Real-world experience of vedolizumab use in Colombian patients with inflammatory bowel disease-EXVEDOCOL.

BACKGROUND: Real-world studies about the effectiveness and safety of vedolizumab (VDZ) in the treatment of inflammatory bowel disease (IBD) in Latin America are scarce. Our study describes the effectiveness and safety of VDZ in Colombian patients with IBD. METHODS: EXVEDOCOL (EXperience of VEDOlizumab in COLombia) was a retrospective, multicenter, observational study. Adults with IBD receiving a first dose of VDZ between July 2016 and October 2018 were included. The co-primary outcomes clinical response, and remission, were determined at week 14 and last visit during the maintenance phase (LVMP). The secondary outcomes, deep remission and loss of response were recorded at LVMP. RESULTS: Thirty-one patients (25 ulcerative colitis (UC), 6 Crohn's disease (CD)) were included. At week 14, clinical response was achieved by 87.1% (27/31) of the patients treated with VDZ, while loss of response was reported in 6.7% (2/30). The remission rate at week 14 was 65.5% (19/29) and 75.9% (22/29) at LVMP. Prior anti-TNF exposure was reported in 61.3% (19 patients) of whom 84.2% (16/19) achieved clinical response at week 14 and 89.5% (17/19) at LVMP. For anti-TNF naïve patients, clinical response was recorded in 91.7% (11/12) at week 14 and 100% (12/12) at LVMP. CONCLUSIONS: High clinical remission rates and safety profile highlight VDZ as a valuable treatment option for IBD patients. Anti-TNF naïve patients may derive greater benefit from therapy. Studies with larger cohorts could confirm these findings.

Attack on crypsis: Molecular and morphological study of Dendrodoris Ehrenberg, 1831 (Mollusca: Gastropoda: Nudibranchia) from the Mediterranean Sea and Northern Atlantic Ocean reinstates Dendrodoris temarana Pruvot-Fol, 1953.

The genus Dendrodoris is ascribed to the family Dendrodorididae, whose members are characterized lacking spicules in the dorsum as well as a radula, one of the most important taxonomic traits to distinguish and define nudibranch species. The absence of this taxonomic character makes difficult to delineate species based on morphologic traits, and consequently, several cryptic species may remain unreported resulting in a potential underestimation of the real diversity of the genus. Species delimitation analyses based on molecular data constitute an important tool to unveil cryptic species, especially when morphology may be misleading. However, for the genus Dendrodoris, only two molecular studies have been performed to date, both based on Indo-pacific species and the molecular marker COI. In the present study, we performed a multilocus approach using the molecular markers COI, 16S and H3 based on 47 Dendrodoris specimens from the North Atlantic Ocean and Mediterranean Sea. As a result, we detected monophyly for five of the previously accepted species plus the presence of an unidentified one. Using morphological and anatomical data from 14 additional individuals and a review of the literature, we verified this unidentified species is the previously synonymized species Dendrodoris temarana Pruvot-Fol, 1953, and we redescribe it morphologically (chromatic pattern, gills, rhinophores and anal papilla), anatomically (neural, circulatory, digestive and reproductive systems), and biologically herein. D. temarana is differentiated by its chromatic pattern, previously thought to be intraspecific variation of D. grandiflora (Rapp, 1827), D. limbata (Cuvier, 1804) and D. herytra Valds Ortea in Valds, Ortea, Avila Ballesteros, 1996, and therefore it is considered a pseudocryptic species. This study increases the number of valid species in the North Atlantic and Mediterranean to nine and confirms the importance of integrative taxonomic approaches to resolve the identification of cryptic species in complex groups.

Primary splenic angiosarcoma. An aggressive and infrequent pathology.

Splenic angiosarcoma is a very rare and aggressive neoplasm originating from the splenic vascular endothelium whose prognosis is very poor despite surgical treatment. Preoperative diagnosis using imaging tests is a challenge due to its similarity to other vascular splenic tumors. The most common treatment is splenectomy, although it is rarely curative because of the aggressive and metastatic nature of the disease.

Controlled Transportation of Light by Light at the Microscale.

We show how light can be controllably transported by light at microscale dimensions. We design a miniature device that consists of a short segment of an optical fiber coupled to transversally oriented input-output microfibers. A whispering gallery soliton is launched from the first microfiber into the fiber segment and slowly propagates along its mm-scale length. The soliton loads and unloads optical pulses at designated input-output microfibers. The speed of the soliton and its propagation direction is controlled by the dramatically small, yet feasible to introduce, permanently or all-optically, nanoscale variations of the effective fiber radius.

Four-port SNAP microresonator device.

It is well known from quantum mechanics that the transmission amplitude of a symmetric double-barrier structure can approach unity at the resonance condition. A similar phenomenon is observed in optics for light which propagates between two waveguides weakly coupled through a microresonator. Examples of microresonators used for this purpose include ring, photonic crystal, toroidal, and bottle microresonators. However, ring and photonic crystal photonic circuits, once fabricated, cannot be finely tuned to arrive at the mentioned resonant condition. In turn, it is challenging to predictably adjust coupling to toroidal and bottle microresonators by translating the input-output microfibers, since the modes of these resonators are difficult to separate spatially. Here we experimentally demonstrate a four-port micro-device based on a SNAP microresonator introduced at the surface of an optical fiber. The eigenmodes and corresponding eigenwavelengths of this resonator are clearly identified for both polarization states by the spectrograms measured along the length of the fiber. This allows us to choose the resonant wavelength and simultaneously determine the positions of the input-output microfiber tapers to arrive at the required resonance condition.

Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II.

Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized by severe encephalopathy with mental retardation, microcephaly, generalized dystonia, and movement disorders. Currently, the etiology of type II RHM is poorly understood and there is no treatment for encephalopathy associated with this disease. Defective CYB5R3 leads to defects in the elongation and desaturation of fatty acids and cholesterol biosynthesis, which are conventionally linked with neurological disorders of type II RHM. Nevertheless, this abnormal lipid metabolism cannot explain all manifestations observed in patients. Current molecular and cellular studies indicate that CYB5R3 deficiency has pleiotropic tissue effects. Its localization in lipid rafts of neurons indicates its role in interneuronal contacts and its presence in caveolae of the vascular endothelial membrane suggests a role in the modulation of nitric oxide diffusion. Its role in aerobic metabolism and oxidative stress in fibroblasts, neurons, and cardiomyocytes has been reported to be due to its ability to modulate the intracellular ratio of NAD⁺/NADH. Based on the new molecular and cellular functions discovered for CYB5R3 linked to the plasma membrane and mitochondria, the conventional conception that the cause of type II RHM is a lipid metabolism disorder should be revised. We hypothesized that neurological symptoms of the disease could be caused by disorders in the synapse, aerobic metabolism, and/or vascular homeostasis rather than in disturbances of lipid metabolism.

Breaking out of the comfort zone: El Niño-Southern Oscillation as a driver of trophic flows in a benthic consumer of the Humboldt Current ecosystem.

The trophic flow of a species is considered a characteristic trait reflecting its trophic position and function in the ecosystem and its interaction with the environment. However, climate patterns are changing and we ignore how patterns of trophic flow are being affected. In the Humboldt Current ecosystem, arguably one of the most productive marine systems, El Niño-Southern Oscillation is the main source of interannual and longer-term variability. To assess the effect of this variability on trophic flow we built a 16-year series of mass-specific somatic production rate (P/B) of the Peruvian scallop (Argopecten purpuratus), a species belonging to a former tropical fauna that thrived in this cold ecosystem. A strong increase of the P/B ratio of this species was observed during nutrient-poor, warmer water conditions typical of El Niño, owing to the massive recruitment of fast-growing juvenile scallops. Trophic ecology theory predicts that when primary production is nutrient limited, the trophic flow of organisms occupying low trophic levels should be constrained (bottom-up control). For former tropical fauna thriving in cold, productive upwelling coastal zones, a short time of low food conditions but warm waters during El Niño could be sufficient to waken their ancestral biological features and display massive proliferations.

The End of the Cold Loneliness: 3D Comparison between Doto antarctica and a New Sympatric Species of Doto (Heterobranchia: Nudibranchia).

Although several studies are devoted to determining the diversity of Antarctic heterobranch sea slugs, new species are still being discovered. Among nudibranchs, Doto antarctica Eliot, 1907 is the single species of this genus described from Antarctica hitherto, the type locality being the Ross Sea. Doto antarctica was described mainly using external features. During our Antarctic research on marine benthic invertebrates, we found D. antarctica in the Weddell Sea and Bouvet Island, suggesting a circumpolar distribution. Species affiliation is herein supported by molecular analyses using cytochrome c oxidase subunit I, 16S rRNA, and histone H3 markers. We redescribe D. antarctica using histology, micro-computed tomography (micro-CT), and 3D-reconstruction of the internal organs. Moreover, we describe a new, sympatric species, namely D. carinova Moles, Avila & Wägele n. sp., and provide an anatomical comparison between the two Antarctic Doto species. Egg masses in both species are also described here for the first time. We demonstrate that micro-CT is a useful tool for non-destructive anatomical description of valuable specimens. Furthermore, our high resolution micro-CT data reveal that the central nervous system of both Doto species possesses numerous accessory giant cells, suggested to be neurons herein. In addition, the phylogenetic tree of all Doto species sequenced to date suggests a scenario for the evolution of the reproductive system in this genus: bursa copulatrix seems to have been reduced and the acquisition of a distal connection of the oviduct to the nidamental glands is a synapomorphy of the Antarctic Doto species. Overall, the combination of thorough morphological and anatomical description and molecular analyses provides a comprehensive means to characterize and delineate species, thus suggesting evolutionary scenarios.

The phosphatase Ptc7 induces coenzyme Q biosynthesis by activating the hydroxylase Coq7 in yeast.

The study of the components of mitochondrial metabolism has potential benefits for health span and lifespan because the maintenance of efficient mitochondrial function and antioxidant capacity is associated with improved health and survival. In yeast, mitochondrial function requires the tight control of several metabolic processes such as coenzyme Q biosynthesis, assuring an appropriate energy supply and antioxidant functions. Many mitochondrial processes are regulated by phosphorylation cycles mediated by protein kinases and phosphatases. In this study, we determined that the mitochondrial phosphatase Ptc7p, a Ser/Thr phosphatase, was required to regulate coenzyme Q6 biosynthesis, which in turn activated aerobic metabolism and enhanced oxidative stress resistance. We showed that Ptc7p phosphatase specifically activated coenzyme Q6 biosynthesis through the dephosphorylation of the demethoxy-Q6 hydroxylase Coq7p. The current findings revealed that Ptc7p is a regulator of mitochondrial metabolism that is essential to maintain proper function of the mitochondria by regulating energy metabolism and oxidative stress resistance.

Plasma concentrations of organohalogenated pollutants in predatory bird nestlings: associations to growth rate and dietary tracers.

The extent to which persistent organic pollutants (POPs) with different physicochemical properties originated from the food (dietary input) was assessed in raptor nestlings. Lipophilic polychlorinated biphenyl (PCB) 153, 1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), and hexachlorobenzene (HCB), and protein-bound perfluorooctane sulfonate (PFOS), were measured repeatedly in blood plasma of individual goshawk (Accipiter gentilis) and white-tailed eagle (Haliaeetus albicilla) nestlings, 1 to 3 wk after hatching and near fledging. Maternally derived POPs dilute as nestlings grow (growth dilution), and increasing plasma concentrations would indicate dietary input. First, plasma concentrations given no dietary input were estimated, and concentrations of p,p'-DDE, HCB, and notably PFOS were significantly higher than predicted from a growth-dilution scenario (approximately 1.5-fold to 2.5-fold higher; p < 0.001). In contrast, PCB 153 declined in both species, although concentrations were still higher than predicted in white-tailed eagle nestlings (p < 0.05). Second, the relationships between plasma POP concentrations and trophic position (δ(15) N) and dietary carbon source (δ(13) C) were analyzed, controlling for growth rate. Both δ(15) N and δ(13) C (measured in body feathers) were significantly associated to the accumulation of most POPs, except PFOS. In conclusion, pollutant data acquired in plasma of nestling raptors should be interpreted and further investigated in the light of individual feeding ecology, and the use of raptor nestlings as sentinels for POP monitoring could be optimized by correcting for different factors such as body condition, brood size, and age.

Ecological and spatial factors drive intra- and interspecific variation in exposure of subarctic predatory bird nestlings to persistent organic pollutants.

Top predators in northern ecosystems may suffer from exposure to persistent organic pollutants (POPs) as this exposure may synergistically interact with already elevated natural stress in these ecosystems. In the present study, we aimed at identifying biological (sex, body condition), ecological (dietary carbon source, trophic level) and spatial factors (local habitat, regional nest location) that may influence intra- and interspecific variation in exposure of subarctic predatory bird nestlings to polychlorinated biphenyl 153 (CB 153), polybrominated diphenyl ether 47 (BDE 47), dichlorodiphenyldichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB). During three breeding seasons (2008-2010), we sampled body feathers from fully-grown nestlings of three ecologically distinct predatory bird species in subarctic Norway: Northern Goshawk (Accipiter gentilis), White-tailed Eagle (Haliaeetus albicilla) and Golden Eagle (Aquila chrysaetos). The present study analysed, for the first time, body feathers for both POPs and carbon (δ(13)C) and nitrogen (δ(15)N) stable isotopes, thus integrating the dietary carbon source, trophic level and POP exposure for the larger part of the nestling stage. Intraspecific variation in exposure was driven by a combination of ecological and spatial factors, often different for individual compounds. In addition, combinations for individual compounds differed among species. Trophic level and local habitat were the predominant predictors for CB 153, p,p'-DDE and BDE 47, indicating their biomagnification and decreasing levels according to coast>fjord>inland. Variation in exposure may also have been driven by inter-annual variation arisen from primary sources (e.g. p,p'-DDE) and/or possible revolatilisation from secondary sources (e.g. HCB). Interspecific differences in POP exposure were best explained by a combination of trophic level (biomagnification), dietary carbon source (food chain discrimination) and regional nest location (historical POP contamination). In conclusion, the combined analysis of POPs and stable isotopes in body feathers from fully-grown nestlings has identified ecological and spatial factors that may drive POP exposure over the larger part of the nestling stage. This methodological approach further promotes the promising use of nestling predatory bird body feathers as a non-destructive sampling strategy to integrate various toxicological and ecological proxies.

Antiparasite treatments reduce humoral immunity and impact oxidative status in raptor nestlings.

Parasites are natural stressors that may have multiple negative effects on their host as they usurp energy and nutrients and may lead to costly immune responses that may cause oxidative stress. At early stages, animals may be more sensitive to infectious organisms because of their rapid growth and partly immature immune system. The objective of this study was to explore effects of parasites by treating chicks of two raptor species (northern goshawk Accipiter gentilis and white-tailed sea eagle Haliaeetus albicilla) against both endoparasites (internal parasites) and ectoparasites (external parasites). Nests were either treated against ectoparasites by spraying with pyrethrin or left unsprayed as control nests. Within each nest, chicks were randomly orally treated with either an antihelminthic medication (fenbendazole) or sterile water as control treatment. We investigated treatment effects on plasma (1) total antioxidant capacity TAC (an index of nonenzymatic circulating antioxidant defenses), (2) total oxidant status TOS (a measure of plasmatic oxidants), and (3) immunoglobulin levels (a measure of humoral immune function). Treatment against ectoparasites led to a reduction in circulating immunoglobulin plasma levels in male chicks. TOS was higher when not receiving any parasite reduction treatment and when receiving both endo- and ectoparasitic reduction treatment compared with receiving only one treatment. TAC was higher in all treatment groups, when compared to controls. Despite the relatively low sample size, this experimental study suggests complex but similar relationships between treatment groups and oxidative status and immunoglobulin levels in two raptor species.

Blood plasma clinical-chemical parameters as biomarker endpoints for organohalogen contaminant exposure in Norwegian raptor nestlings.

Raptors are exposed to biomagnifying and toxic organohalogenated compounds (OHCs) such as organochlorines, brominated flame retardants and perfluorinated compounds. To investigate how OHC exposure may affect biochemical pathways we collected blood plasma from Norwegian northern goshawk (n=56), golden eagle (n=12) and white-tailed eagle (n=36) nestlings during three consecutive breeding seasons. We found that blood plasma concentrations of calcium, sodium, creatinine, cholesterol, albumin, total protein, urea, inorganic phosphate, protein:creatinine, urea:creatinine and uric acid:creatinine ratios and liver enzymes ALKP and ALAT were positively correlated to PCBs, chlordanes, p,p'-DDE, HCB, PFCs and/or PBDEs. Total bilirubin and glucose were negatively correlated to PCBs while magnesium and potassium were negatively correlated to HCB and p,p'-DDE. In addition, protein:creatinine and ALAT were also negatively correlated to PCBs and PFCs, respectively. The most significant relationships were found for the highly contaminated northern goshawks and white-tailed eagles. The statistical relationships between OHCs and BCCPs indicate that biochemical pathways could be influenced while it is uncertain if such changes have any health effects. The OHC concentrations were below concentrations causing reproductive toxicity in adults of other raptor species but similar to those of concern for endocrine disruption of thyroid hormones in e.g., bald eagles.

Respiratory-induced coenzyme Q biosynthesis is regulated by a phosphorylation cycle of Cat5p/Coq7p.

CoQ(6) (coenzyme Q(6)) biosynthesis in yeast is a well-regulated process that requires the final conversion of the late intermediate DMQ(6) (demethoxy-CoQ(6)) into CoQ(6) in order to support respiratory metabolism in yeast. The gene CAT5/COQ7 encodes the Cat5/Coq7 protein that catalyses the hydroxylation step of DMQ(6) conversion into CoQ(6). In the present study, we demonstrated that yeast Coq7 recombinant protein purified in bacteria can be phosphorylated in vitro using commercial PKA (protein kinase A) or PKC (protein kinase C) at the predicted amino acids Ser(20), Ser(28) and Thr(32). The total absence of phosphorylation in a Coq7p version containing alanine instead of these phospho-amino acids, the high extent of phosphorylation produced and the saturated conditions maintained in the phosphorylation assay indicate that probably no other putative amino acids are phosphorylated in Coq7p. Results from in vitro assays have been corroborated using phosphorylation assays performed in purified mitochondria without external or commercial kinases. Coq7p remains phosphorylated in fermentative conditions and becomes dephosphorylated when respiratory metabolism is induced. The substitution of phosphorylated residues to alanine dramatically increases CoQ(6) levels (256%). Conversely, substitution with negatively charged residues decreases CoQ(6) content (57%). These modifications produced in Coq7p also alter the ratio between DMQ(6) and CoQ(6) itself, indicating that the Coq7p phosphorylation state is a regulatory mechanism for CoQ(6) synthesis.

Triterpene glycosides from Antarctic sea cucumbers III. Structures of liouvillosides A(4) and A(5), two minor disulphated tetraosides containing 3-O-methylquinovose as terminal monosaccharide units from the sea cucumber Staurocucumis liouvillei (Vaney).

Two new minor triterpene glycosides, liouvillosides A(4) (1) and A(5) (2) have been isolated from the sea cucumber Staurocucumis liouvillei living in Antarctic and Sub-Antarctic waters. The structures of the new glycosides were elucidated using extensive nuclear magnetic resonance (NMR) spectroscopy ((1)H- and (13)C-NMR spectroscopy, (1)H-(1)H COSY, 1D-TOCSY, HMBC, HSQC and NOESY), ESI-MS and MALDI TOF MS. The glycosides 1 and 2 are disulphated tetraosides having very rare 3-O-methylquinovose as terminal monosaccharide.

Increased RNA polymerase availability directs resources towards growth at the expense of maintenance.

Nutritionally induced changes in RNA polymerase availability have been hypothesized to be an evolutionary primeval mechanism for regulation of gene expression and several contrasting models have been proposed to explain how such 'passive' regulation might occur. We demonstrate here that ectopically elevating Escherichia coli RNA polymerase (Esigma(70)) levels causes an increased expression and promoter occupancy of ribosomal genes at the expense of stress-defense genes and amino acid biosynthetic operons. Phenotypically, cells overproducing Esigma(70) favours growth and reproduction at the expense of motility and damage protection; a response reminiscent of cells with no or diminished levels of the alarmone guanosine tetraphosphate (ppGpp). Consistently, we show that cells lacking ppGpp displayed markedly elevated levels of free Esigma(70) compared with wild-type cells and that the repression of ribosomal RNA expression and reduced growth rate of mutants with constitutively elevated levels of ppGpp can be suppressed by overproducing Esigma(70). We conclude that ppGpp modulates the levels of free Esigma(70) and that this is an integral part of the alarmone's means of regulating a trade-off between growth and maintenance.

Triterpene glycosides from Antarctic sea cucumbers. 1. Structure of liouvillosides A1, A2, A3, B1, and B2 from the sea cucumber Staurocucumis liouvillei: new procedure for separation of highly polar glycoside fractions and taxonomic revision.

Five new triterpene glycosides, liouvillosides A1 (1), A2 (2), A3 (3), B1 (4), and B2 (5), have been isolated from the Antarctic sea cucumber Staurocucumis liouviellei along with the known liouvilloside A(6), isolated earlier from the same species, and hemoiedemosides A (7) and B (8), isolated earlier from the Patagonian sea cucumber Hemioedema spectabilis. The isolation was carried out using a new chromatographic procedure including application of ion-pair reversed-phase chromatography followed by chiral chromatography on a cyclodextrin ChiraDex column. The structures of the new glycosides were elucidated using extensive NMR spectroscopy (1H and 13C NMR spectrometry, DEPT, 1H-(1)H COSY, HMBC, HMQC, and NOESY), ESI-FTMS, and CID MS/MS, and chemical transformations. Glycosides 1-3 are disulfated tetraosides and glycosides 4 and 5 are trisulfated tetraosides. Glycosides 2 and 3 contain 3-O-methylquinovose, found for the first time as a natural monosaccharide in sea cucumber glycosides. On the basis of analyses of glycoside structures a taxonomic revision is proposed.

Influenza A virus in birds during spring migration in the Camargue, France.

Wild aquatic birds are considered to be the natural reservoir for influenza A viruses, and previous studies have focused mainly on species in the orders Anseriformes and Charadriiformes. In this study, we surveyed a larger spectrum of potential hosts belonging to 10 avian orders. Cloacal swabs (n=1,044) from 72 free-living bird species, were analysed by reverse transcription-polymerase chain reaction for the presence of avian influenza virus. Only two Mediterranean Gulls (Larus melanocephalus) tested positive; one of these viruses was identified as an H9N2 subtype. The absence of infection among passerine birds supports the idea that the prevalence of avian influenza virus infection in terrestrial species is low.