Structural and functional insights into asymmetric enzymatic dehydration of alkenols.

The asymmetric dehydration of alcohols is an important process for the direct synthesis of alkenes. We report the structure and substrate specificity of the bifunctional linalool dehydratase isomerase (LinD) from the bacterium Castellaniella defragrans that catalyzes in nature the hydration of ß-myrcene to linalool and the subsequent isomerization to geraniol. Enzymatic kinetic resolutions of truncated and elongated aromatic and aliphatic tertiary alcohols (C5-C15) that contain a specific signature motif demonstrate the broad substrate specificity of LinD. The three-dimensional structure of LinD from Castellaniella defragrans revealed a pentamer with active sites at the protomer interfaces. Furthermore, the structure of LinD in complex with the product geraniol provides initial mechanistic insights into this bifunctional enzyme. Site-directed mutagenesis confirmed active site amino acid residues essential for its dehydration and isomerization activity. These structural and mechanistic insights facilitate the development of hydrating catalysts, enriching the toolbox for novel bond-forming biocatalysis.

Prediction of Synergistic Toxicity of Binary Mixtures to Vibrio fischeri Based on Biomolecular Interaction Networks.

The paradigm of chemical safety assessment is shifting from 'chemical management focusing on single chemicals' to 'product management extending to mixtures and articles'. However, because of the enormous combinatorial complexity, testing the toxicity of all conceivable mixture products is currently not feasible. There exist only few models that allow predicting the synergistic toxicity potentially caused by toxicological interactions among components. In this study, we present a novel approach to qualitatively predict the synergistic toxicity of binary mixtures to Vibrio fischeri. On the basis of information derived from protein-chemical and protein-protein interaction networks, we trained machine learning models for classifying chemical mixtures to have synergistic or nonsynergistic toxicity with accuracies and an area under the receiver operating characteristic (ROC) curve (AUC) up to 0.73. The numbers of shared targets and their neighborhood were found to be the most important features for classifying chemicals into synergistic and nonsynergistic groups.

Folliculocentric cutaneous presentation of disseminated Candida krusei infection in a patient with acute myeloid leukemia.

Candida krusei (C. krusei) is a multidrug-resistant opportunistic fungal pathogen that may cause disseminated infections in immunocompromised hosts. However, its clinical and histologic features are not well-characterized. We present a unique case to contribute to the growing knowledge base associated with this organism. During hospitalization for neutropenic fever, a 19-year-old man with acute myeloid leukemia, who underwent hematopoietic stem cell transplantation, developed a generalized folliculocentric eruption following initiation of antifungal therapy for newly diagnosed C. krusei fungemia. Despite adequate antifungal coverage and negative blood cultures, the follicular-based erythematous papules persisted. Biopsies demonstrated yeast within ruptured follicles, without angiotropism or involvement of the interfollicular dermis, subcutaneous tissue, or stratum corneum. Concurrent skin tissue cultures confirmed C. krusei. The patient remained febrile despite aggressive antifungal therapy, with relapse of leukemia and subsequent death. Our case is unusual given the development of cutaneous lesions following clearance of fungemia, with yeast limited to ruptured follicular lumina, possibly indicating a primary cutaneous source or early transfollicular/transepidermal elimination. Given the limited available descriptions of cutaneous histopathology for C. krusei, we seek to add to the understanding of its pathophysiology and aid in the diagnosis and treatment of this often fatal infection.

Pseudoepitheliomatous hyperplasia and transepidermal elimination in lepromatous leprosy: does T-cell plasticity play a role?

BACKGROUND: The longstanding concept of a Th1-Th2 dichotomy in leprosy, with Th1-predominant tuberculoid leprosy and Th2-predominant lepromatous leprosy (LL), has recently been challenged, and Cbl-b overexpression may emerge as an important factor in anergy and progression of LL. Moreover, Th17 and Th22 subsets have been identified as Th1-Th2 modulators in inflammatory skin diseases, most notably psoriasis, but their roles in leprosy have not yet been elucidated. The occurrence of pseudoepitheliomatous hyperplasia (PEH) with transepidermal elimination of mycobacteria in LL patients, which could theoretically be a portal for contact transmission, thus raises important immunological questions: Do Th17 and/or Th22 subsets mediate epidermal proliferation akin to Th1-driven psoriasis in supposedly Th2-predominant LL disease, and is the Th1-Th2 immunostat set systemically or locally? Furthermore, which microRNAs (miRs), signal transducers, and activators of transcription (STAT) proteins regulate this transition in leprosy, if any, and does differential Cb1-b expression play a role? OBSERVATION: A 71-year-old man presented with an infiltrative dermopathy characteristic of LL, as well as several hyperkeratotic plaques. Microscopic examination of the hyperkeratotic lesions demonstrated PEH with loss of the grenz zone and transepidermal elimination of acid-fast bacilli, whereas classic histopathologic features of LL were present at other sites. HYPOTHESES: We hypothesize that: Th17 and Th22 T-cell subsets act locally to induce T-cell plasticity in LL lesions, manifesting PEH; miR-181a is normal or increased in LL lesions with PEH compared to its expressional loss in classic LL lesions; miR-21 and STAT3 are increased in LL lesions with PEH, given their association with epithelial hyperproliferation; and Cbl-b is diminished in LL lesions with PEH compared to classic LL lesions. CONCLUSION: By understanding the factors that regulate T-cell and cytokine responses in leprosy, it should be possible to recognize these dynamic immunologic processes clinically and histopathologically and devise specific immunologic interventions.

Eruptive basal-cell carcinomas in the setting of human immunodeficiency virus infection.

Patients with human immunodeficiency virus are known to have an increased risk for development of cutaneous malignant conditions. We present a 55-year-old man with a history of an isolated squamous-cell carcinoma five years prior, who presented with 27 cutaneous lesions, which had developed over the course of the preceding year. This occurred in the context of a new diagnosis of human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). The initiation of anti-retroviral therapy and subsequent restoration of CD4 counts was associated with an increase in the number of lesions. Histopathologic examination of representative tumors showed basal-cell carcinomas, which lead to the diagnosis of eruptive basal-cell carcinomas in the setting of HIV-related immunosuppression. The incidence and epidemiology of malignant conditions that are related and non-related to AIDS are reviewed as well as discussion of the current literature regarding presentation, treatment, and prevention of non-melanoma skin cancers in patients with HIV infection.

Perifollicular Langerhans cell histiocytosis.

A 25-year-old man presented with a 13-year history of an erythematous, papular eruption of his face and trunk, which was treated in the past as acne and psoriasis with isotretinoin and methotrexate, respectively. Histopathologic examination demonstrated an infiltrate of Langerhans cells, which was consistent with Langerhans cell histiocytosis. The epidemiology, clinical presentation, and treatment options of this disease are reviewed.

Erythema annulare centrifugum.

Erythema annulare centrifugum (EAC) is a gyrate erythema, which is typically characterized by annular, erythematous plaques with trailing scale. It is considered to be a reactive condition with a wide variety of inciting causes but unclear pathophysiology. The mean duration of the eruption is 11 months. We present a patient with a 50-year history of recurrent EAC with no known cause. Although it does follow a previously reported pattern of seasonal recurrence, this case represents the longest reported duration of EAC.

Disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis, which was described in 1966, is characterized by small, atrophic patches with distinctive keratin rims that occur on sun-exposed areas of the extremities, shoulders, and back. The diagnosis is based on the histopathologic finding of a cornoid lamella, absence of a granular layer, and often a thin epidermis. It is associated with exposure to ultraviolet radiation. Gene studies suggest a pathway defect in which several mutations in keratinocyte proliferation and differentiation lead to development of porokeratosis.

Purpura annularis telangiectoides.

Purpura annularis telangiectoides of Majocchi (PATM) is a clinical variant of pigmented purpuric dermatoses. It is characterized by asymptomatic or mildly pruritic, erythematous, annular patches that vary in size. The patches exhibit central clearing and peripheral cayenne pepper petechiae. It classically occurs on the lower legs but may be more generalized. Histopathologic features include a lymphocytic capillaritis with subsequent capillary leakage and extravasated erythrocytes, which is typical of all pigmented purpuric dermatoses. The pathogenesis of PATM is unknown, but it may uncommonly be associated with underlying diseases such as hematologic disorders and rarely cutaneous T-cell lymphoma. There is no standard effective treatment.

Eruptive vellus hair cysts.

Eruptive vellus hair cyst (EVHC), described initially in 1977, is a benign dermatologic condition that is characterized by the sudden appearance of monomorphic, follicular, asymptomatic, small papules in children and young adults. The diagnosis is based on the histopathologic findings of stratified-squamous epithelium with a granular layer that surrounds a cystic space filled with laminated keratin and a variable number of vellus hair cysts. EVHC can be associated with steatocystoma multiplex. A current hypothesis suggests that EVHC originates from a cystic change at the insertion of the pilosebaceous duct. EVHC is primarily treated for cosmesis with retinoids, surgery, and lasers.

Verrucous and macular sarcoidosis.

We present a case of cutaneous sarcoidosis in a 77-year-old woman without systemic disease, who presented with two subtypes of lesions: erythematous and hyperpigmented macules on the arms and anterior upper legs and erythematous, hyperkeratotic nodules, some crateriform, on the lower legs and feet. Whereas cutaneous sarcoidosis is present in up to one-third of cases and may present with a wide variety of lesions, verrucous sarcoidosis is uncommon. Diagnosis is by clinical and histopathologic exclusion of other entities, which include other causes of granulomatous inflammation such as infections and foreign-body reactions. Management options include topical, intralesional, or systemic glucocorticoids, antimalarials, tetracycline derivatives, and methotrexate.

Localized pemphigus with vegetative features.

We present a 58-year-old Jamaican man with an eight-month history of an isolated, vegetative, eroded, and crusted plaque on the posterior aspect of the scalp. One month prior to referral to the Charles C. Harris Skin and Cancer Pavilion he developed a few, scattered erosions on the extremities. A biopsy specimen showed suprabasal acantholysis along with deposition of C3 and IgG on a direct immunofluorescence test. Localized pemphigus is a rare variant of pemphigus vulgaris. Localized pemphigus presents with a localized plaque that remains localized for an extended period of time without generalized bullae formation. Our patient represents an unusual case of localized pemphigus of the scalp with vegetative features.

Angiofibromas in multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is a familial tumor syndrome with autosomal dominant inheritance. Cutaneous tumors in MEN1, which include multiple angiofibromas, collagenomas, and lipomas can easily be overlooked because of their subtle appearance. As markers of this tumor syndrome, recognition of the mucocutaneous manifestations of MEN1 is important in order to facilitate early interdisciplinary care and diagnosis of associated internal disease in both patients and family members.

Linear morphea of the forehead (en coup de sabre).

Linear morphea of the forehead or en coup de sabre (ECDS) is an unusual variant of morphea. It typically occurs in children although cases of adult-onset ECDS exist as reported here. ECDS has a specific distribution on the frontal scalp and forehead and is usually unilateral. Sclerosis in ECDS lesions may invade deeply to involve underlying muscle and bone and may exist on the same clinicopathologic spectrum as Parry-Romberg syndrome. Extracutaneous involvement is frequent, with neurologic and ophthalmologic findings occurring most commonly. The etiology of ECDS is unclear but may be autoimmune in origin. The question of whether Borrelia infection also plays a role remains controversial. Current evidence supports first-line treatment with methotrexate and oral glucocorticoids followed by phototherapy and mycophenolate mofetil.

Anetoderma secondary to antiphospholipid antibodies.

Anetoderma is an elastolytic disorder that is associated with a number of infectious and autoimmune disorders. We present a case of a patient with generalized anetoderma, who was later found to have positive antinuclear antibodies and antiphospholipid antibodies (APAs). Numerous other cases have been reported in literature and some authors have suggested that anetoderma is a highly specific sign of APAs, with or without other manifestations of systemic lupus erythematosus or antiphospholipid syndrome [14]. Thus, work up for connective-tissue disorders should be considered in any patients who present with this skin finding.

Hypergammaglobulinemic purpura of Waldenström.

We report a case of a 33-year-old-woman with a one-year history of bilateral lower extremity vasculitis and laboratory evidence of hypergammaglobulinemia with otherwise unremarkable routine laboratory and rheumatologic studies. Her clinical picture, together with histopathologic evidence of leukocytoclastic vasculitis, favor a diagnosis of hypergammaglobulinemic purpura of Waldenström.

Poikilodermatous mycosis fungoides.

Poikilodermatous mycosis fungoides (MF) is a variant of MF, formerly referred to as poikiloderma vasculare atrophicans. The lesions are classically characterized by large plaques of hypopigmentation and hyperpigmentation with atrophy and telangiectases. The plaques may be asymptomatic or mildly pruritic and typically involve the major flexural areas and trunk. Poikilodermatous MF has an early stage (IA-IIA) at diagnosis and a male predominance. Poikilodermatous MF shows an atypical T-cell infiltrate in the papillary dermis with evidence of epidermotropism, epidermal atrophy, dilated blood vessels in the dermis, melanophages, and melanin incontinence. Recent studies suggest a predominance of a CD8+, CD4- immunophenotype. Treatment modalities are similar to classic MF with phototherapy being the most common first-line therapy. Poikilodermatous MF has an excellent prognosis.

Dissecting cellulitis of the scalp.

Dissecting cellulitis of the scalp is a chronic, relapsing, inflammatory disease of the scalp that results in scarring alopecia. We present a case of a 32-year-old man with recalcitrant disease who is now responding to treatment with isotretinoin. The pathogenesis, clinical presentation, disease associations, and histopathological findings are reviewed. Treatment can be challenging. The literature on medical and surgical therapeutic options is reviewed.

Verrucous lymphangioma circumscriptum.

A 19-year-old woman with a seven-year history of pruritic, grouped, verrucous papules and plaques on the left arm presented for consultation. The lesion slightly flattened in appearance with topical glucocorticoid treatment. The histopathological features were consistent with lymphangioma circumscriptum. This entity is the most common subtype of lymphangioma and presents with grouped, clear vesicles that may appear pink to purple. However, a rare verrucous type can present a diagnostic challenge. Whereas the definitive treatment option is surgical excision, other treatments, which include sclerotherapy, radiotherapy, and laser therapy, have been reported to cause resolution or improvement. In the future, propranolol may hold promise as a medical therapy for lymphangioma.

Papular variant of annular elastolytic giant-cell granuloma.

A 53-year-old woman presented with a six-month history of non-pruritic, erythematous papules and papular-plaques that were localized to the anterior and lateral aspects of the neck. A biopsy specimen showed elastolysis and granuloma formation, which were consistent with a diagnosis of annular elastolytic giant-cell granuloma. This is one of the few reported cases of this entity that consists predominantly of papular lesions rather than annular plaques.