Comparative model building of interleukin-7 using interleukin-4 as a template: a structural hypothesis that displays atypical surface chemistry in helix D important for receptor activation.

Using a combination of theoretical sequence structure recognition predictions and experimental disulfide bond assignments, a three-dimensional (3D) model of human interleukin-7 (hIL-7) was constructed that predicts atypical surface chemistry in helix D that is important for receptor activation. A 3D model of hIL-7 was built using the X-ray crystal structure of interleukin-4 (IL-4) as a template (Walter MR et al., 1992, J Mol Biol. 224:1075-1085; Walter MR et al., 1992, J Biol Chem 267:20371-20376). Core secondary structures were constructed from sequences of hIL-7 predicted to form helices. The model was constructed by superimposing IL-7 helices onto the IL-4 template and connecting them together in an up-up down-down topology. The model was finished by incorporating the disulfide bond assignments (Cys3, Cys142), (Cys35, Cys130), and (Cys48, Cys93), which were determined by MALDI mass spectroscopy and site-directed mutagenesis (Cosenza L, Sweeney E, Murphy JR, 1997, J Biol Chem 272:32995-33000). Quality analysis of the hIL-7 model identified poor structural features in the carboxyl terminus that, when further studied using hydrophobic moment analysis, detected an atypical structural property in helix D, which contains Cys 130 and Cys142. This analysis demonstrated that helix D had a hydrophobic surface exposed to bulk solvent that accounted for the poor quality of the model, but was suggestive of a region in IL-7 that maybe important for protein interactions. Alanine (Ala) substitution scanning mutagenesis was performed to test if the predicted atypical surface chemistry of helix D in the hIL-7 model is important for receptor activation. This analysis resulted in the construction, purification, and characterization of four hIL-7 variants, hIL-7(K121A), hIL-7(L136A), hIL-7(K140A), and hIL-7(W143A), that displayed reduced or abrogated ability to stimulate a murine IL-7 dependent pre-B cell proliferation. The mutant hIL-7(W143A), which is biologically inactive and displaces [125I]-hIL-7, is the first reported IL-7R system antagonist.

Laser scar revision: comparison of CO2 laser vaporization with and without simultaneous pulsed dye laser treatment.

BACKGROUND: Over the past decade, the 585-nm pulsed dye laser (PDL) has been used successfully to treat a variety of cutaneous vascular lesions as well as hypertrophic scars. Laser scar revision has been revolutionized by the recent development of high-energy, pulsed carbon dioxide (CO2) laser systems. These new CO2 lasers allow controlled vaporization of thin layers of skin while minimizing damage to surrounding dermal structures. OBJECTIVE: To determine the effect of a high-energy, pulsed CO2 laser alone and in combination with a 585-nm PDL on nonerythematous hypertrophic scars. METHODS: Twenty patients with nonerythematous hypertrophic scars were treated with a high-energy, pulsed CO2 laser. One-half of each scar was additionally treated with the 585-nm PDL laser. Sequential clinical and photographic analyses were performed independently by two blinded assessors. In addition, erythema reflectance spectrometry measurements were obtained from the scars before and at regular postoperative intervals. RESULTS: Global assessment scores and erythema spectrometry measurements were significantly improved after laser treatment. Combination CO2 and PDL laser treatment resulted in more significant improvement than CO2 laser irradiation alone. CONCLUSION: Concomitant use of the high-energy, pulsed CO2 and PDL laser systems was superior to CO2 laser vaporization alone for revision of nonerythematous hypertrophic scars. Once again, the vascular specificity of the 585-nm PDL has been linked to improvement in hypertrophic scar tissue.

Multiple trichoepitheliomas successfully treated with a high-energy, pulsed carbon dioxide laser.

BACKGROUND: Multiple trichoepitheliomas are transmitted in an autosomal dominant fashion and can be clinically disfiguring. As with other dermal tumors, destructive techniques such as cryotherapy, electrodesiccation, and radiation therapy can improve the cosmetic appearance, but each of these treatments carries a significant risk of side effects and recurrence. OBJECTIVE: We describe a patient with a severe case of recurrent multiple trichoepitheliomas following excision, cryotherapy, and electrodesiccation. RESULTS: Treatment with a high-energy, pulsed carbon dioxide laser produced an excellent clinical response with no recurrence noted in the treated area for 12 months. CONCLUSION: Laser vaporization of trichoepitheliomas using a pulsed carbon dioxide delivery system may provide superior clinical results without scanning and evidence of regrowth.

Comparison of the Q-switched alexandrite (755 nm) and Q-switched Nd:YAG (1064 nm) lasers in the treatment of benign melanocytic nevi.

BACKGROUND: A variety of pigmented lesions have been shown to be effectively treated with several pigment-specific laser systems currently available. There has been recent evidence to indicate that they may also be useful in the treatment of melanocytic nevi. OBJECTIVE: To compare the clinical and histologic effects of the Q-switched (QS) alexandrite (755 nm) and Nd:YAG (1064 nm) lasers in the treatment of melanocytic nevi. METHODS: Eighteen patients received three QS alexandrite and Nd:YAG laser treatments to either half of a large nevus or to two small adjacent nevi. Tissue biopsies were obtained for histologic examination. Degree of clinical improvement was determined by comparative photographic global assessment scores. The amount of melanin present within the nevi before and after laser irradiation was measured by reflectance spectrometry. RESULTS: Clinical global assessment scores were significantly reduced in all QS alexandrite and QS Nd:YAG laser-treated nevi after three treatments. Melanin reflectance spectrometry scores improved after the first laser treatment only. Histologically, a significant reduction in epidermal pigmentation and melanocytes were observed following laser irradiation with either QS system. CONCLUSION: Both the QS alexandrite and Nd:YAG laser systems resulted in significant improvement (lightening) of treated nevi. The QS alexandrite laser produced slightly better results using the parameters outlined.

Long-term low-dose cyclosporine therapy for severe psoriasis: effects on renal function and structure.

BACKGROUND: The effectiveness of cyclosporine in the treatment of severe psoriasis is well known. OBJECTIVE: We evaluated the efficacy and toxicity of systemic cyclosporine in patients with severe psoriasis, observing short-term (12 weeks) and long-term (3 to 5 years) effects. METHODS: To further elucidate efficacy and safety, 42 patients with severe psoriasis were treated initially with cyclosporine 5 to 6 mg/kg per day for 12 weeks. A subset of 14 patients continued maintenance treatment for 3.5 years to study the long-term effects of cyclosporine on renal function and structure. Renal biopsies were performed after 2.5 years and 3.5 years of treatment. Renal histologic findings were correlated with renal function. RESULTS: By weeks 8 and 12, 64% (n = 27) and 86% (n = 36) of patients, respectively, were rated clear or almost clear of the psoriasis. However, a subpopulation of 15 patients did not respond to 5 mg/kg daily but improved when the dose was increased to 6 mg/kg daily. Clearance or near clearance was achieved in 67% of this subpopulation after 4 weeks. For the 29 patients whose glomerular filtration rate (GFR) was measured, mean GFR fell by 7% from baseline to week 4 (p < 0.05). This change was reversible when dosage was reduced by 1 mg/kg per day in each of these patients. Patients older than 45 years of age experienced significant elevation of mean diastolic blood pressure and had reduced GFR and increased serum creatinine. After 2.5 years, of the 14 patients who continued maintenance treatment, two had biopsy specimens that showed moderate interstitial fibrosis and tubular atrophy. The remainder showed only minimal to mild structural damage. After 3.5 years of cyclosporine treatment, repeat renal biopsy specimens revealed slight increases in structural changes in nine subjects. These changes correlated with increasing age and drug-induced hypertension. CONCLUSION: We conclude that 5 mg/kg of cyclosporine daily is usually an effective initial dose for psoriasis. Patients who do not respond will often benefit from elevation of the dose to 6 mg/kg daily. Older patients experience cyclosporine-induced hypertension and changes in renal function and structure more frequently than do younger patients.

Cutaneous lasers: a review.

Lasers are versatile instruments capable of treating an ever-increasing array of cutaneous conditions. Various vascular, pigmented, epidermal, and dermal lesions can be selectively destroyed without damaging normal uninvolved skin structures by utilizing lasers that correspond to the absorption characteristics of the intended target. Recently, lasers have been used with much success in the treatment of rhytides, photodamaged skin, and scarring. The rapid development of laser technology has made many lasers obsolete that only a few years ago were considered state of the art. Lasers are more reliable, emit light at higher energies with shorter pulse widths, and at faster delivery rates. As is typically the case with high-technology devices, lasers are becoming less expensive and more consolidated. For this reason, laser techniques will continue to evolve and new indications for their use will, no doubt, be discovered in the near feature. Physicians treating the skin are in a unique position to study the clinical and histological effects of lasers, as the skin remains an easy-access organ. Laser medicine and surgery will continue to be enhanced by the contributions made through the investigative efforts of laser surgeons treating the skin.

The introduction of a methadone prescribing programme to a drug-free treatment service: implications for harm reduction.

In 1990, a National Health drug treatment service with a non-opiate prescribing policy introduced an oral methadone treatment programme for problem opiate users, in addition to existing counselling services. The present study aimed to evaluate the implications of this policy change by comparing two client groups in terms of defined harm reduction variables. The groups consisted of 39 clients presenting to the service prior to methadone prescribing (pre-methadone group), and 41 clients who attended for treatment after methadone prescribing had commenced (post-methadone group). Data analysis revealed that 83% of the post-methadone group remained in treatment for longer than 6 months, in comparison with 13% of clients in the pre-methadone group (p < 0.00001). Other significant differences were noted in treatment outcome, where findings indicated that clients in the post-methadone group were more likely to report cessation of injecting behaviour and continued illicit drug use. Detected crime in the post-methadone group was reduced, and greater positive change in terms of personal relationships was reported. The study concludes that the introduction of a methadone treatment programme appears to have improved treatment outcome significantly for problem opiate users presenting in the service.