Fixed drug eruption caused by tadalafil - Case report

Fixed drug eruptions (FDE) are commonly reported type of mucocutaneous drug eruption. The aim of this paper is to present a patient with multiple mucocutaneous erythema fixum type lesions caused by oral tadalafil use. A short course of topical corticosteroid therapy resulted in complete resolution of all lesions leaving residual hyperpigmentation of the involved skin sites. Mucosal oral lesions were effectively treated with gingival hyaluronic acid 0.2% gel. Conclusion: when assessing a patient of any age with drug eruptions, a thorough personal history should be obtained, in particular data on regular or recreational use of phospodiesterase type 5 inhibitors.     

Effect of semiconductor GaAs laser irradiation on pain perception in mice

The influence of subacute exposure (11 exposures within 16 days) of mice to the low power (GaAs) semiconductive laser-stimulated irradiation on pain perception was investigated. The pain perception was determined by the latency of foot-licking or jumping from the surface of a 53 degrees C hot plate. Repeated hot-plate testing resulted in shortening of latencies in both sham- and laser-irradiated mice. Laser treatment (wavelength, 905 nm; frequency, 256 Hz; irradiation time, 50 sec; pulse duration, 100 nsec; distance, 3 cm; peak irradiance, 50 W/cm2 in irradiated area; and total exposure, 0.41 mJ/cm2) induced further shortening of latencies, suggesting its stimulatory influence on pain perception. Administration of morphine (20 mg/kg) prolonged the latency of response to the hot plate in both sham- and laser-irradiated mice. This prolongation tended to be lesser in laser-irradiated animals. Further investigations are required to elucidate the mechanism of the observed effect of laser.     

HAART drugs induce mitochondrial damage and intercellular gaps and gp 120 causes apoptosis

HIV-1 infection is associated with serious cardiovascular complications, but the roles of HIV-1, viral proteins, and highly active antiretroviral therapy (HAART) drugs are not understood. HAART decreases the overall risk of heart disease but leads to metabolic disturbances and possibly coronary artery disease. We investigated toxicities of HIV-1, HIV-1 glycoprotein 120 (gp120), and HAART drugs for human coronary artery endothelial cells (CAECs), brain microvascular endothelial cells, and neonatal rat ventricular myocytes (NRVMs). HIV-1 and gp120, but not azidothymidine (AZT), induced apoptosis of NRVMs and CAECs. Ethylisothiourea, an inhibitor of nitric oxide synthase, inhibited apoptosis induction by gp120. AZT, HIV-1, and gp120 all damaged mitochondria of cardiomyocytes. HAART drugs, AZT, and indinavir, but not HIV-1, produced intercellular gaps between confluent endothelial cells and decreased transendothelial electrical resistance. In conclusion, HIV-1 and gp120 induce toxicity through induction of cardiomyocyte and endothelial cell apoptosis. HAART drugs disrupt endothelial cell junctions and mitochondria and could cause vascular damage.     

Increased incidence of subacute lead perforation noted with one implantable cardioverter-defibrillator.

BACKGROUND: The rapid evolution of implantable cardioverter-defibrillator (ICD) leads has resulted in thinner active fixation leads. While these advances have made the leads more versatile, new configurations may be associated with unforeseen complications. OBJECTIVE: The purpose of this study was to determine the incidence of perforation and dislodgement of defibrillator leads in a single center in the year 2005. METHODS: All patients who underwent percutaneous ICD implantation at the Massachusetts General Hospital using an endocardial right ventricular lead were included in this study. The specific leads analyzed were the Riata (1580/1581 and 1590/1591, St. Jude Medical, St Paul, Minnesota, USA;) and Sprint Fidelis (6949-65, Medtronic, Minneapolis, Minnesota, USA.). Information was collected retrospectively. RESULTS: A total of 130 Riata leads and 111 Sprint Fidelis leads were implanted at the Massachusetts General Hospital during this time period. A total of five lead perforations occurred in patients implanted with the Riata lead as compared with none with the Sprint Fidelis lead (3.8% vs. 0%, respectively; P <.05). Two of the five patients with perforation required pericardiocentesis for tamponade. Clinical symptoms of perforation developed 1-10 days after implant. Moreover, there were five additional lead revisions in the Riata group, which were likely due to dislodgement and/or microperforation, as compared with none in the Sprint Fidelis group (7.7% vs. 0%, respectively; P <.005). CONCLUSIONS: In 2005, at one institution, there were significantly more cardiac perforations and lead revisions with the Riata lead as compared with the Sprint Fidelis right ventricular defibrillator lead. Further data are required to determine whether certain lead characteristics are responsible for this observation.     

Alström Syndrome: Mutation Spectrum of ALMS1

Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone‐rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world‐wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.     

Linked selection and recombination rate variation drive the evolution of the genomic landscape of differentiation across the speciation continuum of Ficedula flycatchers

Speciation is a continuous process during which genetic changes gradually accumulate in the genomes of diverging species. Recent studies have documented highly heterogeneous differentiation landscapes, with distinct regions of elevated differentiation (“differentiation islands”) widespread across genomes. However, it remains unclear which processes drive the evolution of differentiation islands; how the differentiation landscape evolves as speciation advances; and ultimately, how differentiation islands are related to speciation. Here, we addressed these questions based on population genetic analyses of 200 resequenced genomes from 10 populations of four Ficedula flycatcher sister species. We show that a heterogeneous differentiation landscape starts emerging among populations within species, and differentiation islands evolve recurrently in the very same genomic regions among independent lineages. Contrary to expectations from models that interpret differentiation islands as genomic regions involved in reproductive isolation that are shielded from gene flow, patterns of sequence divergence (d_xy and relative node depth) do not support a major role of gene flow in the evolution of the differentiation landscape in these species. Instead, as predicted by models of linked selection, genome-wide variation in diversity and differentiation can be explained by variation in recombination rate and the density of targets for selection. We thus conclude that the heterogeneous landscape of differentiation in Ficedula flycatchers evolves mainly as the result of background selection and selective sweeps in genomic regions of low recombination. Our results emphasize the necessity of incorporating linked selection as a null model to identify genome regions involved in adaptation and speciation.Uncovering the genetic architecture of reproductive isolation and its evolutionary history are central tasks in evolutionary biology. The identification of genome regions that are highly differentiated between closely related species, and thereby constitute candidate regions involved in reproductive isolation, has recently been a major focus of speciation genetic research. Studies from a broad taxonomic range, involving organisms as diverse as plants (Renaut et al. 2013), insects (Turner et al. 2005; Lawniczak et al. 2010; Nadeau et al. 2012; Soria-Carrasco et al. 2014), fishes (Jones et al. 2012), mammals (Harr 2006), and birds (Ellegren et al. 2012) contribute to the emerging picture of a genomic landscape of differentiation that is usually highly heterogeneous, with regions of locally elevated differentiation (“differentiation islands”) widely spread over the genome. However, the evolutionary processes driving the evolution of the differentiation landscape and the role of differentiation islands in speciation are subject to controversy (Turner and Hahn 2010; Cruickshank and Hahn 2014; Pennisi 2014).Differentiation islands were originally interpreted as “speciation islands,” regions that harbor genetic variants involved in reproductive isolation and are shielded from gene flow by selection (Turner et al. 2005; Soria-Carrasco et al. 2014). During speciation-with-gene-flow, speciation islands were suggested to evolve through selective sweeps of locally adapted variants and by hitchhiking of physically linked neutral variation (“divergence hitchhiking”) (Via and West 2008); gene flow would keep differentiation in the remainder of the genome at bay (Nosil 2008; Nosil et al. 2008). In a similar way, speciation islands can arise by allopatric speciation followed by secondary contact. In this case, genome-wide differentiation increases during periods of geographic isolation, but upon secondary contact, it is reduced by gene flow in genome regions not involved in reproductive isolation. In the absence of gene flow in allopatry, speciation islands need not (but can) evolve by local adaptation, but may consist of intrinsic incompatibilities sensu Bateson-Dobzhansky-Muller (Bateson 1909; Dobzhansky 1937; Muller 1940) that accumulated in spatially isolated populations.However, whether differentiation islands represent speciation islands has been questioned. Rather than being a cause of speciation, differentiation islands might evolve only after the onset of reproductive isolation as a consequence of locally accelerated lineage sorting (Noor and Bennett 2009; Turner and Hahn 2010; White et al. 2010; Cruickshank and Hahn 2014; Renaut et al. 2014), such as in regions of low recombination (Nachman 2002; Sella et al. 2009; Cutter and Payseur 2013). In these regions, the diversity-reducing effects of both positive selection and purifying selection (background selection [BGS]) at linked sites (“linked selection”) impact physically larger regions due to the stronger linkage among sites. The thereby locally reduced effective population size (N_e) will enhance genetic drift and hence inevitably lead to increased differentiation among populations and species.These alternative models for the evolution of a heterogeneous genomic landscape of differentiation are not mutually exclusive, and their population genetic footprints can be difficult to discern. In the cases of (primary) speciation-with-gene-flow and gene flow at secondary contact, shared variation outside differentiation islands partly stems from gene flow. In contrast, under linked selection, ancestral variation is reduced and differentiation elevated in regions of low recombination, while the remainder of the genome may still share considerable amounts of ancestral genetic variation and show limited differentiation. Many commonly used population genetic statistics do not capture these different origins of shared genetic variation and have the same qualitative expectations under both models, such as reduced diversity (π) and skews toward an excess of rare variants (e.g., lower Tajima''s D) in differentiation islands relative to the remainder of the genome. However, since speciation islands should evolve by the prevention or breakdown of differentiation by gene flow in regions not involved in reproductive isolation, substantial gene flow should be detectable in these regions (Cruickshank and Hahn 2014) and manifested in the form of reduced sequence divergence (d_xy) or as an excess of shared derived alleles in cases of asymmetrical gene flow (Patterson et al. 2012). Under linked selection, predictions are opposite for d_xy (Cruickshank and Hahn 2014), owing to reduced ancestral diversity in low-recombination regions. Further predictions for linked selection include positive and negative relationships of recombination rate with genetic diversity (π) and differentiation (F_ST), respectively, and inverse correlations of the latter two with the density of targets for selection. Finally, important insights into the nature of differentiation islands may be gained by studying the evolution of differentiation landscapes across the speciation continuum. Theoretical models and simulations of speciation-with-gene-flow predict that after an initial phase during which differentiation establishes in regions involved in adaptation, differentiation should start spreading from these regions across the entire genome (Feder et al. 2012, 2014; Flaxman et al. 2013).Unravelling the processes driving the evolution of the genomic landscape of differentiation, and hence understanding how genome differentiation unfolds as speciation advances, requires genome-wide data at multiple stages of the speciation continuum and in a range of geographical settings from allopatry to sympatry (Seehausen et al. 2014). Although studies of the speciation continuum are emerging (Hendry et al. 2009; Kronforst et al. 2013; Shaw and Mullen 2014, and references therein), empirical examples of genome differentiation at multiple levels of species divergence remain scarce (Andrew and Rieseberg 2013; Kronforst et al. 2013; Martin et al. 2013), and to our knowledge, have so far not jointly addressed the predictions of alternative models for the evolution of the genomic landscape of differentiation. In the present study, we implemented such a study design encompassing multiple populations of four black-and-white flycatcher sister species of the genus Ficedula (Fig. 1A,B; Supplemental Fig. S1; for a comprehensive reconstruction of the species tree, see Nater et al. 2015). Previous analyses in collared flycatcher (F. albicollis) and pied flycatcher (F. hypoleuca) revealed a highly heterogeneous differentiation landscape across the genome (Ellegren et al. 2012). An involvement of gene flow in its evolution would be plausible, as hybrids between these species occur at low frequencies in sympatric populations in eastern Central Europe and on the Baltic Islands of Gotland and Öland (Alatalo et al. 1990; Sætre et al. 1999), although a recent study based on genome-wide markers identified no hybrids beyond the F₁ generation (Kawakami et al. 2014a). Still, gene flow from pied into collared flycatcher appears to have occurred (Borge et al. 2005; Backström et al. 2013; Nadachowska-Brzyska et al. 2013) despite premating isolation (for review, see Sætre and Sæther 2010), hybrid female sterility (Alatalo et al. 1990; Tegelström and Gelter 1990), and strongly reduced long-term fitness of hybrid males (Wiley et al. 2009). Atlas flycatcher (F. speculigera) and semicollared flycatcher (F. semitorquata) are two closely related species, which have been less studied, but may provide interesting insights into how genome differentiation evolves over time. Here, we take advantage of this system to identify the processes underlying the evolution of differentiation islands based on the population genetic analysis of whole-genome resequencing data of 200 flycatchers.Open in a separate windowFigure 1.A recurrently evolving genomic landscape of differentiation across the speciation continuum in Ficedula flycatchers. (A) Species’ neighbor-joining tree based on mean genome-wide net sequence divergence (d_A). The same species tree topology was inferred with 100% bootstrap support from the distribution of gene trees under the multispecies coalescent (Supplemental Fig. S1). (B) Map showing the locations of population sampling and approximate species ranges. (C) Population genomic parameters along an example chromosome (Chromosome 4A) (see Supplemental Figs. S2, S4 for all chromosomes). Color codes for specific–specific parameters: (blue) collared; (green) pied; (orange) Atlas; (red) semicollared. Color codes for d_xy: (green) collared-pied; (light blue) collared-Atlas; (blue) collared-semicollared; (orange) pied-Atlas; (red) pied-semicollared; (black) Atlas-semicollared. For differentiation within species, comparisons with the Italian (collared) and Spanish (pied) populations are shown. Color codes for F_ST within collared flycatchers: (cyan) Italy–Hungary; (light blue) Italy–Czech Republic; (dark blue) Italy–Baltic. Color codes for F_ST within pied flycatchers: (light green) Spain–Sweden; (green) Spain–Czech Republic; (dark green) Spain–Baltic. (D) Distributions of differentiation (F_ST) from collared flycatcher along the speciation continuum. Distributions are given separately for three autosomal recombination percentiles (33%; 33%–66%; 66%–100%) corresponding to high (>3.4 cM/Mb, blue), intermediate (1.3–3.4 cM/Mb, orange), and low recombination rate (0–1.3 cM/Mb, red), and the Z Chromosome (green). Geographically close within-species comparison: Italy–Hungary. Comparisons within species include the geographically close Italian and Hungarian populations (within [close]), and the geographically distant Italian and Baltic populations (within [far]). Geographically far within-species comparison: Italy–Baltic. (E) Differentiation from collared flycatcher along an example chromosome (Chromosome 11) (see Supplemental Fig. S3 for all chromosomes). Color codes for between-species comparisons: (green) pied; (orange) Atlas; (red) semicollared; (dark red) red-breasted; (black) snowy-browed flycatcher. Color codes for within-species comparisons: (cyan) Italy–Hungary; (blue) Italy–Baltic. Flycatcher artwork in panel A courtesy of Dan Zetterström.     

Ultrastructural Changes of Mitochondria in the Cultivated Skin Fibroblasts of Patients with Point Mutations in Mitochondrial DNA

Mitochondrial disorders represent a heterogeneous group of multisystem diseases with extreme variability in clinical phenotype. The diagnosis of mitochondrial disorders relies heavily on extensive biochemical and molecular analyses combined with morphological studies including electron microscopy. Although muscle is the tissue of choice for electron microscopic studies, the authors investigated cultivated human skin fibroblasts (HSF) harboring 3 different pathologic mtDNA mutations: 3243A > G, 8344A > G, 8993T > G. They addressed to the possibility of whether mtDNA mutations influence mitochondrial morphology in HSF and if ultrastructural changes of mitochondria may be used for differential diagnostics of mitochondrial disorders caused by mtDNA mutations. Ultrastructural analysis of patients' HSF revealed a heterogeneous mixture of mainly abnormal, partially swelling mitochondria with unusual and sparse cristae. The most characteristic cristal abnormalities were heterogeneity in size and shapes or their absence. Typical filamentous and branched mitochondria with numerous cristae as appeared in control HSF were almost not observed. In all lines of cultured HSF with various mtDNA mutations, similar ultrastructural abnormalities and severely changed mitochondrial interior were found, although no alterations in function and amount of OXPHOS were detected by routinely used biochemical methods in two lines of cultured HSF. This highlights the importance of morphological analysis, even in cultured fibroblasts, in diagnostics of mitochondrial disorders.     

Cell-Free Lactobacillus casei 21L10 Modulates Nitric Oxide Release and Cell Proliferation/Cell Death in Lipopolysaccharide-Challenged HT-29 Cells

Inflammation - Lactobacillus casei (L. casei) is one of the probiotic strains that may influence intestinal injury and inflammation in nonspecific intestinal diseases. We aimed to evaluate the...     

Investigating unset endodontic sealers’ eugenol and hydrocortisone roles in modulating the initial steps of inflammation

Endodontic treatment success is achieved not only when the cement provides a hermetic seal but also when the injured periapical tissue is regenerated. Howe