Xeroderma pigmentosum-variant (XP-V) patients have sun sensitivity and increased skin cancer risk. Their cells have normal nucleotide excision repair, but have defects in the POLH gene encoding an error-prone polymerase, DNA polymerase eta (pol eta). To survey the molecular basis of XP-V worldwide, we measured pol eta protein in skin fibroblasts from putative XP-V patients (aged 8-66 years) from 10 families in North America, Turkey, Israel, Germany, and Korea. Pol eta was undetectable in cells from patients in eight families, whereas two showed faint bands. DNA sequencing identified 10 different POLH mutations. There were two splicing, one nonsense, five frameshift (3 deletion and 2 insertion), and two missense mutations. Nine of these mutations involved the catalytic domain. Although affected siblings had similar clinical features, the relation between the clinical features and the mutations was not clear. POLH mRNA levels were normal or reduced by 50% in three cell strains with undetectable levels of pol eta protein, indicating that nonsense-mediated message decay was limited. We found a wide spectrum of mutations in the POLH gene among XP-V patients in different countries, suggesting that many of these mutations arose independently.

We present a concept for reducing formation of fibrotic deposits by inhibiting self-assembly of collagen molecules into fibrils, a main component of fibrotic lesions. Employing monoclonal antibodies that bind to the telopeptide region of a collagen molecule, we found that blocking telopeptide-mediated collagen/collagen interactions reduces the amount of collagen fibrils accumulated in vitro and in keloid-like organotypic constructs. We conclude that inhibiting extracellular steps of the fibrotic process provides a novel approach to limit fibrosis in a number of tissues and organs.Collagen I is the most abundant structural protein of connective tissues such as skin, bone, and tendon. This protein is first synthesized as a precursor molecule, procollagen, that is characterized by the presence of a rod-like central triple-helical domain flanked by short linear telopeptides and globular N-terminal and C-terminal propeptides (1). Single procollagen molecules are the building blocks for the biologically and mechanically relevant collagen fibrils. Formation of collagen fibrils is initiated by enzymatic cleavage of the N-terminal and the C-terminal propeptides. The N-terminal propeptides are cleaved by a group of enzymes that includes a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-2, -3, and -14, whereas the C-terminal propeptides are cleaved by the metalloprotease bone morphogenetic protein 1 (BMP-1) 2 and by the other members of a closely related family of mammalian tolloid-like metalloproteases (2-4). Such a removal of procollagen propeptides exposes telopeptides, which by engaging in site-specific intermolecular interactions drive collagen self-assembly.In native tissues a precise balance between the processes of biosynthesis and degradation maintains the physiological homeostasis of tissue collagens. At the same time, accelerated biosynthesis is required for proper wound healing, whereas excessive accumulation of collagen is the hallmark of a number of localized fibrotic diseases, such as keloids and hypertrophic scars, and systemic fibrosis, such as systemic scleroderma.Localized fibrotic reactions are quite common and frequently develop as a consequence of surgical procedures. For instance, after surgery of the abdomen, the formation of excessive scar tissue around abdominal organs, such as the intestines, can interfere with the functionality of such organs and may cause severe pain and even death. Another situation where excessive scar formation presents a major complication is in the eye after glaucoma surgery performed to create a pressuremaintenance valve. Frequently, however, excessive scar formation closes this pressure-reducing valve, thereby forcing the intraocular pressure to rise (5). Moreover, excessive scarring of the vocal folds may severely alter their ability to vibrate, thereby causing a number of voice disorders (6).At present, several biological processes critical for development of fibrotic lesions are considered potential targets for inhibitors of fibrosis. These inhibit...

IMPORTANCE Despite several recent reports on the elevated risk of bullous pemphigoid in patients with type 2 diabetes treated with dipeptidyl peptidase-4 (DPP-4) inhibitors, evidence on the absolute risk and comparative safety against other antidiabetics is limited.OBJECTIVE To characterize the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas.

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Glaucoma is the second leading cause of blindness worldwide. Although the mechanism of the development of primary open-angle glaucoma (POAG) is not fully understood, elevated intraocular pressure (IOP) is considered the most important risk factor. Several vascular factors have also been identified as risk factors and can lead to hypoperfusion of the optic nerve head and thus may play an important role in the pathogenesis and progression of POAG. The results of the present study suggest that both high and low blood pressure (BP) are associated with an increased risk of POAG based on a comprehensive literature review. Elevated BP is associated with elevated IOP, leading to increased risk of glaucoma, but excessive BP lowering in glaucoma patients may cause a drop in ocular perfusion pressure (OPP) and subsequent ischemic injury. The relationship between IOP, OPP, and BP suggests that the relationship between BP and glaucoma progression is U-shaped.

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