the neutrophils in the dermis, while the nonselective beta blockers (propranolol, nadolol, and sotalol) were marked by excessive release of proteolytic enzymes from macrophages, which are thought to possess beta 2-adrenergic receptors. Surprisingly, excessive release of enzymes by lymphocytes were noted in both the beta 1-selective and in the nonselective induced syndromes. It is believed that excessive lysosomal enzyme release by neutrophils, lymphocytes, and macrophages is responsible for the presence of basal keratinocyte herniations, which have previously been shown to correlate with hyperproliferation and psoriasiform changes, as well as with the presence of excessive proteolytic enzymes in the skin. It is postulated that the beta-blocker-induced syndrome may result from enhanced proliferation, motility, and activity of lymphocytes, neutrophils, and cells of the macrophage-Langerhans cell series, stemming from depressed intracellular cyclic adenosine monophosphate levels caused by the beta blockade.