Drug-induced panniculitides.

A substantial number of all panniculitides fails to recognize a specific etiology, and that is true also for a relatively frequent type of panniculitis, such as erythema nodosum (EN). Between the recognized causative factors of panniculitides, infectious, physical agents, autoimmune mechanisms and neoplastic disorders are well known. On the contrary, the role of drugs as inducers of panniculitides is marginally considered, and their report limited to anecdotal observations, often without due histopathological support. Since the clinical and histopathological features of drug-induced panniculitides are indistinguishable from those caused by other agents, the causative relationship may be demonstrated by the history of previous drug intake and by clinical improvement after drug discontinuation. We reviewed the currently reported descriptions of drug-induced panniculitis, including a few exemplificative original observations. EN results as the most frequently reported drug-induced panniculitis. Among the causative drugs of EN a variety of medications, with disparate, or even opposite, mechanisms of action are reported, thus limiting the understanding of the pathogenesis. Common causative drugs include oral contraceptives, nonsteroidal anti-inflammatory drugs, antiobiotics and leukotriene-modifying agents. Unfortunately, in several cases, the diagnosis of drug-induced EN is done on clinical findings alone. In those cases, the lack of histopathological support does not allow to define a precise clinicopathological correlation on etiologic grounds. Drug-induced lobular and mixed panniculitides, including eosinophilic panniculitis, are even more rarely described. Reported causative agents are glatiramer acetate, interferon beta and heparin (at sites of injections), and systemic steroids, tyrosine kinase inhibitors and BRAF with subcutaneous fat involvement at distance. In view of the recent introduction of new classes of drugs, attention should be paid to disclose their possible etiologic role in inducing among other side effects, also panniculitides.

Acute generalized exanthematous pustulosis: report of five cases and systematic review of clinical and histopathological findings.

Acute generalized exanthematous pustulosis (AGEP) is a rare, drug-related pustular eruption usually starting from folds with edema and erythema and with subsequent spreading. Clinically AGEP is characterized by the sudden appearance of dozen of sterile, non follicular, small pustules on erythematous and edematous skin. Mild non erosive mucosal involvement, mostly oral, may sometimes occur. Fever, neutrophilia and peripheral blood eosinophilia (in a third of patients) are present. Other skin signs such as facial edema, purpura, target-like lesions and blisters have been described but are not typical for AGEP. Diagnostic criteria for AGEP were established by an international committee of experts, the European Study of Severe Cutaneous Adverse Reactions (EuroSCAR). The most relevant histopathological feature is represented by the detection of non-follicular subcorneal and/or intracorneal spongiform pustules that are usually large, contiguous and tend to coalesce. After elimination of the causative drug, pustules usually spontaneously disappear in a few days with desquamation and the reaction fully resolves within 15 days. Internal organs are not usually involved and no systemic treatment is required. Withdrawal of the culprit drug is mandatory. Although AGEP is a self-limiting disease with a favourable prognosis, secondary infections are a not infrequent complication in patients in poor general medical conditions. The reported mortality is about 5%. The most severe cases are associated with drug rechallenge.

Histopathologic spectrum of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): a diagnosis that needs clinico-pathological correlation.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by an heterogeneous group of severe dermatologic manifestations and systemic involvement, due to several groups of medicaments. A series of 9 consecutive cases, observed from 2008 to 2013 in the Department of Dermatology, University of Pavia, is reported, all satisfying the clinical, hematological and systemic diagnostic criteria of DRESS. Clinically, 4 out of 9 patients had an urticarial and papular eruption, 2 an erythema-multiforme-like (EM-like) pattern, 2 erythroderma and 1 had an erythematous and macular reaction. Aim of the study was to describe the histopathologic features of DRESS and to trace a possible correlation between the four clinical recognized types of the syndrome and the histopathological patterns. Predominantly, a superficial perivascular lymphocytic infiltrate, extravasation of erythrocytes, and focal interface changes characterized DRESS cases. Less frequently, histopathology revealed the presence of necrotic keratinocytes; surprisingly, only in 2 cases the presence of rare dermal eosinophils was detected, even if all the patients had significant peripheral eosinophilia. A histopathological diagnosis of DRESS seems per se, according to our data, not feasible, since the main histopathological changes (interface changes, superficial perivascular dermatitis, focal spongiosis, lichenoid infiltrate, rare presence of necrotic keratinocytes) can be interpreted generically as a drug induced dermatitis. The above mentioned histopathological changes, however, when associated with clinical information on cutaneous and systemic involvement of the patient, allow the pathologist or the dermatopathologist to make a diagnosis of DRESS with a reliable margin of certainty.

Cloning, characterization and identification of the gene encoding phosphatidylinositol 4-kinase.

The vast majority of AIDS-related deaths are associated with opportunistic infections. For fungal infections, there are few effective antifungals, particularly for systemic use. The discovery that very low doses of the bleomycin family of anticancer chemical congeners compromise the integrity of fungal cell walls led to our approach to identify genes that complement-cell wall defects, and develop methods to facilitate the identification of new antifungals targeted to fungal cell walls. This report describes one of the genes cloned by complementation of the blm1-1 mutation of S. cerevisiae using a YCp50-based yeast genomic library. Characterization and identification of the gene were carried out using drug screening tests, Southern hybridization analyses, DNA sequencing and DNA sequence similarity searches in databases. The gene STT4, is essential for viability and encodes a phosphatidylinositol 4-kinase that plays an important role in the phosphatidylinositol-mediated signal transduction pathway required for cell wall integrity. Like blm1-1 mutant strains, stt4 cells arrest mostly in the G2/M phase of the cell cycle. Further studies using this approach should help us understand the role of PI4-K in maintaining fungal cell-wall integrity, identify additional genes affecting potential target structures in cell walls of opportunistic fungal pathogens in AIDS patients, and assist in drug discovery and antifungal drug design.

A mutant approach and molecular strategy to study fungal cell walls.

The current study describes recombinant plasmids which complement the hypersusceptibility to killing bleomycin of blm1-1 mutant cells of Saccharomyces cerevisiae, and a strategy developed and used to recover active clones from a stable yeast genomic library. The resistance of a spontaneous revertant isolated from the original blm1-1 mutant strain and of mutant cells transformed with each of several recombinant plasmids which complemented the recessive blm1-1 mutation was comparable to the resistance of the parental (non-mutant) strain from which the original blm1-1 mutant was derived. The strategy for cloning S. cerevisiae DNA was based on complementation and in situ hybridization. This strategy employed 32P-labelled 6.6-kb BamHI and 3.8-kb BamHI-ClaI probes from a cloned DNA fragment to recover clones which either fully or partially complemented the hypersensitivity of mutant cells to killing by bleomycin. This method considerably reduced the time and effort required to recover biologically active clones from a genomic library.

Aplicacion de la tecnica de autorradiografia en el estudio de la sintesis del DNA celular. / Use of autoradiography technic in the study of cellular DNA synthesis

En el presente estudio se utiliza la tecnica de autorradiografia en la deteccion de la sintesis del DNA en celulas hepaticas y renales. Ademas se analiza su aplicacion clinica en las alteraciones que conllevan a la proliferacion anormal de celulas cancerigenas y la importancia en la identificacion de cromosomas normales y anormales