Herpesvirus hominis hepatitis and disseminated intravascular coagulation. Occurrence in an adult with pemphigus vulgaris.

Herpesvirus hominis (HVH) hepatitis, a rarely recognized manifestation of HVH infection in adults, occurred in a 36-year-old woman who had received prednisone therapy for pemphigus vulgaris continuously for seven years. After an acute terminal illness that was characterized by fulminant hepatic failure and disseminated intravascular coagulation (DIC), postmortem examination disclosed massive hepatic necrosis. Herpesvirus hominis (type 1) was isolated from the liver. The association of disseminated HVH infection with impaired immunologic defenses, as well as the occurrence of DIC in association with acute hepatic failure, are discussed. Greater awareness of the clinical manifestations of HVH hepatitis should lead to early diagnosis, although sucessful modes of therapy await development.

Effects of neutron radiation on mouse hair matrix cell populations.

We have investigated the effects of a single low dose of 42 rads neutron radiation on hair matrix cell kinetics. Anagen hair skin sites in 3-mo-old Carworth Farms no. 1 female mice were exposed to a fast neutron beam yielding a modal energy of 3.6 MeV. In contrast to low LET (linear energy transfer) radiation at a 2 1/2 fold higher dose, neutrons induced a markedly prolonged depression (greater than 60%) in the mitotic index for more than 18 hr postradiation. In addition, from 10--18 hr after neutron irradiation sharp elevations (greater than 80%) in the labeling indices apparently reflected significant impairment in cell maturation rates and/or slowed exit rates from the proliferative compartments. Postradiation reductions of up to 20% in the size of proliferating matrix cell populations were found. At the cellular level, this study confirms previous findings of a disproportionately high relative biological effectiveness for neutron radiation following low dose level exposure.

Radiobiology of the skin: review of some effects on epidermis and hair.

Significant doses of ionizing radiation produce an acute skin reaction characterized by erythema, epilation, and dry or moist desquamation with or without erosions. These early acute changes are dose-dependent and reflect damage to the germinative cells of the epidermis and to the cutaneous vasculature. Studies in the pig, for example, have shown that the degenerative phase of cell loss (2-3 weeks) results from reproductive failure in germinative cells and a sharp reduction in the proliferation rate of basal cell "survivors." D0 values for epidermal cells in different species generally range from 100-140 rads. Cell maturation and ascension rates in the suprabasilar layers are largely unaffected. A regenerative phase of cell replacement, characterized by sharply increased cell replication rates, occurs from the 3rd to 5th postradiation weeks. The postregenerative phase of hyperplasia reflects a temporary overshoot of cell density above control levels; a subsequent decrease in hyperplasia indicates feedback control of cellular proliferation. Postradiation changes in the highly proliferative anagen hair matrix cell populations result in hair dysplasia, slowed growth rates, impaired metabolic processes, and alopecia. Dosages of 700-800 rads or more induce some degree of permanent hair loss. G0 telogen matrix cells are 2-3 times more radioresistant than proliferating anagen matrix cells, but may "store" radiation damage for prolonged periods. Altered matrix cell uptake of amino acids, the incidence of dysplasia, and the degree of alopecia occurring after irradiation have all been used as quantitative biological end-points for the general study of cellular radiation effects, as well as studies on the enhancement of or protection against radiation damage provided by certain pharmacologic or physical agents.

Prostaglandins protect against murine hair injury produced by ionizing radiation or doxorubicin.

Several years ago we showed that prostaglandins (PGs) are potent radioprotective agents. To investigate further the potential use of these compounds we employed quantitative measures of murine hair loss and regrowth to assess the effects of PG administration before multi-dose fractionated radiation exposures. We compared these results with findings utilizing the thiol compounds WR-2721 or WR-1065, the "gold standard" laboratory radioprotectors. Three weeks after systemic administration of 16-16 dm PGE2 (Upjohn Company) or WR-2721, given 1 h before each dose of 2-4.5 Gy per fraction for 10-15 fractions, regrowing hair counts increased up to 100% compared to irradiated-only skin sites. The thiol compound effects were slightly superior to the PG effects in these studies. Local applications of 16-16 dm PGE2 or WR-1065 given 15 min before each radiation fraction also enhanced post-radiation hair regrowth, although systemic administration of either agent was more effective than the topical route. We also evaluated possible protective effects of PGs given before doxorubicin, measuring murine hair loss 1 week after parenteral injections of the drug. Five daily doses of doxorubicin, 0.1 mg/25 g animal, reduced the number of hairs in a 4.42 mm2 area of skin from 241 +/- 5 (controls) to 144 +/- 3. Misoprostol (G.D. Searle & Co.), 25 micrograms/mouse, applied locally 2 h before each dose of doxorubicin, resulted in 213 +/- 8 residual hairs. We conclude that clinical use of these compounds may provide significant protection of hair follicles and possibly other normal tissues (skin; oral, rectal, and bladder mucosa) lying within a radiation field or in patients treated with chemotherapeutic agents. Further assessment of possible tumor protection effects are needed, however.

Nalidixic acid-induced photosensitivity in mice: a model for pseudoporphyria.

Porphyria cutanea tarda (PCT)-like photosensitivity eruptions have occurred in patients treated with nalidixic acid, furosemide (Lasix), or tetracycline. An animal model for nalidixic acid photosensitivity was developed in young CF-1 female mice. The hair on the back was plucked from groups of animals that were injected i.p. each day with nalidixic acid or saline. The animals were exposed to black-lamp radiation for 12 h daily for 6 weeks, followed by a 2-week rest period, and then 4 more weeks of UV radiation exposure. The nalidixic acid-treated animals developed far greater gross and chronic inflammatory changes than the saline-treated animals; microscopically and ultrastructurally they showed blister formation beneath the basal lamina at the same level as that found in PCT. This model appears to be suitable for the study of PCT-like and other photosensitivity reactions.

Dapsone-induced peripheral neuropathy.

Peripheral neuropathy is a rare complication of dapsone therapy. This neuropathy appears primarily to be of the motor type, and recovery occurs on discontinuation of the drug therapy. The patient in this report developed a marked motor deficit as well as a selective marked loss of vibration sense shortly after the initiation of a relatively low dose of dapsone. Recovery was rapid on cessation of the therapy. This patient was found to be a slow acetylator of isoniazid, and therefore is probably a slow acetylator of dapsone. The possible mechanisms of the neurotoxicity of dapsone and the role of altered metabolism are discussed.

Subcutaneous or topical administration of 16,16 dimethyl prostaglandin E2 protects from radiation-induced alopecia in mice.

Alopecia, a common sequel of radiation treatment of brain tumors, increases patient stress to the extent that refusal of treatment may occur. The expectation that loss of hair will be prevented, or that regrowth will occur, is extremely important to patients. To investigate prostaglandin-induced radiation protection against alopecia, the hair of B6D2F1 male mice was plucked from the right thigh and surrounding area to induce anagen. Fourteen days later, mice were injected subcutaneously in the neck with 10 micrograms 16,16 dm PGE2 in 0.2 ml of vehicle, or with the vehicle alone. In another group of previously plucked mice, 16,16 dm PGE2 in the same concentration, or the vehicle was applied topically. One hour later, graded single doses from 6.5 to 12.5 Gy 137Cs gamma irradiation were given to groups of six animals. On day 21 post-plucking, all animals were killed and a portion of the irradiated site was excised. The average hair counts per field in irradiated animals were 85 +/- 4 (6.5 Gy), 25 +/- 5 (8.5 Gy), and 5.5 +/- 0.7 (10 Gy). Animals receiving the prostaglandin systemically had values of 60 +/- 10 (6.5 Gy), 54 +/- 3 (8.5 Gy), 66 +/- 6 (10 Gy), and 30.1 +/- 8 (12.5 Gy). Topical application of the prostaglandin resulted in protection that yielded 52 +/- 3 (8.5 Gy), 34 +/- 4 (10 Gy), and 3.2 +/- 0.9 (12.5 Gy) hairs per field. Both systemic and topical application of 16,16 dm PGE2 protected from some degree of radiation-induced alopecia, which supports the conclusion that prostaglandins may be useful in the protection of hair follicles in patients treated with radiation for brain tumors.

Ionizing radiation induces early, sustained increases in collagen biosynthesis: a 48-week study in mouse skin and skin fibroblast cultures.

Groups of 10 CF1 female mice, irradiated to the thorax with a dual-head 137Cs gamma-RAY source, received single doses of 0, 5, 10, 15, or 25 Gy. One to forty-eight weeks later collagen synthesis was measured in minced skin specimens incubated in medium containing [3H]proline and then assayed for radioactive hydroxyproline. A progressive, generally dose-dependent increase in collagen biosynthesis, up to 50% above control sites, was found 1, 4, and 12 weeks after radiation exposure. These changes showed further small fluctuations at 12-36 weeks, increasing again at the 48-week interval. At the same times throughout the study fibroblasts were cultured from skin explants. Following the second subculture, these cells were also incubated in medium containing [3H]proline, and collagen synthesis was again determined by [3H]hydroxyproline assay. At all radiation dose levels studied, collagen production increased threefold by 12 weeks postradiation and remained elevated for the 48-week duration of the study. In vitro radiation dose response differences were not observed.

Pyoderma gangrenosum. Response to cyclophosphamide therapy.

A 46-year-old woman had a 17-year history of intermittently severe pyoderma gangrenosum without identifiable associated systemic disease. Her condition had become unresponsive to corticosteroid and sulfone therapy given for systemic effect, but responded completely to 150 mg/day of cyclophosphamide. Immunosuppressive therapy should be considered in patients with severe, recalcitrant pyoderma gangrenosum, even in the absence of associated systemic disease.

Hydroxychloroquine treatment of porphyria cutanea tarda.

Six patients with skin changes and urinary porphyrin excretion patterns characteristic for porphyria cutanea tarda were treated with hydroxychloroquine sulfate therapy. During treatment periods ranging from five to 13 months, cutaneous symptoms disappeared and urinary porphyrin excretion abnormalities were completely or almost completely reversed. In three subjects, hydroxychloroquine therapy was accompanied by changes in the urinary excretion of iron. The first four patients, followed up for nine to 24 months after treatment, all had relapse, and substantial porphyrinuria developed once more; cutaneous symptoms recurred in two of these. Three of the four patients were re-treated, and their conditions again improved or went into remission with hydroxychloroquine therapy. In two patients, treatment responses were slower than those initially seen, despite the use of higher drug doses; in the third patient, the response to re-treatment was more rapid than that seen during the first treatment course.

Staphylococcal scalded skin syndrome in an adult and a child.

Two patients had staphylococcal scalded skin syndrome (SSSS) with typical clinical and histopathologic findings. In both cases, the disease was reproduced by injections of staphylococci into mice. The adult patient, who had no other physical or laboratory abnormalities, showed intact humoral and cellular immunity; her uneventful clinical course was clearly different from the eight previously reported cases in adults. To our knowledge, the child represents the first case report of SSSS as a result of infection by a non-group 2 Staphylococcus.

Topical or systemic 16, 16 dm prostaglandin E2 or WR-2721 (WR-1065) protects mice from alopecia after fractionated irradiation.

Our previous studies in mice demonstrated that systemic or topical 16,16 dm PGE2 protected against single dose radiation-induced hair loss. We have now investigated prostaglandin, or WR-2721, protection against murine alopecia produced by varying doses and schedules of fractionated radiation. On days one to eight after hair was plucked from the thighs of B6D2F1 mice, groups of 6 animals each were given daily exposures of 4.0 or 4.5 Gy for 5 days; 2.5, 3.5, 4.5 or 5.5 Gy for 10 days; or 2 Gy for 15 days. One hour before irradiation each mouse received 10 microgram 16,16 dm PGE2, either by subcutaneous injection into the neck or topical application, 8 mg WR-2721 by injection, or 0.3 mg WR-1065 by topical application. Three weeks later counts of regrowing hairs were recorded from excised skin samples. For the radioprotectors used, hair regrowth was increased 25-100% in the various radiation groups in comparison to irradiated-only control sites. In some studies with the radioprotector given systemically, WR-2721 afforded slightly greater radioprotection than 16,16 dm PGE2. The two compounds were essentially equally radioprotective in the topical application studies. Since both systemic and topical applications of the agents tested enhanced hair regrowth following radiation, we conclude that clinical use of these compounds may provide some protection of hair follicles, and perhaps other tissues, lying within a radiation therapy field.

Nitrofurantoin-associated Sweet's syndrome.

A 53-year-old woman was seen for arthralgias, fever, and a painful rash developing at the end of a 7-day course of nitrofurantoin for a urinary tract infection. Her only other medication was naproxen, which was started after the onset of symptoms. Initial biopsy showed microscopic changes suggestive of a toxic eruption, but within 3 days the clinical signs and symptoms typical of Sweet's syndrome evolved. A repeat biopsy showed microscopic features characteristic of that diagnosis. The patient subsequently cleared with prednisone therapy. We report this patient as a case consistent with drug-induced Sweet's syndrome induced by nitrofurantoin.