Epidermal necrolysis: mechanisms of keratinocyte apoptosis

Toxic epidermal necrolysis and Stevens-Johnson syndrome are acute and severe adverse reaction to drugs, characterized by the widespread destruction of the epithelium of the skin and mucous membranes. This destruction by massive apoptosis leads to a clinical pattern of epidermal necrolysis resembling second degree burns, with sheets of necrotic epidermis detached from the underlying dermis. The mechanisms of acute and extensive destruction of the skin are not yet fully understood. At the onset of the reaction blisters develop from the fluid that accumulates between the dead epidermis and the dermis. High concentrations of mononuclear cells are present in this blister fluid, principally CD8 T-lymphocytes that may exhibit a drug specific MHC class I restricted cytotoxicity against autologous cells. The intervention of soluble mediators such as TNFalpha, perforin/granzyme, or Fas-Ligand may be necessary for amplifying the apoptosis of keratinocytes. A strong association between epidermal necrolysis to certain drugs and rare HLA-B genotypes suggests that direct interaction between these drugs and HLA-B molecules may initiate a reaction resembling the acute rejection of allogeneic epidermis.     

The first report of <Emphasis Type="Italic">Spondias</Emphasis> native to Madagascar: <Emphasis Type="Italic">Spondias tefyi</Emphasis>, sp. nov. (Anacardiaceae)

Spondias represents a genus new to Madagascar’s native flora. Like Campnosperma, it is now known from both American and Asian tropics and Madagascar but not from continental Africa. The new species Spondias tefyi is easily distinguished from all of its Asian congeners by having the stamens shorter than the pistil and fruits brown and lenticellate at maturity (vs. greenish, yellow, orange or red, and relatively smooth). The new species is one of several Anacardiaceae whose fruits are eaten by lemurs in the Analavelona Forest, highlighting the importance of conserving this threatened subhumid forest remnant in southern Madagascar.     

An all-purpose antimalarial drug target

The recent re-emphasis on malaria eradication has made developing drugs that block transmission and terminate latent disease critical. Most drugs do not affect the liver stages-an ability that is crucial to the latter goal. Addressing this problem, Hoepfner et?al. (2012) uncover the parasite's lysyl-tRNA synthetase as?a druggable target.     

Reef Fishes Have Higher Parasite Richness at Unfished Palmyra Atoll Compared to Fished Kiritimati Island

We compared parasite communities at two coral atolls in the Line Islands chain of the central Pacific (Kiritimati Island and Palmyra Atoll). Palmyra Atoll is relatively pristine while Kiritimati Island is heavily fished. At each island, we sampled five fish species for helminth and arthropod endoparasites: Chromis margaritifer, Plectroglyphidodon dickii, Paracirrhites arcatus, Acanthurus nigricans, and Lutjanus bohar. The surveys found monogeneans, digeneans, cestodes, nematodes, acanthocephalans, and copepods. Parasite richness was higher at Palmyra compared to Kiritimati for all five fish species. Fishes from Palmyra also tended to have more parasites species per host, higher parasite prevalence, and higher parasite abundance than did fishes from Kiritimati. The lower parasitism at Kiritimati may result from a simplified food web due to over fishing. Low biodiversity could impair parasite transmission by reducing the availability of hosts required by parasites with complex life cycles. Most notably, the lower abundances of larval shark tapeworms at Kiritimati presumably reflect the fact that fishing has greatly depleted sharks there in comparison to Palmyra.     

Analysis of genetic variations in the resistin gene shows no associations with obesity in women

Resistin is thought to be involved in the development of obesity and insulin resistance. Polymorphisms in the gene encoding resistin could contribute to this link, but different studies have yielded contradictory results. In this study, we investigated whether polymorphisms in resistin are involved in the development of obesity in a Belgian female population. We selected three single-nucleotide polymorphisms (SNPs; rs1862513, rs3745367, and rs3745369) and compared their genotype and allele frequencies between female obese patients (N = 541) and control individuals (N = 235). This analysis showed association with neither obesity for any of the variants nor with the haplotypes of these SNPs. Furthermore, we also investigated whether these variants have an influence on BMI. After Kruskal-Wallis analysis, we found that there was no difference in BMI between the genotypes for all variants. Together, these results suggest that these variants in resistin are not associated with obesity in the female population.     

ASAP3 is a focal adhesion-associated Arf GAP that functions in cell migration and invasion

ASAP3, an Arf GTPase-activating protein previously called DDEFL1 and ACAP4, has been implicated in the pathogenesis of hepatocellular carcinoma. We have examined in vitro and in vivo functions of ASAP3 and compared it to the related Arf GAP ASAP1 that has also been implicated in oncogenesis. ASAP3 was biochemically similar to ASAP1: the pleckstrin homology domain affected function of the catalytic domain by more than 100-fold; catalysis was stimulated by phosphatidylinositol 4,5-bisphosphate; and Arf1, Arf5, and Arf6 were used as substrates in vitro. Like ASAP1, ASAP3 associated with focal adhesions and circular dorsal ruffles. Different than ASAP1, ASAP3 did not localize to invadopodia or podosomes. Cells, derived from a mammary carcinoma and from a glioblastoma, with reduced ASAP3 expression had fewer actin stress fiber, reduced levels of phosphomyosin, and migrated more slowly than control cells. Reducing ASAP3 expression also slowed invasion of mammary carcinoma cells. In contrast, reduction of ASAP1 expression had no effect on migration or invasion. We propose that ASAP3 functions nonredundantly with ASAP1 to control cell movement and may have a role in cancer cell invasion. In comparing ASAP1 and ASAP3, we also found that invadopodia are dispensable for the invasive behavior of cells derived from a mammary carcinoma.     

Test for positional candidate genes for body composition on pig chromosome 6

One QTL affecting backfat thickness (BF), intramuscular fat content (IMF) and eye muscle area (MA) was previously localized on porcine chromosome 6 in an F₂ cross between Iberian and Landrace pigs. This work was done to study the effect of two positional candidate genes on these traits: H-FABP and LEPR genes. The QTL mapping analysis was repeated with a regression method using genotypes for seven microsatellites and two PCR-RFLPs in the H-FABP and LEPR genes. H-FABP and LEPR genes were located at 85.4 and 107 cM respectively, by linkage analysis. The effects of the candidate gene polymorphisms were analyzed in two ways. When an animal model was fitted, both genes showed significant effects on fatness traits, the H-FABP polymorphism showed significant effects on IMF and MA, and the LEPR polymorphism on BF and IMF. But when the candidate gene effect was included in a QTL regression analysis these associations were not observed, suggesting that they must not be the causal mutations responsible for the effects found. Differences in the results of both analyses showed the inadequacy of the animal model approach for the evaluation of positional candidate genes in populations with linkage disequilibrium, when the probabilities of the parental origin of the QTL alleles are not included in the model.     

Acylureas: A new class of barbiturate-like bacterial cytochrome P-450 inducers

The soluble, cytochrome P-450-dependent fatty acid monooxygenase of Bacillus megaterium ATCC 14581 is induced by phenobarbital and at least twelve other barbiturates (Kim, B.-H. and Fulco, A.J. 91983) Biochem. Biophys. Res. Commun. 116, 843–850). We have since found that the inducer potency of phenobarbital and of six other of these barbiturates was enhanced by adding them to growth medium prior to sterilization by autoclaving. A similar ‘activation’ was effected simply by autoclaving these barbiturates in distilled water at pH 8.0. When the hydrolytic products resulting from such treatment of phenobarbital were identified and screened for inducer activity, the major product, 2-phenulbutyrylurea, was found to be 3–5-times more potent than phenobarbital itself. The racemic mixture, (±-)-2-phenylbutyryluera was somewhat more active as an inducer than was either of the enantiomers (±) or (?) tested singly. Of the other hydrolytic products of phenobarbital, only 2-phenylbutyramide had significant inducer activity (about the same as phenobarbital). Among other ureides tested, tow monosubstituted acetylureas (phenylacetylurea and dodecanoylurea) were inactive as inducers, but six of seven disubstituted acetylureas were better inducers than 2-phenylbutyrylurea.