Distinctive histopathologic findings in linear morphea (en coup de sabre) alopecia.

Linear morphea en coup de sabre is a localized form of morphea that presents as paramedian face or frontal scalp depression. The histopathology of alopecia in linear morphea is typically characterized by sclerosis and a reduction in the number of follicular units. We present a 26-year-old Caucasian female with a 1.5-year history of linear morphea and alopecia with unique atrophic follicular remnants on scalp biopsy. Transverse and vertical sections of biopsy specimens showed dense, dermal sclerosis with marked eccrine gland atrophy and replacement of much of the adipose by collagenous tissue. All sebaceous glands had disappeared, but erector pili muscles persisted. Numerous vertical, columnar and epithelial structures were present at the sites of formerly viable hair follicles. Transverse sections of these atrophic follicular remnants had a resemblance to telogen follicles but were microscopically different. The morphology of these follicular remnants indicates an end-stage process or permanent alopecia. Similar follicular remnants have been reported in chemotherapy-induced permanent alopecia but not in alopecia secondary to morphea or other cicatricial alopecias. We discuss the significance of these findings and their relationship to other forms of cicatricial or permanent alopecia based on the literature and case review.

The crystal structure of MexR from Pseudomonas aeruginosa in complex with its antirepressor ArmR.

The intrinsic antimicrobial resistance of the opportunistic human pathogen Pseudomonas aeruginosa is compounded in mutant strains that overexpress multidrug efflux pumps such as the prominent drug-proton antiporter, MexAB-OprM. The primary regulator of the mexAB-oprM operon is the MarR family repressor, MexR. An additional repressor, NalC, also regulates mexAB-oprM by controlling expression of ArmR, an antirepressor peptide that is hypothesized to prevent the binding of MexR to its cognate DNA operator via an allosteric protein-peptide interaction. To better understand how ArmR modulates MexR, we determined the MexR-binding region of ArmR as its C-terminal 25 residues and solved the crystal structure of MexR in a 2:1 complex with this ArmR fragment at 1.8 A resolution. This structure reveals that the C-terminal residues of ArmR form a kinked alpha-helix, which occupies a pseudosymmetrical and largely hydrophobic binding cavity located at the centre of the MexR dimer. Although the ArmR-binding cavity partially overlaps with the small molecule effector-binding sites of other MarR family members, it possesses a larger and more complex binding surface to accommodate the greater size and specific physicochemical properties of a peptide effector. Comparison with the structure of apo-MexR reveals that ArmR stabilizes a dramatic conformational change that is incompatible with DNA-binding. Thus, this work defines the structural mechanism by which ArmR allosterically derepresses MexR-controlled gene expression in P. aeruginosa and reveals important insights into the regulation of multidrug resistance.

Papillary intralymphatic angioendothelioma of the thigh: A case report and review of the literature.

The term angiosarcoma, encompasses several neoplasms, all of which exhibit a malignant process derived from endothelial cells of the vessels. The most common form of angiosarcoma is highly aggressive, often fatal, and usually affects the head and neck region of elderly white men. Other low-grade forms of angiosarcoma, including papillary intralymphatic angioendothelioma, also known as Dabska tumor, are less invasive, affect a wider age range, and offer a better prognosis. There are several predisposing factors that increase the risk of angiosarcoma and include chronic lymphedema of the extremities, preexisting vascular lesions, and prior radiation, often as therapy for other malignancies. We report an unusual case of a very small, low-grade angiosarcoma on the thigh of an adult female with no known predisposing risk factors.

Beta-lactam antibiotic resistance: a current structural perspective.

Bacterial resistance to beta-lactam antibiotics can be achieved by any of three strategies: the production of beta-lactam-hydrolyzing beta-lactamase enzymes, the utilization of beta-lactam-insensitive cell wall transpeptidases, and the active expulsion of beta-lactam molecules from Gram-negative cells by way of efflux pumps. In recent years, structural biology has contributed significantly to the understanding of these processes and should prove invaluable in the design of drugs to combat beta-lactam resistance in the future.

Protein modulator of multidrug efflux gene expression in Pseudomonas aeruginosa.

nalC multidrug-resistant mutants of Pseudomonas aeruginosa show enhanced expression of the mexAB-oprM multidrug efflux system as a direct result of the production of a ca. 6,100-Da protein, PA3719, in these mutants. Using a bacterial two-hybrid system, PA3719 was shown to interact in vivo with MexR, a repressor of mexAB-oprM expression. Isothermal titration calorimetry (ITC) studies confirmed a high-affinity interaction (equilibrium dissociation constant [K(D)], 158.0 +/- 18.1 nM) of PA3719 with MexR in vitro. PA3719 binding to and formation of a complex with MexR obviated repressor binding to its operator, which overlaps the efflux operon promoter, suggesting that mexAB-oprM hyperexpression in nalC mutants results from PA3719 modulation of MexR repressor activity. Consistent with this, MexR repression of mexA transcription in an in vitro transcription assay was alleviated by PA3719. Mutations in MexR compromising its interaction with PA3719 in vivo were isolated and shown to be located internally and distributed throughout the protein, suggesting that they impacted PA3719 binding by altering MexR structure or conformation rather than by having residues interacting specifically with PA3719. Four of six mutant MexR proteins studied retained repressor activity even in a nalC strain producing PA3719. Again, this is consistent with a PA3719 interaction with MexR being necessary to obviate MexR repressor activity. The gene encoding PA3719 has thus been renamed armR (antirepressor for MexR). A representative "noninteracting" mutant MexR protein, MexR(I104F), was purified, and ITC confirmed that it bound PA3719 with reduced affinity (5.4-fold reduced; K(D), 853.2 +/- 151.1 nM). Consistent with this, MexR(I104F) repressor activity, as assessed using the in vitro transcription assay, was only weakly compromised by PA3719. Finally, two mutations (L36P and W45A) in ArmR compromising its interaction with MexR have been isolated and mapped to a putative C-terminal alpha-helix of the protein that alone is sufficient for interaction with MexR.

Crystal structures of the Apo and penicillin-acylated forms of the BlaR1 beta-lactam sensor of Staphylococcus aureus.

Staphylococcus aureus is among the most prevalent and antibiotic-resistant of pathogenic bacteria. The resistance of S. aureus to prototypal beta-lactam antibiotics is conferred by two mechanisms: (i) secretion of hydrolytic beta-lactamase enzymes and (ii) production of beta-lactam-insensitive penicillin-binding proteins (PBP2a). Despite their distinct modes of resistance, expression of these proteins is controlled by similar regulation systems, including a repressor (BlaI/MecI) and a multidomain transmembrane receptor (BlaR1/MecR1). Resistance is triggered in response to a covalent binding event between a beta-lactam antibiotic and the extracellular sensor domain of BlaR1/MecR1 by transduction of the binding signal to an intracellular protease domain capable of repressor inactivation. This study describes the first crystal structures of the sensor domain of BlaR1 (BlaRS) from S. aureus in both the apo and penicillin-acylated forms. The structures show that the sensor domain resembles the beta-lactam-hydrolyzing class D beta-lactamases, but is rendered a penicillin-binding protein due to the formation of a very stable acyl-enzyme. Surprisingly, conformational changes upon penicillin binding were not observed in our structures, supporting the hypothesis that transduction of the antibiotic-binding signal into the cytosol is mediated by additional intramolecular interactions of the sensor domain with an adjacent extracellular loop in BlaR1.