Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Analysis of the mitochondrial and nuclear genomes of two basidiomycetes, Coprinus cinereus and Coprinus stercorarius

The mitochondrial and nuclear genomes of Coprinus stercorarius and C. cinereus were compared to assess their evolutionary relatedness and to characterize at the molecular level changes that have occurred since they diverged from a common ancestor. The mitochondrial genome of C. stercorarius (91.1 kb) is approximately twice as large as that of C. cinereus (43.3 kb). The pattern of restriction enzyme recognition sites shows both genomes to be circular, but reveals no clear homologies; furthermore, the order of structural genes is different in each species. The C. stercorarius mitochondrial genome contains a region homologous to a probe derived from the yeast mitochondrial var1 gene, whereas its nuclear genome does not. By contrast, the C. cinereus nuclear, but not mitochondrial, genome contains a region homologous to the var1 probe. Only a small fraction of either the nuclear or mitochondrial genomes, perhaps corresponding to the coding sequences, is capable of forming duplexes in interspecies solution reassociations, as measured by binding to hydroxylapatite. Those sequences capable of reassociating were found to have approximately 15% divergence for the mitochondrial genomes and 7%–15% divergence for the nuclear genomes, depending on the conditions of reassociation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46959/1/294_2004_Article_BF00447385.pd

Achlya mitochondrial DNA: gene localization and analysis of inverted repeats

Mitochondrial DNA from four strains of the oomycete Achlya has been compared and nine gene loci mapped, including that of the ribosomal protein gene, var1 . Examination of the restriction enzyme site maps showed the presence of four insertions relative to a map common to all four strains. All the insertions were found in close proximity to genic regions. The four strains also cotained the inverted repeat first observed in A. ambisexualis (Hudspeth et al. 1983), allowing an examination by analysis of retained restriction sites of the evolutionary stability of repeated DNA sequences relative to single copy sequences. Although the inverted repeat is significantly more stable than single copy sequences, more detailed analysis indicated that this stability is limited to the portion encoding the ribosomal RNA genes. Thus, the apparent evolutionary stability of the repeat does not appear to derive from the inverted repeat structure per se.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47563/1/438_2004_Article_BF00330510.pd

BBK32, a fibronectin-binding MSCRAMM from <em>Borrelia burgdorferi</em> contains a disordered region that undergoes a conformational change on ligand binding.

BBK32 is a fibronectin-binding lipoprotein on Borrelia burgdorferi, the causative agent of Lyme disease. Analysis using secondary structure prediction programs suggested that BBK32 is composed of two domains, an N-terminal segment lacking well defined secondary structure and a C-terminal segment composed largely of alpha-helices. Analysis of purified recombinant forms of the two domains by circular dichroism spectroscopy, gel permeation chromatography, and intrinsic viscosity determination were consistent with an N-terminal-extended, unstructured segment and a C-terminal globular domain in BBK32. Solid phase binding experiments suggest that the unstructured N-terminal domain binds fibronectin. Analysis of changes in circular dichroism spectra of the N-terminal segment of BBK32 upon binding of the N-terminal domain of fibronectin revealed an increase in beta-sheet content in the complex. Hence, BBK32, which belongs to a different family of proteins and shows no overall sequence similarity with the fibronectin binding MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) of Gram-positive bacteria, binds fibronectin by a mechanism that is reminiscent of the "tandem beta-zipper" previously demonstrated for the fibronectin binding of streptococcal adhesins (Schwarz-Linek, U., Werner, J.M., Pickford, A. R., Gurusiddappa, S., Kim, J.H., Pilka, E. S., Briggs, J.A., Gough, T. S., Hook, M., Campbell, I. D., and Potts, J.R. (2003) Nature 423, 177-181).</p

Sintomas psicóticos e cognitivos associados à busca de tratamento por dependentes de substâncias: um estudo qualitativo Psychotic and cognitive symptoms associated to treatment seeking behavior: a qualitative study

Há algumas décadas, busca-se compreender melhor o processo subjacente ao comportamento de procura de tratamento por usuários que fazem uso nocivo ou são dependentes de substâncias psicoativas. Os modelos atualmente propostos baseiam-se principalmente na análise epidemiológica de certas características individuais quanto ao poder que têm de influenciar esse comportamento de disposição para tratamento. OBJETIVOS: Interpretar e compreender possíveis significados pessoais associados a alterações psicopatológicas, sobre como podem se relacionar à procura de tratamento, na visão dos próprios pacientes. MÉTODO: Pesquisa qualitativa com entrevistas semidirigidas com amostra intencional de 13 dependentes de substâncias que procuraram tratamento. RESULTADOS: Houve relatos espontâneos de alterações de forma, curso e conteúdo de pensamento e juízo de realidade, alterações de sensopercepção, de atenção, memória e linguagem. Os membros da amostra pareceram relacioná-las à motivação para tratamento. Os dados foram interpretados considerando o contexto psicocultural dos entrevistados e seus quadros clínicos de síndrome de dependência, de abstinência e de comorbidade. CONCLUSÕES: Pesquisas qualitativas contribuem para aprimorar os modelos explicativos sobre procura de tratamento por dependentes de substâncias. Investigar clinicamente alterações psicopatológicas parece poder contribuir para motivar pacientes para tratamentos específicos do uso disfuncional de substâncias.<br>During the last few decades it is aimed to better understand the process underlying treatment seeking behavior by harmful or dependent psychoactive substances users. The currently proposed models are mainly based on the epidemiological analysis of certain number of individual characteristics, as they have the power to influence this behavior of readiness for treatment. OBJECTIVES: To interpret and understand possible personal meanings associated with psychopathological disorders and how they can be related to treatment seeking behavior, as described by the patients themselves. METHOD: Qualitative study conducted on an intentional sample of 13 substance dependents seeking for formal treatment; in-depth semi-structured interviews. RESULTS: The participants spontaneously reported: shape, course and content thought disturbances and sense of reality, sensory perception disorders, and attention, memory and language deficits. The sample's participants seemed to relate these disorders to the treatment seeking motivations. The data were interpreted considering the interviewees' psycho-cultural context their clinical presentations (dependence or withdrawal syndromes and comorbidities). CONCLUSIONS: Qualitative research contribute to improve current models of substance dependents' treatment seeking behavior. The clinical investigation of psychopathologic disorders seem to motivate patients to specific treatments of dysfunctional use of substances

The Genome Sequence of Lone Star Virus, a Highly Divergent Bunyavirus Found in the Amblyomma americanum Tick

Viruses in the family Bunyaviridae infect a wide range of plant, insect, and animal hosts. Tick-borne bunyaviruses in the Phlebovirus genus, including Severe Fever with Thrombocytopenia Syndrome virus (SFTSV) in China, Heartland virus (HRTV) in the Unite