Behcet disease: an undifferentiating and complex vasculitis.

Behçet Disease is a relapsing and remitting variable vessel vasculitis characterized by recurrent mucocutaneous ulcers that can involve almost every organ system in the body. Indeed, the presence of recurrent oral or genital ulcers with other auto-inflammatory symptoms should raise suspicion for this elusive disease. It is unique among the vasculitides in that it can affect vessels of small, medium, and large size and tends to involve venous rather than arterial circulation, and its effects on the pulmonary venous circulation are particularly notable for their role in disease mortality. Classically seen in Mediterranean, Middle-Eastern, and eastern Asian countries, and relatively rare in the United States, prevalence has been increasing, prompting an increased need for internists to be aware of Behcet's clinical presentation and treatment. As early recognition and diagnosis of the disease is key to successful treatment and better prognosis, this review provides a brief summary of the current etiological theories, important clinical manifestations, and treatments including newer biologic alternatives.

Using mutagenesis and structural biology to map the binding site for the Plasmodium falciparum merozoite protein PfRh4 on the human immune adherence receptor.

To survive and replicate within the human host, malaria parasites must invade erythrocytes. Invasion can be mediated by the P. falciparum reticulocyte-binding homologue protein 4 (PfRh4) on the merozoite surface interacting with complement receptor type 1 (CR1, CD35) on the erythrocyte membrane. The PfRh4 attachment site lies within the three N-terminal complement control protein modules (CCPs 1-3) of CR1, which intriguingly also accommodate binding and regulatory sites for the key complement activation-specific proteolytic products, C3b and C4b. One of these regulatory activities is decay-accelerating activity. Although PfRh4 does not impact C3b/C4b binding, it does inhibit this convertase disassociating capability. Here, we have employed ELISA, co-immunoprecipitation, and surface plasmon resonance to demonstrate that CCP 1 contains all the critical residues for PfRh4 interaction. We fine mapped by homologous substitution mutagenesis the PfRh4-binding site on CCP 1 and visualized it with a solution structure of CCPs 1-3 derived by NMR and small angle x-ray scattering. We cross-validated these results by creating an artificial PfRh4-binding site through substitution of putative PfRh4-interacting residues from CCP 1 into their homologous positions within CCP 8; strikingly, this engineered binding site had an ∼30-fold higher affinity for PfRh4 than the native one in CCP 1. These experiments define a candidate site on CR1 by which P. falciparum merozoites gain access to human erythrocytes in a non-sialic acid-dependent pathway of merozoite invasion.

TNF-alpha antagonism and cancer risk in rheumatoid arthritis: is continued vigilance warranted?

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory arthritis that can lead to significant damage and dysfunction of involved joints. Prior to 1998, treatment options were limited to disease modifying anti-rheumatic drugs, commonly referred to as DMARDs like methotrexate, sulfasalazine, hydroxychloroquine, and gold salts. Tumor necrosis factor alpha (TNF-α) is a central cytokine that drives the inflammation in RA; hence inhibition of TNF-α offers an attractive treatment strategy in RA. The introduction of TNF-α inhibitors, a class of biologic DMARDs, has dramatically changed the treatment of RA as these are highly effective therapies. Medication-related adverse events remain a major problem in health care. This is true of the TNF-α antagonists as well, with particular concerns about increased risks of infections and malignancy. Because clinical trials performed prior to medication approval are limited by the number and clinical complexity of participants and the duration of the trials, post-marketing surveillance is critical in identifying adverse events. In order to better clarify the safety issues related to the use of TNF-α inhibitors in RA, several studies using large observational registries along with pooled meta-analyses of these studies have been published. This review will summarize the data from these recent studies on the question of malignancy risk associated with TNF-α inhibitor use in RA. It is comforting that the data from these studies do not support an increased risk of cancer, except non-melanoma skin cancer, with the use of TNF-α antagonists in adults with RA.

Neoplastic and paraneoplastic vasculitis, vasculopathy, and hypercoagulability.

It is essential to be aware of both neoplastic and paraneoplastic vasculitides, vasculopathy, and hypercoagulability, considering the importance of an accurate diagnosis and timely treatment of the underlying malignancy. Characteristics such as the type of vasculitis, age, gender, atypical presentation, and lack of response to common therapies should prompt investigation for an occult malignancy, whereas vasculitis such as GPA require due malignancy vigilance given a significantly increased risk of malignancy at the time of diagnosis and in the following years. Vasculopathies are rarer than vasculitides, but are associated with specific malignancies and, in the context of such malignancies, should be kept in mind. Hypercoagulability is a well-documented neoplastic phenomenon with an increased risk of thrombosis in the setting of positive aPLs. Most neoplastic and paraneoplastic vascular syndromes require no specific treatment outside of treatment of the underlying malignancy. The two key exceptions are PACNS, because of its poor prognosis, and erythromelalgia, in which aspirin is an effective agent.

Cathelicidin family of antimicrobial peptides: proteolytic processing and protease resistance.

Cathelicidins are a gene family of antimicrobial peptides produced as inactive precursors. Signal peptidase removes the N-terminal signal sequence, while peptidylglycine alpha-amidating monooxygenase often amidates and cleaves the C-terminal region. Removal of the cathelin domain liberates the active antimicrobial peptide. For mammalian sequences, this cleavage usually occurs through the action of elastase, but other tissue-specific processing enzymes may also operate. Once released, these bioactive peptides are susceptible to proteolytic degradation. We propose that some mature cathelicidins are naturally resistant to proteases due to their unusual primary structures. Among mammalian cathelicidins, proline-rich sequences should resist attack by serine proteases because proline prevents cleavage of the scissile bond. In hagfish cathelicidins, the unusual amino acid bromotryptophan may make the active peptides less susceptible to proteolysis for steric reasons. Such protease resistance could extend the pharmacokinetic lifetimes of cathelicidins in vivo, sustaining antimicrobial activity.