Hermansky-Pudlak syndrome (HPS) is an often-fatal autosomal recessive disease in which albinism, bleeding, and lysosomal storage result from defects of diverse cytoplasmic organelles: melanosomes, platelet dense bodies, and lysosomes. HPS is the most common single-gene disorder in Puerto Rico, with an incidence of 1 in 1,800. We have identified the HPS gene by positional cloning, and found homozygous frameshifts in this gene in Puerto Rican, Swiss, Irish and Japanese HPS patients. The HPS polypeptide is a novel transmembrane protein that is likely to be a component of multiple cytoplasmic organelles and that is apparently crucial for their normal development and function. The different clinical phenotypes associated with the different HPS frameshifts we observed suggests that differentially truncated HPS polypeptides may have somewhat different consequences for subcellular function.

Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. As reported elsewhere, we mapped the human HPS gene to chromosome segment 10q23, positionally cloned the gene, and identified three pathologic mutations of the gene, in patients from Puerto Rico, Japan, and Europe. Here, we describe mutation analysis of 44 unrelated Puerto Rican and 24 unrelated non-Puerto Rican HPS patients. A 16-bp frameshift duplication, the result of an apparent founder effect, is nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 may be the most frequent HPS mutation in Europeans. We also describe six novel HPS mutations: a 5' splice-junction mutation of IVS5, three frameshifts, a nonsense mutation, and a one-codon in-frame deletion. These mutations define an apparent frameshift hot spot at codons 321-322. Overall, however, we detected mutations in the HPS gene in only about half of non-Puerto Rican patients, and we present evidence that suggests locus heterogeneity for HPS.

The registry program of amniotic fluid embolism (AFE) in Japan started in 2003. More than 400 hundred clinical diagnosed amniotic fluid embolism has been accumulated. Those data showed that there were two etiologies of AFE: the fetal materials create physical obstructions in the maternal microvessels in various organs, such as the lung; and (ii) the liquids cause an anaphylactoid reaction that leads to pulmonary vasospasm and activation of platelets, white blood cells and/or complements. The clinical findings showed that AFE was characterized mainly by cardiopulmonary collapse, the other involves the presence of disseminated intravascular coagulation (DIC) and atonic bleeding. Zinc coproporphyrin-1, sialyl Tn antigen (STN), complement C3, C4 and interleukin-8 have been used as serum markers of AFE. The levels of zinc coproporphyrin-1 and STN were increased in cardiopulmonary collapse type AFE, and a marked reduction of C3 and C4 was observed in DIC type AFE. At the primary medical institution, initial treatments for shock airway management, vascular management, fluid replacement, administration of anti-DIC therapy such as antithrombin, and administration of fresh frozen plasma should be provided. C1 esterase inhibitor activity in AFE cases was significantly lower than those of normal pregnant women. C1 esterase inhibitor may be a promising candidate of treatment of AFE.

Although numerous carbohydrates play significant roles in mammalian cells, carbohydrate-based drug discovery has not been explored due to the technical difficulty of chemically synthesizing complex carbohydrate structures. Previously, we identified a series of carbohydrate mimetic peptides and found that a 7-mer peptide, designated I-peptide, inhibits hematogenous carbohydrate-dependent cancer cell colonization. During analysis of the endothelial surface receptor for I-peptide, we found that I-peptide bound to annexin 1 (Anxa1). Because Anxa1 is a highly specific tumor vasculature surface marker, we hypothesized that an I-peptide-like peptide could target anticancer drugs to the tumor vasculature. This study identifies IFLLWQR peptide, designated IF7, as homing to tumors. When synthetic IF7 peptide was conjugated to fluorescent Alexa 488 (A488) and injected intravenously into tumor-bearing mice, IF7-A488 targeted tumors within minutes. IF7 conjugated to the potent anticancer drug SN-38 and injected intravenously into nude mice carrying human colon HCT116 tumors efficiently suppressed tumor growth at low dosages with no apparent side effects. These results suggest that IF7 serves as an efficient drug delivery vehicle by targeting Anxa1 expressed on the surface of tumor vasculature. Given its extremely specific tumor-targeting activity, IF7 may represent a clinically relevant vehicle for anticancer drugs.angiogenesis | carbohydrate binding protein | geldanamycin | phage display | chemiluminescence

Although all T lymphocytes express antigen-specific receptors, there is increasing evidence that a population of blood T cells are "naive" in that they respond poorly to recall antigens, while other blood T lymphocytes are "memory" cells in that they proliferate readily in response to recall antigens, function efficiently as immune effector cells, and express surface molecules involved in antigen presentation and adhesion to endothelial cells and extracellular matrix components (1-5). The populations of "naive" and "memory" T cells are defined by the expression of the family of CD45 leukocyte common antigens coded by a single 130 kb, 33 exon gene (6) . The CD45 gene uses differential splicing to generate multiple mRNA transcripts that direct the synthesis of 220, 205, 200, 190, and 180 kD glycoproteins (7-12) . While the 220 and 205 kD glycoproteins are expressed on the surface of "naive" T cells and are detected by the 2144 mAb, the 180 kD glycoprotein is expressed only on "memory" T cells and is detected by the UCHL1 antibody (11-14) . Relative to the 33 exon CD45 gene, the mRNA transcript coding for the 220 kD 2144 + protein contains the sequence information of all 33 exons, while the transcript coding for the 205 kD 2144 + protein is missing residues coded by exon VI (12, 13) . In contrast, the CD45 mRNA transcript coding for the 180 kD UCHL1 + protein is missing exons IV, V,.A number of observations about T cells at sites of chronic inflammation suggest that the relative proportions of "naive" and "memory" T cell populations can vary within the body . In this regard, while blood T cells include both "naive" and "memory" T cells in approximately equal proportions, T cells participating in chronic inflammatory diseases in tissues are mostly comprised of"memory" T cells (15)(16)(17)(18) .