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A chromosome is a single long DNA molecule assembled along its length with nucleosomes and proteins. During interphase, a mammalian chromosome exists as a highly organized supramolecular globule in the nucleus. Here, we discuss new insights into how genomic DNA is packaged and organized within interphase chromosomes. Our emphasis is on the structural principles that underlie chromosome organization, with a particular focus on the intrinsic contributions of the 10-nm chromatin fiber, but not the regular 30-nm fiber. We hypothesize that the hierarchical globular organization of an interphase chromosome is fundamentally established by the self-interacting properties of a 10-nm zig-zag array of nucleosomes, while histone post-translational modifications, histone variants, and chromatin-associated proteins serve to mold generic chromatin domains into specific structural and functional entities.

The GLS1 gene encodes a mitochondrial glutaminase that is highly expressed in brain, kidney, small intestine and many transformed cells. Recent studies have identified multiple lysine residues in glutaminase that are sites of N-acetylation. Interestingly, these sites are located within either a loop segment that regulates access of glutamine to the active site or the dimer:dimer interface that participates in the phosphate-dependent oligomerization and activation of the enzyme. These two segments also contain the binding sites for bis-2[5-phenylacetamido-1,2,4-thiadiazol-2-yl]ethylsulfide (BPTES), a highly specific and potent uncompetitive inhibitor of this glutaminase. BPTES is also the lead compound for development of novel cancer chemotherapeutic agents. To provide a preliminary assessment of the potential effects of N-acetylation, the corresponding lysine to alanine mutations were constructed in the hGACΔ1 plasmid. The wild type and mutated proteins were purified by Ni(+)-affinity chromatography and their phosphate activation and BPTES inhibition profiles were analyzed. Two of the alanine substitutions in the loop segment (K311A and K328A) and the one in the dimer:dimer interface (K396A) form enzymes that require greater concentrations of phosphate to produce half-maximal activation and exhibit greater sensitivity to BPTES inhibition. By contrast, the K320A mutation results in a glutaminase that exhibits near maximal activity in the absence of phosphate and is not inhibited by BPTES. Thus, lysine N-acetylation may contribute to the acute regulation of glutaminase activity in various tissues and alter the efficacy of BPTES-type inhibitors.

Phase separation has emerged as a new paradigm currently revolutionizing our understanding of cell biology and intracellular organization. Disordered protein domains have recently been demonstrated as integral drivers of phase separation into condensed liquids with emergent material properties. Using in vitro model systems employing purified protein components is necessary to interrogate the molecular mechanisms underlying phase separation; however, these systems pose many experimental challenges. In this chapter we describe general strategies for purifying, handling, imaging, and characterizing the phase behavior of disordered proteins. We further outline methods for the purification of the model P granule protein LAF-1, the construction of phase diagrams, and the quantification of liquid droplet fusion or coalescence.

SUMMARY Mycophenolic acid (MPA) is a fermentation product of a penicillium mould which has shown anti-tumour activity in certain animal models. It blocks nucleic acid synthesis by interfering with the interconversions of inosine monophosphate (IMP), xanthine monophosphate (XMP) and guanine monophosphate (GMP) thereby inhibiting growth and/or replication of tumour cells. In vivo activity depends on the presence of a β-glucuronidase which is abundant in the cell wall of epithelial tissues. Encouraged by results obtained in earlier clinical trials, we have studied 28 patients with psoriasis, 21 in double-blind fashion. A comparison of disease severity in patients before and after receiving MPA versus patients receiving placebo clearly showed the superiority of drug over placebo. The mean severity score of patients receiving MPA as an initial course of therapy improved by 56% versus 9% in patients receiving placebo. Patients receiving MPA after an initial course of placebo therapy showed improvement in their mean severity score averaging 86%. Those patients receiving placebo after an initial course of MPA showed worsening of their mean severity score averaging 70%. Overall, about 75% of MPA treated patients have shown good to excellent responses, and toxicity appears low. Evidence suggests that MPA may be very useful in treating severe psoriasis.

We have examined the properties of a new class of microfiltration and ultrafiltration membranes that are fabricated by assembling particles onto the surface of a microporous substrate and stabilizing the porous array into a composite. The particle array contains interstitial voids having a narrow size distribution that serve as channels for size sieving. This aqueous based technology has advantages relative to other membrane fabrication methods in terms of the control of asymmetry, the facile adjustment of pore size, and the ability to easily modify pore surfaces during the synthesis of particles. In this work we study the properties of the membranes (gas and water permeabilities) fabricated from different size particles and of varying thickness on a number of different supports. The experimental data is then analyzed with a standard model, Carman–Kozeny, to develop guidelines for the design of such membranes. For all of the composites, the volume porosity was found to be approximately 0.3, close to what would be expected for hexagonal closest packed array which corresponds to the visual appearance from electron micrographs. In this study, membranes with narrow pore size distributions from 0.038 to 0.122 μm were fabricated with fluxes three to four times higher than the commercial membranes of similar pore size manufactured by phase inversion processes.

Background: Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the ideal dosing regimen for treating psoriasis was not established. Objective: We examined the safety and efficacy of denileukin diftitox in patients with severe plaque-type psoriasis. Methods: This was a cohort dose-escalation trial. Patients were administered denileukin diftitox on 3 consecutive days every other week. Patients were evaluated for toxicity, improvement in psoriasis, immunogenicity, and serum levels. Results: Thirty-five patients were treated at 3 dose levels. Eight patients had a 50% decrease or more in Psoriasis Area and Severity Index score from baseline (0/10 at 0.5 μg/kg per day, 1/10 at 1.5 μg/kg per day, and 7/15 at 5 μg/kg per day). Adverse events primarily consisted of constitutional events and skin reactions. Conclusions: The potential antipsoriatic activity of denileukin diftitox demonstrated in this study was comparable to that observed in other psoriasis studies with this agent. However, this dosing regimen was better tolerated than the dosing regimen used in the last study with denileukin diftitox in psoriasis patients. (J Am Acad Dermatol 2001;45:871-81.)

Exposure of C3HBYB/Wq hairless (hr/hr) mice to ultra-violet radiation (UVR) for 15 days induced intense tanning of their dorsal skin. Small, dark freckles appeared first, gradually enlarging and coalescing as treatment progressed yielding a uniform tan. Histologically, the gross changes in skin color were matched initially by the appearance of scattered epidermal melanocytes that subsequently proliferated to form discrete, progressively expanding and abutting populations resulting in a uniform melanocyte network throughout the basal layer of the interfollicular epidermis. In contrast, when applied topically before each daily exposure to UVR, a cream or lotion vehicle containing both vitamins C and E (Vits C/E) inhibited UVR-induced erythema and tanning. Application of Vits C/E, both before and after irradiation, was no more effective in providing photoprotection than pre-treatment only. At the tissue level, UVR-induced proliferation and melanogenesis of melanocytes were reduced compared with irradiated controls. The density of individual melanocyte populations was reduced, as was the number of melanocyte populations achieving merger (confluence) with others. Confluence grades and cell counts, estimating the maximum density of melanocyte populations in UVR-Vits C/E-treated mice, were approximately two thirds those of UVR-vehicle-treated controls. However, tanning was only one fifth that of UVR-vehicle-treated controls, suggesting that melanogenesis was also inhibited. In addition to its inhibitory actions on irradiated melanocytes, Vits C/E also inhibited UVR-induced suppression of contact hypersensitivity (CHS) in haired (Hr/hr) and hr/hr mice of the C3HBYB/Wq strain. The common denominators for most, if not all, of the influences of topically-applied Vits C/E in muting the responses of the melanocyte and immune systems to UVR may stem from the vitamins' combined ability to suppress UVR-stimulated inflammation and its associated cascade of mediators.

The modification of an emulsion polymerization with a water-miscible alcohol and a hydrocarbon nonsolvent for the polymer can influence the morphology of the particles. The formation of monodispersed particles with a hollow structure or diffuse microvoids is possible. Both kinetic and thermodynamic aspects of the polymerization dictate which particle morphology is obtained. Complete encapsulation of the hydrocarbon occurs provided low molecular weight polymer is formed initially in the process. Subsequent addition of a cross-linking monomer stabilizes the morphology. The final particle size can be defined by small nucleating latex seed particles. Monodispersed hollow particles with diameters from 0.2 to 1 μm are possible. Void fractions as high as 50% are feasible. The phase separation of polystyrene within the styrene−isooctane dispersion has been modeled with the Flory−Huggins theory. The encapsulation has been discussed in terms of interaction parameters, transport processes, polymer molecular weight, ...

BACKGROUND An increase in the proportion of prostate carcinomas diagnosed at early, potentially curable stages has led to several changes in treatment of patients with this disease. Greater use of radical prostatectomy and external beam radiation has been documented, and recent data suggest that the use of radiation implant (brachytherapy) also has increased. Recent results from the National Cancer Data Base (NCDB) are available to explore this trend in greater detail. METHODS Data provided by 1758 hospital cancer registries for 435,264 patients diagnosed between 1992 and 1996 were studied. Reported use of brachytherapy was analyzed by year of diagnosis, region, patient age at diagnosis, and tumor grade. RESULTS The proportion of all prostate carcinoma patients treated with brachytherapy increased from 1.4% in 1992 to 3.0% in 1995. Ninety-six percent of brachytherapy patients were American Joint Committee on Cancer Stage I or II (with tumors classified as T1 or T2). As a proportion of patients in a stage group, the use of brachytherapy was greatest in Stage I; 3.7% of patients in this stage were treated by this modality. The increase in brachytherapy also was greatest among Stage I patients, rising from 2.0% in 1992 to 5.8% in 1996. Rates of use were greatest in the northeastern and southeastern U.S. and least frequently reported by institutions in the Midwest and the South. Brachytherapy was used across a wide range of patient age groups. Analysis by grade showed that 89.8% of patients treated with brachytherapy had well-differentiated or moderately differentiated tumors. CONCLUSIONS Brachytherapy represented a small component of the overall pattern of care for prostate carcinoma patients in the U.S. during the interval studied. However, the rate of use of this modality for patients with localized prostate carcinoma increased substantially over the 5-year interval. This may reflect a trend toward more conservative management of prostate carcinoma. Additional monitoring and analysis of the more recent use of brachytherapy for the treatment of prostate carcinoma patients is warranted. [See editorial on pages 1632–4, this issue.] Cancer 1999;86:1877–82. © 1999 American Cancer Society.

Skin cancer is the most frequently diagnosed cancer in the United States. Melanoma is the major cause of deaths due to skin cancer, however, squamous cell carcinoma and basal cell carcinoma account for considerable morbidity also. All three types are potentially curable if diagnosed at an early stage. Visual examination of the skin by a trained observer is a simple and effective screening tool which may be utilized in a multitude of settings. Patient education and self-examination augment the impact of office-based screening and mass screening programs.

The National Cancer Data Base (NCDB), a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, collects and analyzes data from a wide variety of sources throughout the United States, including small community hospitals. Due to this unique reporting system, individual facilities can compare their own data with the aggregate data from the NCDB, using their findings to evaluate local patient care practices. This article highlights the principal findings of the NCDB and Patient Care Evaluation articles published in 1998 on breast, prostate, cervical, endometrial, gallbladder, head and neck, nasopharyngeal, rectal, thyroid, and vaginal cancers, as well as on melanoma, brain tumors, and Hodgkin's disease. With more than five million cancer cases in the NCDB for the years between 1985 and 1995, sufficient numbers of even rare cancers have been accrued to permit some types of epidemiologic and clinical assessments.

A new class of microfiltration (MF) and ultrafiltration (UF) membranes has been developed. By placing latex particles onto the surface of a microporous substrate and stabilizing the porous array, voids are formed between the particles which provide narrowly distributed pores that serve as separation channels. The size of the interstitial voids in the array is governed by the diameter of the latex particle. This aqueous based technology has advantages relative to other membrane fabrication processes in terms of the high asymmetry of the membranes, the facile adjustment of pore sizes, and the ability to easily modify pore surfaces during the synthesis of particles. A number of approaches were examined for placement of particles and stabilization of latex composite membranes (LCMs). Filtration of particles with reactive surface groups that provide covalent linkages at the contact points in the particle array proved most effective in obtaining stable membranes. These membranes had narrow size distributions in both the UF and MF range and were capable of being cleaned and backflushed. The membranes were characterized in terms of gas permeabilities, pure water permeabilities and electron microscopy. The rejection properties of LCMs were also examined during filtration of monodispersed latex particles and a broadly dispersed dextran mixture.

As with other pharmacologic agents used in the treatment of human disease, the administration of anticancer drugs often results in toxic adverse effects to the skin, hair, and nails. Toxic drug reactions in the skin may occur as idiosyncratic or allergic drug reactions at ordinary therapeutic drug dosages or in a dose-dependent manner. In general, three classes of anticancer agents have unique dermatologic toxicities: cytotoxic chemotherapy, radiation therapy, and targeted anticancer therapy.

Pili annulati is a rare autosomal-dominant hair shaft abnormality. It is characterized by alternating light and dark bands along the shaft due to air-filled cavities within the cortex of the hair shaft. Alopecia areata has been previously described as a common association with pili annulati, with improvement in alopecia areata coinciding with resolution of pili annulati. We report the case of a patient with a history of alopecia areata and alopecia universalis who developed the characteristic banded hair of pili annulati upon resolution of her alopecia areata. We provide direct microscopic examination of postregrowth hairs compared to normal and cross-polarized light microscopy.

Each May since 1984, the American Academy of Dermatology, using dermatologist members and American Cancer Society volunteers, has conducted a National Melanoma/Skin Cancer Prevention Program. Through free patient screenings at hospitals, community centers, and health fairs, more than 600,000 individuals have been reached. Through its educational and screening functions, this program has been considered «one of the finest examples of preventive medicine in the country» and as a model for other mass screening programs. This paper reviews some of the concepts that guide the Academy's screening program, some organizational aspects of the program, its accomplishments to date, and possible future directions

Rabbit polyclonal antibodies against isoproterenol-induced mouse proline-rich proteins (PRPs) were used to localize PRPs in the parotid salivary glands of normal adult BALB/c mice. The antibodies recognized both acidic-type and basic-type PRPs. Immunoblotting experiments revealed that the glands contained an acidic-type and a basic-type PRP. Parotid gland tissue was fixed with Karnosky's fixative and embedded in Lowicryl resin at low temperature. PRPs were localized at the electron microscope level using an indirect post-embedding staining technique with protein A-gold. The secretion granules of the acinar cells were strongly labelled. Pre-absorption of the antibody with purified acidic-type and basic-type PRPs indicated that the basic-type PRP is mainly located at the periphery of the granules but that the acidic-type PRP is more evenly distributed within the granules. Pre-absorption of the antibody with alpha-amylase did not affect the staining pattern, suggesting minimal cross-reactivity. PRPs were also detected within the rough endoplasmic reticulum and the Golgi apparatus of acinar cells, within the granules of the proacinar cells and in the lumena of the ducts, but not within the intercalated or striated duct cell granules.

cDNA clones for mRNA sequences regulated by isoprenaline in mouse parotid glands were identified by differential colony hybridisation and all hybridised to a diagnostic proline-rich protein (PRP) oligonucleotide. They were divided into two cross-hybridisation groups, A and B, which were shown by hybrid-selected translations to encode acidic PRP and basic PRP, respectively. The A-type subgroup consisted of sequences homologous to the previously identified mouse PRP genes MP2 and MP3. The B-type subgroup comprised clones for the previously identified cDNA pUMP125 (MP4) as well as other PRP sequences. Six of the B-type clones contained a novel PRP cDNA (MP5) and these were sequenced. The composite MP5 cDNA was 897 nucleotides long and contained an open reading frame capable of encoding a 260-residue-long salivary PRP precursor (30% Pro, 19% Gln and 18% Gly), containing nine variant repeat units of consensus PGNQQGPPPQGGPQQ(GPP)R(PPQ). MP5 was 80% identical to the sequence of MP4 and had a high degree of similarity (60%) at its 3′-untranslated region to rat salivary glutamate/glutamine-rich protein (GRP) cDNA. Two MP5 clones contained a 273-bp intron-like insertion in the 3′ untranslated region, being derived, therefore, from incompletely spliced MP5 transcripts. Northern blotting showed that, although PRP mRNA species were induced by isoprenaline, a B-type PRP mRNA was present in normal parotid glands. RNA dot-blots probed with PRP-genespecific oligonucleotides established that MP3, MP4 and MP5 PRP mRNA were all induced by isoprenaline.

A mouse genomic B-type proline-rich protein (PRP) cosmid clone was isolated by cDNA hybridisation and mapped, the gene region was subcloned and 3770 bp were sequenced. This gene (MP4) contained three introns and encoded a 1020-nt (nt, nucleotide) mRNA for a PRP precursor 300 amino acids long arranged with 11 imperfect 18-residue proline-rich repeats. The transcriptional start point was determined by S1 nuclease mapping and primer extension to be 26 bp downstream of a TATAA sequence. Sequence comparisons revealed that only two regions from positions -650 bp - -30 bp were highly conserved in all other PRP genes, PRP boxes 1 and 2. Box 1 at positions -112 to -135 contained ets-like and rel/NFkB-like elements and was 74% conserved over 23 bp. Box 2 at positions -33 - -51 was 53% conserved over 19 bp. A search of the EMBL and GenBank sequence libraries indicated that PRP box 1 was only present upstream of the known mammalian PRP gene sequences and was absent from other genes. These conserved sequences may thus be relevant to the tissue-specific and beta-adrenergic regulation of PRP gene transcription.

In the first 24 h after a single injection of the β-adrenergic agonist isoprenaline to mice, the level of β-actin mRNA in the parotid glands increased significantly above that observed in untreated mice. The increase was transient, reaching 11 times the normal level 18 h after treatment and declining thereafter. Repeated daily doses of isoprenaline did not result in any further increase in β-actin mRNA. Nuclear transcription experiments showed that there was no increase in the transcription rate of the β-actin gene 8 h after an injection of isoprenaline, although β-actin mRNA levels were increasing at this time. Immunoblotting revealed an increase in β-actin protein in parotid gland samples after isoprenaline treatment, although the increase was not to the same extent as the mRNA, perhaps indicating that degradation of β-actin had also increased. Using immunocytochemistry it was found that β-actin was located mainly in the apical cortex of the normal acinar cell. There was a significant decrease in cortical β-actin 24 h after isoprenaline treatment, suggesting that the β-actin was under the process of redistribution. From these data we propose that isoprenaline caused an increase in β-actin synthesis by a post-transcriptional mechanism and a redistribution of β-actin in preparation for the well-known subsequent change in morphology and function of the parotid glands.

Multicentric reticulohistiocytosis (MRH) is a rare histocytic disease characterized by destructive arthritis in association with classic skin findings. Although MRH is not strictly a paraneoplastic disease, one quarter of cases are malignancy related. We report a case of MRH with an initial remission followed by an acute exacerbation several years later heralding the clinical presentation of endometrial carcinoma. During this flareup a skin biopsy specimen revealed a diffuse dermal infiltrate composed of histiocytes with ground-glass cytoplasm and multiple atypical mitoses. Approximately 40% of the cells stained with the proliferation marker Ki-67. Treatment of endometrial carcinoma resulted in improvement of skin and joint symptoms, and a repeat biopsy specimen no longer demonstrated mitotic figures. These findings support a reactive and proliferative cause of MRH.

One of the major developments in emulsion polymerization over the last two decades has been the ability to make hollow latex particles. This has contributed many fundamental insights into the synthesis and the development of structure in particles. Hollow latex particles also enhance the performance of industrial coatings and potentially are useful in other technologies such as microencapsulation and controlled release. Ever since the publication of the initial process patents describing these particles, there has been a global R&D effort to extend the synthetic techniques and applications. One prominent synthetic approach to hollow particles is based on osmotic swelling. This dominates the literature, and usually starts with the synthesis of a structured latex particle containing an ionizable core that is subsequently expanded with the addition of base. Fundamental to this approach are a sophisticated control of transport phenomena, chemical reactivity within the particle, and the thermoplastic properties of the polymer shell. Hydrocarbon encapsulation technology has also been employed to make hollow latex particles. One approach involves a dispersed ternary system that balances transport, conversion kinetics, and phase separation variables to achieve the hollow morphology. Other techniques, including the use of blowing agents, are also present in the literature. The broad range of approaches that affords particles with a hollow structure demonstrates the unique flexibility of the emulsion polymerization process.

Background: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. Objective: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. Methods: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. Results: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steady-state concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. Conclusion: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global outcomes. (J Am Acad Dermatol 1998;38:S110-6.)

Proline-rich protein (PRP) gene MP6 was isolated from a mouse BALB/c genomic DNA library in lambda EMBL3, characterised by hybridisation and restriction mapping and the promoter region, from -162 to +72 around the PRP consensus cap-site, was sequenced. In gel shift assays this region formed complexes C1 and C2 with parotid nuclear proteins which were induced by the beta-adrenergic agonist isoprenaline. DNA competition studies and direct binding assays of promoter subfragments showed that it was the sequence from -157 to -91 that was forming the isoprenaline-dependent complexes. All PRP genes conserve a 23bp. sequence, termed PRP Box1, with ets and NFkB/rel binding site-like elements, upstream of their promoters. In the MP6 promoter, PRP Box1 was within the region forming the complexes. Further gel shift assays using PRP Box1 oligonucleotides as competitors and targets indicated that the NFkB/rel binding site-like element was important in formation of the isoprenaline-inducible complexes. HeLa nuclear extracts also formed complexes with PRP Box1 similar to C1 and C2 but nuclear extracts from spleen, submandibular gland and liver did not. These complexes are thus candidate regulators for the isoprenaline-dependent and tissue-specific transcription of PRP genes.

Background and Design: The treatment of advanced mycosis fungoides is a therapeutic challenge. A variety of treatment approaches have been used. In our experience, chemotherapy has been most useful. The purpose of this study was to evaluate the effectiveness of the synergy previously demonstrated between methotrexate and fluorouracil in the treatment of advanced mycosis fungoides. Ten patients with mycosis fungoides and Sezary syndrome stages Ha (n=1), II-b (n=4), III (n=1), IVa (n=2), and IVb (n=2) were treated with sequential methotrexate followed by fluorouracil and leucovorin rescue. Each patient received several courses of chemotherapy at varying intervals, as required for control of their disease. Results: The duration of treatment ranged from 3 to 78 months, with an average duration of 33 months. The number of cycles of chemotherapy administered to each patient ranged from five to 45, with an average of 18 infusions per patient. The average survival in patients with tumors was 5.25 years, with a median survival of 6 years. Eight of 10 patients achieved at least 80% clearing and the remaining two achieved at least 60% clearing. Adverse reactions were minimal and included nausea and vomiting, mucositis, and leukopenia in only one patient. Conclusion: Sequential methotrexate and fluorouracil chemotherapy is an effective and safe treatment for advanced mycosis fungoides and Sezary syndrome. This regimen is extremely well tolerated, with minimal toxic side effects. (Arch Dermatol. 1995;131:307-313)

Wolverton and Wilkin prefaceSystemic Drugs for Skin Diseaseswith this statement, "This text represents an attempt to increase the clinician's skill and comfort, while minimizing the anxiety that commonly accompanies the use of systemic agents for dermatologic problems. The focus of the book is clearly on `how to use' and `how to use safely' the spectrum of systemic drugs prescribed by dermatologists." This book, the work of 21 authors, is designed principally for the use of clinicians in dermatology and physicians in the primary care specialties. Initially, as I scanned through the table of contents and the outline of the book's 17 chapters, I was bothered by the paucity of topics that were authored by generally acknowledged experts. True, many of the authors are well-known dermatologists, but one does not generally associate them with discussions of drugs such as cyclosporine or methotrexate. Yet, in most areas, the authors have

To the Editor.— Immunosuppressive therapy with cyclosporine introduced in the 1970s dramatically improved the survival of kidney, liver, and heart transplants. The reported use of cyclosporine for treatment of dermatological disease is increasing in frequency, and favorable responses have been observed in the treatment of psoriasis, Behcet's disease, bullous pemphigoid, pemphigus vulgaris, dermatomyositis, polymyositis, ichthyosis, and several other cutaneous disorders.1We report on the successful treatment of a patient with severe bullous erythema multiforme that had previously responded only partially to high dosages of systemic corticosteroids. Report of a Case.— A 23-year-old white woman was referred to our dermatology service in August 1987 for evaluation of a bullous eruption of 3 years' duration. The patient was in good health until 1984 when, approximately 1 week after a dental procedure, she developed a generalized eruption and oral ulcerations. The initial eruption cleared after an intramuscular dose of penicillin. Four

Raynaud's syndrome is a relatively common conditions that is seen principally in young women. Although previously thought to be idiopathic in most patients, it has recently been estimated that an underlying disease is present in 50 to 100 per cent. Presented is the latest information on the cause, diagnosis, and treatment of this increasingly common vascular disorder.

SUMMARY The effects of trimethylpsoralcn and 8-mcthoxypsoralen on the pigmentary characteristics of cultured murine melanoma cells were investigated in the absence of ultraviolet irradiation. Stimulation of pigmentation was assayed by gross examination of centrifuged cell pellets, light microscopy of cells, electron microscopy, a biochemical determination of cell tyrosinase activity, and a chemical determination of cell melanin content. It was found that an adequate concentration (10-5 M) of trimethylpsoralen for an adequate exposure time stimulated pigmentation in the dark, whereas 8-methoxypsoralcn in the same experimental setting did not stimulate pigmentation.

In an effort to improve clinical response and reduce systemic toxicity, nine patients with recalcitrant psoriasis were treated with rational combinations of chemotherapeutic agents. Five patients received methotrexate by injection, 7.5 or 10 mg, followed 1 hour later by intravenous 5-fluorouracil, 170 to 562 mg/m2, on a weekly schedule. Four patients received oral triacetyl-azauridine, 2 to 4 gm daily, in combination with intravenous 5-fluorouracil, 225 to 600 mg/m2, administered every week. Three patients experienced greater than 75% clearing of disease, five patients experienced greater than 50% clearing, and only one patient failed to respond. Response rates did not differ between the two treatment groups. Adverse effects of these therapies were mild and infrequent. We conclude that 5-fluorouracil in combination with either methotrexate or triacetyl-azauridine is a relatively safe and effective alternative for the therapy of patients with severe psoriasis.

Five major basic polypeptides with characteristics typical of proline-rich proteins, accumulated in parotid glands after long term isoprenaline treatment of Balb C mice. They were studied by two-dimensional gel electrophoresis and designated B1 degree, B2' degrees, B2 degrees, B3 degrees and B4 degrees on the basis of pI-dependent mobility. They were not observed in the glands of normal mice and were precipitated when glands were homogenized in 10% trichloroacetic acid unlike the three isoprenaline-induced proline-rich proteins of murine parotid glands reported previously. Isoprenaline induced six proline-rich in vitro translation products which were absent normally. Four of these species had pI-dependent mobilities almost identical to B1 degree, B2 degrees, B3 degrees and B4 degrees, indicating not only precursor/product relationships, but also that isoprenaline induced the accumulation of the proteins by regulating the mRNA. Identical salivary counterparts of the basic glandular proline-rich proteins were not detected whereas a series of smaller and more basic isoprenaline-induced polypeptides were observed in saliva (major speices B1s-B4s). The glandular proline-rich proteins were secreted from parotid tissue in vitro and the data indicate that proline-rich proteins are synthesised as precursors and processed into salivary form in the parotid glands after secretion. The relationships between the B-type in vitro translation products, parotid gland precursors and salivary proteins were also confirmed immunologically.

Spectrometrie RMN et IR de polymere obtenu en presence de rayonnement gamma ou d'hydroxyde de sodium

The structure of a 70/30 ethyl acrylate-acrylamide latex made in a semi-continuous process with surfactant has been investigated. The molar composition and relative concentration of the polymers in the serum phase, on the surface and in the particle were characterized by coupling a filtration procedure, serum replacement, with carbon-13 NMR spectroscopy. The development of polymer in the different phases could be monitored by taking samples at timed intervals during the polymerization. Post-treatment of the latex with sodium hydroxide selectively hydrolyzed the copolymerized ethyl acrylate in the serum and on the surface. By measurement of spin lattice relaxation times it was possible to estimate surface concentration of oligomeric polymer

The skin should not be thought of as an isolated organ system. When the skin is involved by disease, other organs may be affected as well. Cutaneous xanthomas commonly occur with plasma lipid abnormalities, necrobiosis lipoidica diabeticorum with diabetes mellitus, and the porphyrias with altered heme synthesis. Erythema multiforme and erythema nodosum may be considered hypersensitivity reactions, occurring in response to a wide range of inciting agents, including infections, drugs, neoplasms, and rarely, collagen vascular diseases.

Testosterone controls the synthesis of seminal vesicle protein F in male rats by regulating the cellular concentration of its mRNA (mRNAF). Phage lambda recombinants have been isolated containing the complete F gene. In addition plasmids have been constructed containing cDNAF sequences some of which are probably full-length (approximately 700 bp). Detailed restriction mapping shows that the F gene is 1.7 kbp long and contains approximately 1.0 kbp of intervening sequence arranged in at least two introns (420 bp and 600 bp). Part of cDNAF has been sequenced showing that the terminal 125 bp of the 3' untranslated region of mRNAF has substantial (greater than 70%) sequence homology with the 3' end of the mRNA coding for another androgen-dependent seminal vesicle protein (protein S). The cloned F gene has been detected in liver and seminal vesicle DNA along with an homologous but structurally different gene. The hormonal control of mRNAF was examined with cDNAF. A pronounced (approximately 3000-fold) differential response to testosterone was observed.

Seminal vesicle F gene, encoding an androgen-regulated serine-rich structural protein of the rat copulatory plug, has been sequenced together with 5' and 3' flanking regions. The intron/exon arrangement of the gene deduced from restriction maps was confirmed. The major and possible minor transcriptional start points were located by primer extension analysis and S1 nuclease mapping. A published nucleotide sequence for seminal vesicle S gene which also encodes an androgen-regulated protein of the copulatory plug has been extended to allow comparison of F and S genes. The considerable sequence homology between the two genes confirms their evolutionary relatedness. Homology is especially high in their promoter regions and their transcriptional start points are identical. They share several regions of dyad symmetry including one just upstream of the promoter. The upstream regions of F and S genes were compared with those of five other androgen-responsive rodent genes in an attempt to identify common sequence motifs that might be involved in hormonal regulation of gene expression.