The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma

Repetitive mammalian dwarfing during ancient greenhouse warming events

Abrupt perturbations of the global carbon cycle during the early Eocene are associated with rapid global warming events, which are analogous in many ways to present greenhouse warming. Mammal dwarfing has been observed, along with other changes in community structure, during the largest of these ancient global warming events, known as the Paleocene-Eocene Thermal Maximum [PETM; ~56 million years ago (Ma)]. We show that mammalian dwarfing accompanied the subsequent, smaller-magnitude warming event known as Eocene Thermal Maximum 2 [ETM2 (~53 Ma)]. Statistically significant decrease in body size during ETM2 is observed in two of four taxonomic groups analyzed in this study and is most clearly observed in early equids (horses). During ETM2, the best-sampled lineage of equids decreased in size by ~14%, as opposed to ~30% during the PETM. Thus, dwarfing appears to be a common evolutionary response of some mammals during past global warming events, and the extent of dwarfing seems related to the magnitude of the event.Applied Geolog

Basal Cell Carcinoma and Eccrine Porocarcinoma of the Eyelid

An 81-year-old woman presented with a progressively enlarging indurated, firm lesion encompassing one-third of the left upper eyelid. Four years prior, a similar lesion at that same site had been excised and diagnosed as a basal cell carcinoma. The patient underwent a full-thickness excision of the lesion with frozen section, cryotherapy, and reconstruction. A free tarsal graft and hard palate composite graft was used to reconstruct the posterior lamella. A Mustarde myocutaneous rotational flap was used to reconstruct the anterior lamella. Histopathology illustrated nests of pleomorphic basophilic cells with varying mitotic activity and immunohistochemical staining consistent with eccrine porocarcinoma. This case highlights similarities in the presentation and appearance of basal cell carcinoma and periorbital eccrine porocarcinoma. It is possible that there was de novo development of the 2 tumors on the eyelid or recurrence of a misdiagnosed eccrine porocarcinoma. Eccrine porocarcinomas are rare malignant sweat gland tumors associated with a risk of recurrence after excision and metastasis