Methotrexate-induced cutaneous ulceration in patients with erythrodermic mycosis fungoides

Methotrexate-induced cutaneous ulceration has rarely been reported in patients with mycosis fungoides. We report 4 patients with mycosis fungoides who developed cutaneous ulceration as an initial manifestation of methotrexate toxicity. Methotrexate dose at the time of ulceration ranged from 10–60 mg. All 4 patients were erythrodermic, which may have predisposed them to this toxic effect. It is important to recognize cutaneous ulceration as an uncommon, but potentially serious, side effect of methotrexate in these patients, and to differentiate it from ulceration due to progressive lymphoma

Long-term effects of total skin electron beam therapy for mycosis fungoides on hair and nail loss and regrowth

Objective To better document the risk of permanent hair and nail loss after total skin electron beam therapy (TSEBT) for mycosis fungoides (MF). Methods Interviews and evaluations were conducted in 13 patients with MF treated with TSEBT alone and two patients treated with concomitant TSEBT and chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Evaluated parameters included time to hair and nail loss and regrowth, the density of hair regrowth, and quality of hair and nail regrowth. Results Most patients had complete loss of scalp hair during treatment, and new growth appeared about 2 months following treatment completion. After 18 months, most patients felt their hair had regrown to about 70% of baseline thickness without cosmetically obvious alopecia. The patients treated with TSEBT and concomitant chemotherapy had substantially less scalp hair regrowth with persistent cosmetically obvious alopecia. Some lost eyebrows and eyelashes, but complete or near-complete regrowth generally occurred. Most patients lost their nails following TSEBT, with complete regrowth noted by most patients 5 months after treatment. New nails were most often normal, but a few patients developed post-therapy nail dystrophies. Conclusion This data can be used to better inform patients of likely long-term changes of hair and nails following TSEBT

Atypical vascular lesions extending outside the radiation field: a diagnostic challenge

Atypical vascular lesion (AVL) is an uncommon, benign vascular proliferation seen in previously irradiated skin, most commonly after radiotherapy for breast cancer. Atypical vascular lesion and angiosarcoma may share overlapping clinical and histopathologic features. We report the first case of AVL occurring outside the field of radiation. This patient's clinical course and histopathology was overall consistent with AVL, including two biopsies with focal MYC positivity. However, due to variations in the interpretation of her histopathology, the management plans devised by two centers involved in her care were widely discordant and she was treated with chemotherapy and extensive surgery for angiosarcoma. Great care must be taken to distinguish between these entities, as treatment for angiosarcoma may be associated with significant morbidity

Elimination of Staphylococcus aureus Nasal Carriage in Health Care Workers: Analysis of Six Clinical Trials with Calcium Mupirocin Ointment

Six double-blind, independently randomized studies evaluated the efficacy and safety of calcium mupirocin ointment in eliminating nasal carriage of Staphylococcus aureus among health care workers. Healthy volunteers with stable nasal carriage of S. aureus (n = 339) received either calcium mupirocin ointment (n = 170) or an identical placebo ointment (n = 169) intranasally for 5 days. Nasal carriage was eliminated 48–96 hours after completion of treatment in 130 (91%) of 143 evaluable volunteers receiving mupirocin but in only 8 (6%) of 142 evaluable volunteers receiving placebo. The 85% crude difference represents a 90% pooled (adjusted) estimate of the risk difference (95% confidence interval, 0.86–0.95) and a risk ratio of 16 (P \u3c.0001). This effect of treatment with mupirocin was observed consistently (risk ratio, 8–32) in all six centers. In addition, 96 of the 130 mupirocin-treated volunteers and 1 of the 8 placebo-treated volunteers who were culture-negative at the end of therapy remained free of S. aureus 4 weeks after treatment. Adverse events in each treatment arm were mild and equally frequent. These data, consistent across six institutions, demonstrate that calcium mupirocin ointment administered intranasally for 5 days is safe and effective in eliminating stable nasal carriage of S. aureus

Broken-Symmetry DFT Computations for the Reaction Pathway of IspH, an Iron–Sulfur Enzyme in Pathogenic Bacteria

The recently discovered methylerythritol phosphate (MEP) pathway provides new targets for the development of antibacterial and antimalarial drugs. In the final step of the MEP pathway, the [4Fe–4S] IspH protein catalyzes the 2<i>e</i>^–/2H⁺ reductive dehydroxylation of (<i>E</i>)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) to afford the isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). Recent experiments have attempted to elucidate the IspH catalytic mechanism to drive inhibitor development. Two competing mechanisms have recently emerged, differentiated by their proposed HMBPP binding modes upon 1<i>e</i>^– reduction of the [4Fe–4S] cluster: (1) a Birch reduction mechanism, in which HMBPP remains bound to the [4Fe–4S] cluster through its terminal C₄–OH group (ROH-bound) until the −OH is cleaved as water; and (2) an organometallic mechanism, in which the C₄–OH group rotates away from the [4Fe–4S] cluster, allowing the HMBPP olefin group to form a metallacycle complex with the apical iron (η²-bound). We perform broken-symmetry density functional theory computations to assess the energies and reduction potentials associated with the ROH- and η²-bound states implicated by these competing mechanisms. Reduction potentials obtained for ROH-bound states are more negative (−1.4 to −1.0 V) than what is typically expected of [4Fe–4S] ferredoxin proteins. Instead, we find that η²-bound states are lower in energy than ROH-bound states when the [4Fe–4S] cluster is 1<i>e</i>^– reduced. Furthermore, η²-bound states can already be generated in the oxidized state, yielding reduction potentials of ca. −700 mV when electron addition occurs after rotation of the HMBPP C₄–OH group. We demonstrate that such η²-bound states are kinetically accessible both when the IspH [4Fe–4S] cluster is oxidized and 1<i>e</i>^– reduced. The energetically preferred pathway gives 1<i>e</i>^– reduction of the cluster after substrate conformational change, generating the 1<i>e</i>^– reduced intermediate proposed in the organometallic mechanism

Use of Broken-Symmetry Density Functional Theory To Characterize the IspH Oxidized State: Implications for IspH Mechanism and Inhibition

With current therapies becoming less efficacious due to increased drug resistance, new inhibitors of both bacterial and malarial targets are desperately needed. The recently discovered methylerythritol phosphate (MEP) pathway for isoprenoid synthesis provides novel targets for the development of such drugs. Particular attention has focused on the IspH protein, the final enzyme in the MEP pathway, which uses its [4Fe–4S] cluster to catalyze the formation of the isoprenoid precursors IPP and DMAPP from HMBPP. IspH catalysis is achieved via a 2<i>e</i>^–/2H⁺ reductive dehydroxylation of HMBPP; the mechanism by which catalysis is achieved, however, is highly controversial. The work presented herein provides the first step in assessing different routes to catalysis by using computational methods. By performing broken-symmetry density functional theory (BS–DFT) calculations that employ both the conductor-like screening solvation model (DFT/COSMO) and a finite-difference Poisson–Boltzmann self-consistent reaction field methodology (DFT/SCRF), we evaluate geometries, energies, and Mössbauer signatures of the different protonation states that may exist in the oxidized state of the IspH catalytic cycle. From DFT/SCRF computations performed on the oxidized state, we find a state where the substrate, HMBPP, coordinates the apical iron in the [4Fe–4S] cluster as an alcohol group (ROH) to be one of two, isoenergetic, lowest-energy states. In this state, the HMBPP pyrophosphate moiety and an adjacent glutamate residue (E126) are both fully deprotonated, making the active site highly anionic. Our findings that this low-energy state also matches the experimental geometry of the active site and that its computed isomer shifts agree with experiment validate the use of the DFT/SCRF method to assess relative energies along the IspH reaction pathway. Additional studies of IspH catalytic intermediates are currently being pursued