Safety, pharmacokinetics, and pharmacodynamics of RSLV-132, an RNase-Fc fusion protein in systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study.

Blood-borne RNA circulating in association with autoantibodies is a potent stimulator of interferon production and immune system activation. RSLV-132 is a novel fully human biologic Fc fusion protein that is comprised of human RNase fused to the Fc domain of human IgG1. The drug is designed to remain in circulation and digest extracellular RNA with the aim of preventing activation of the immune system via Toll-like receptors and the interferon pathway. The present study describes the first clinical study of nuclease therapy in 32 subjects with systemic lupus erythematosus. The drug was well tolerated with a very favorable safety profile. The approximately 19-day serum half-life potentially supports once monthly dosing. There were no subjects in the study that developed anti-RSLV-132 antibodies. Decreases in B-cell activating factor correlated with decreases in disease activity in a subset of patients.

Interspecific transmission and recovery of TCBS-induced disease between Acanthaster planci and Linckia guildingi.

The susceptibility of the coral-feeding crown-of-thorns starfish Acanthaster planci to disease may provide an avenue with which to effectively control population outbreaks that have caused severe and widespread coral loss in the Indo-Pacific. Injecting thiosulfate-citrate-bile-sucrose (TCBS) agar into A. planci tissues induced a disease characterized by dermal lesions, loss of skin turgor, collapsed spines, and accumulation of mucus on spine tips. Moreover, the symptoms (and presumably the agent) of this disease would spread rapidly intraspecifically, but interspecific transmission (to other species of echinoderms) is yet to be examined. Vibrio rotiferianus, which was previously reported as a pathogen isolated from lesions of experimentally infected A. planci, was also recovered from Linckia guildingi lesions after several days of direct contact with diseased A. planci, demonstrating disease transmission. However, all L. guildingi fully recovered after 31 ± 16 d. Further studies are in progress to understand the ecology of Vibrio infection in A. planci and the potential transmission risk to corals, fishes, and other echinoderms to evaluate whether injections of TCBS could be a viable tool for controlling A. planci outbreaks.

Refined identification of Vibrio bacterial flora from Acanthasther planci based on biochemical profiling and analysis of housekeeping genes.

We used a polyphasic approach for precise identification of bacterial flora (Vibrionaceae) isolated from crown-of-thorns starfish (COTS) from Lizard Island (Great Barrier Reef, Australia) and Guam (U.S.A., Western Pacific Ocean). Previous 16S rRNA gene phylogenetic analysis was useful to allocate and identify isolates within the Photobacterium, Splendidus and Harveyi clades but failed in the identification of Vibrio harveyi-like isolates. Species of the V harveyi group have almost indistinguishable phenotypes and genotypes, and thus, identification by standard biochemical tests and 16S rRNA gene analysis is commonly inaccurate. Biochemical profiling and sequence analysis of additional topA and mreB housekeeping genes were carried out for definitive identification of 19 bacterial isolates recovered from sick and wild COTS. For 8 isolates, biochemical profiles and topA and mreB gene sequence alignments with the closest relatives (GenBank) confirmed previous 16S rRNA-based identification: V. fortis and Photobacterium eurosenbergii species (from wild COTS), and V natriegens (from diseased COTS). Further phylogenetic analysis based on topA and mreB concatenated sequences served to identify the remaining 11 V harveyi-like isolates: V. owensii and V. rotiferianus (from wild COTS), and V. owensii, V. rotiferianus, and V. harveyi (from diseased COTS). This study further confirms the reliability of topA-mreB gene sequence analysis for identification of these close species, and it reveals a wider distribution range of the potentially pathogenic V. harveyi group.

Injection of Acanthaster planci with thiosulfate-citrate-bile-sucrose agar (TCBS). I. Disease induction.

This is the first report of the successful induction of a transmissible disease in the coral-eating crown-of-thorns starfish Acanthaster planci (COTS). Injection of thiosulfate-citrate-bile-sucrose agar (TCBS) culture medium into COTS induced a disease characterized by discoloured and necrotic skin, ulcerations, loss of body turgor, accumulation of colourless mucus on many spines especially at their tip, and loss of spines. Blisters on the dorsal integument broke through the skin surface and resulted in large, open sores that exposed the internal organs. Oedema and reddened digestive tissues and destruction of connective fibers were common. Moreover, healthy COTS in contact with these infected animals also displayed signs of disease and died within 24 h. TCBS induced 100% mortality in injected starfish. There was no introduction of new pathogens into the marine environment. TCBS promoted the growth of COTS' naturally occurring Vibrionales to high densities with subsequent symbiont imbalance followed by disease and death.

Injection of Acanthaster planci with thiosulfate-citrate-bile-sucrose agar (TCBS). II. Histopathological changes.

We assessed histological changes in the tissues of the crown-of-thorns starfish Acanthaster planci (COTS) after injection of thiosulfate-citrate-bile-sucrose agar (TCBS) which was used as a disease inducer (potential outbreak control method), by conventional and scanning electron microscopy. Digestive glands were processed and stained with hematoxylin and eosin to describe the histological architecture of the intestinal epithelium. Subsequently comparison of healthy versus infected tissues and Gram stains were carried out to confirm bacterial occurrence on infected tissues, characterize the structural changes induced by bacterial communities in COTS tissues, and to determine if the histopathological changes of intestinal tissues were consistent with vibrio infection. TCBS injections induced marked epithelial desquamation, hypertrophy and hypersecretion of glandular cells, epithelial cell destruction, pyknosis, reduction of thickness and disorganization of connective tissue and associated nerve plexus, presence of bacterial colonies, irregular eosinophilic foci in glandular cells, brush border disruption, atrophy and detachment of intestinal microvilli and cell debris in the lumen. All these changes were attributed to a fulminating systemic dysbiosis and were consistent with vibrio infections.

A mathematical model for predicting the viability of airborne viruses.

A mathematical model was developed to predict the viability of airborne viruses. The model uses water activity as the primary independent variable and an exponential decay function for the viability of the virus. This model was tested using published experimental data obtained by different investigators for influenza, Langat and polio viruses. The aerosolized media were modelled as a binary solution of water and sodium chloride. The water activity is related directly to the solute concentration in the binary solution. The minimum viability usually occurred just above the efflorescence point, which is the relative humidity at which the solution crystallizes. The relationship between water activity and relative humidity is based on the Köhler theory, whereby the Kelvin term was taken into account. Physical explanations are provided on the variation of viral viability at different relative humidity levels. The predictions obtained by the proposed mathematical model compare well with most of the published experimental data.

Giant congenital mesenteric hernia in the adult.

INTRODUCTION: Internal hernia is a visceral protrusion through a defect or aperture, either mesenteric or peritoneal and is an uncommon cause of intestinal obstruction. Within this group, the congenital mesenteric (transmesenteric) hernia is extremely rare, being more common in the pediatric population. OBJECTIVE: To present the case of a 38-year-old woman with intestinal obstruction and acute abdomen who underwent surgery. A giant mesenteric (transmesenteric) hernia was found. The hernia was reduced and the defect closed. Discharge was made without complications. CONCLUSIONS: Congenital mesenteric hernias are an infrequent pathology that may cause intestinal obstruction, predominantly in the pediatric population. Occurrence in adults is extremely rare.

JNK, but not MAPK, activation is associated with Fas-mediated apoptosis in human T cells.

Fas is a cell surface molecule that is expressed on a wide array of cell types and triggers apoptosis. While in most situations Fas ligation activates programmed cell death, on resting T lymphocytes it can co-stimulate proliferation with the T cell receptor (TCR)/CD3 complex. This incongruity suggests that Fas may elicit signaling events that overlap with those used by proliferation cues. We observe that in the human T cell line Jurkat and in human peripheral blood lymphocytes, Fas stimulation does not signal by the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway or by increased intracellular calcium. Rather, Fas ligation strongly activates Jun kinase (JNK). This activity, as well as Fas-induced apoptosis, is blocked by increased levels of cAMP. The balance between proliferation and apoptosis by Fas triggering of T lymphocytes may therefore reflect a signaling ratio between TCR activation of the Ras/Raf-1/MAPK pathway versus JNK activation by Fas.

The seven-transmembrane-spanning receptors for endothelin and thrombin cause proliferation of airway smooth muscle cells and activation of the extracellular regulated kinase and c-Jun NH2-terminal kinase groups of mitogen-activated protein kinases.

In airway smooth muscle cells ligand binding to the seven-transmembrane endothelin and thrombin receptors stimulates cell growth. Rapid activation of the extracellular regulated kinase 2 and c-Jun NH2-terminal kinase groups of mitogen-activated protein kinases was also observed. The results demonstrate a novel mechanism of seven-transmembrane receptor signaling involving activation of the Jun kinase pathway. Receptor coupling to Jun kinase activation may involve heterotrimeric G proteins since the kinase was enzymatically activated in cells treated with aluminum fluoride. The activity of Raf-1, measured by immune complex kinase assay, revealed that platelet-derived growth factor and phorbol 12-myristate 13-acetate both stimulated Raf-1 activity, while thrombin and endothelin did not appreciably stimulate Raf-1. The data suggest that endothelin and thrombin stimulate Raf-1-independent mechanisms of mitogen-activated protein kinase activation. Endothelin- or thrombin-induced activation of mitogen-activated protein kinases was significantly inhibited by activation of cyclic AMP-dependent protein kinase by forskolin. Proliferation of airway smooth muscle cells, measured by incorporation of [3H]thymidine into DNA, was also greatly attenuated by forskolin.

Estadios de melanomas primarios que evolucionaron a metastasicos / Stadia of primary melanomas evolving metastasis

Realizamos el analisis de 75 melanomas primarios(25 por ciento ) que dieron metastasis,de una serie continua de 296 con el objeto de catalogarlos segun su estadio. Analizamos edad,sexo color de piel y de ojos,lesiones pigm,entadas previas,sindrome del nevo displasico,melanomas multiples,melanomas familiares,localizacion del primitivo,tipo,nivel,espesor,ulceracion,tipo celular predominante,indice miotico,infiltrado linfositario,regresion,estadio,tiempo que transcurre hasta el diagnostico del primario y de este al final del seguimiento.El estadio se determino segun la clasificacion utilizada por la American Joint Committee on Cancer-Union Internationale contre le Cancer(A.J.C.C.-U.I.C.C.) corregida en 1992. En nuestra serie obtuvimos los siguientes en 65 casos:estadop 1,7,(IA:pt1 No Mo y IB 5 pt2 No Mo);II,19,(IIA:7 pt3 No Mo y IIB 12 pt4 No Mo);III,30,(cualquier pt N1 Mo 11,cualquier pt N2 Mo 8 y en 11 casos no se determ,ino el tamanio de las metastasis ganglionares);IV,9,(cualquier pt,cualquier N,M1): Fueron esxcluidos 10 melanomas porque a)dicha clasificacion no contempla ciertas situaciones:ocular(2),recaida(2),secundario a nevo intradermico (1) y a nevo azul(1),polipoide(1),y escrotal(1),[por invacion del musculo dartoico,b)por falta de detreminacion del espesor (2). La clasificacion de la A.J.C.C.-U.I.C.C.tiene como objeto uniformar estadios para permitir obtener resultados equiparables,con el fin de podercomparar la eficacia terapeutica. Es sucinta y concreta. Seria deseable agregar datos sobre el estudio clinico de la piel,factores desencadenantes ,lesiones precursoras,genetica e inmunologia. Es solo aparentemente multidisciplinaria,aunque creemos sigue siendo la mas util

Estadios de melanomas primarios que evolucionaron a metastasicos / Stadia of primary melanomas evolving metastasis

Realizamos el analisis de 75 melanomas primarios(25 por ciento ) que dieron metastasis,de una serie continua de 296 con el objeto de catalogarlos segun su estadio. Analizamos edad,sexo color de piel y de ojos,lesiones pigm,entadas previas,sindrome del nevo displasico,melanomas multiples,melanomas familiares,localizacion del primitivo,tipo,nivel,espesor,ulceracion,tipo celular predominante,indice miotico,infiltrado linfositario,regresion,estadio,tiempo que transcurre hasta el diagnostico del primario y de este al final del seguimiento.El estadio se determino segun la clasificacion utilizada por la American Joint Committee on Cancer-Union Internationale contre le Cancer(A.J.C.C.-U.I.C.C.) corregida en 1992. En nuestra serie obtuvimos los siguientes en 65 casos:estadop 1,7,(IA:pt1 No Mo y IB 5 pt2 No Mo);II,19,(IIA:7 pt3 No Mo y IIB 12 pt4 No Mo);III,30,(cualquier pt N1 Mo 11,cualquier pt N2 Mo 8 y en 11 casos no se determ,ino el tamanio de las metastasis ganglionares);IV,9,(cualquier pt,cualquier N,M1): Fueron esxcluidos 10 melanomas porque a)dicha clasificacion no contempla ciertas situaciones:ocular(2),recaida(2),secundario a nevo intradermico (1) y a nevo azul(1),polipoide(1),y escrotal(1),[por invacion del musculo dartoico,b)por falta de detreminacion del espesor (2). La clasificacion de la A.J.C.C.-U.I.C.C.tiene como objeto uniformar estadios para permitir obtener resultados equiparables,con el fin de podercomparar la eficacia terapeutica. Es sucinta y concreta. Seria deseable agregar datos sobre el estudio clinico de la piel,factores desencadenantes ,lesiones precursoras,genetica e inmunologia. Es solo aparentemente multidisciplinaria,aunque creemos sigue siendo la mas util

Human multidrug resistant KB cells overexpress protein kinase C: involvement in drug resistance.

Among the many phenotypic characteristics of multidrug resistance (MDR), the presence of P-glycoprotein is nearly always observed, and it appears that the plasma membrane of the multidrug resistant cell is integrally involved in controlling drug resistance. Another membrane-associated protein kinase, protein kinase C (PKC), has been shown to regulate the flow of information to the cell interior and to control the efflux of a number of different compounds. We therefore initiated a study of PKC and MDR. We found that multidrug resistant sublines from both mouse sarcoma 180 and human KB lines exhibited 80-90% increases in basal PKC activity. The mechanism of the increase appears to be quite different in the two cell lines. The human KB cells overexpress the alpha isozyme of PKC, commensurate with the increase in alpha-PKC protein, whereas the mouse cells do not overexpress alpha-mRNA but increase alpha-PKC protein. Furthermore, it appears that PKC activity plays a functional role in drug resistance, since inhibition of endogenous PKC activity by staurosporine resulted in decreased resistance to Adriamycin. We also found that phosphorylation of MDR cell membrane vesicles by purified PKC, followed by immunoprecipitation of P-glycoprotein with monoclonal antibody C219, resulted in a level of phosphorylation of P-glycoprotein that was greater than the endogenous phosphorylation level. The data presented indicate that MDR cells of diverse species exhibited enhanced PKC activity but that the mechanisms were different. The increased kinase activity may have biological relevance to MDR since PKC appears to be coupled to P-glycoprotein function.