Atorvastatin added to interferon beta for relapsing multiple sclerosis: a randomized controlled trial

Statins have anti-inflammatory and immunomodulatory properties in addition to lipid-lowering effects. The present study evaluated the effect of atorvastatin added to interferon beta-1b in multiple sclerosis (MS) in a multicenter, randomized, parallel-group, rater-blinded study performed in eight Swiss hospitals. Seventy-seven patients with relapsing-remitting MS started interferon beta-1b every other day. After 3 months, they were randomized 1:1 to receive atorvastatin 40 mg/day or not in addition to interferon beta-1b until month 15. The primary endpoint was the proportion of patients with new lesions on T2-weighted images at month 15 compared to baseline at month three. At study end, the proportion of patients with new lesions on T2-weighted images was equal in both groups (odds ratio 1.14; 95 % CI 0.36-3.56; p = 0.81). All predefined secondary endpoints including number of new lesions and total lesion volume on T2-weighted images, total number of new Gd-enhancing lesions on T1-weighted images, total brain volume, volume of grey matter, volume of white matter, EDSS, MSFC, relapse rate, time to first relapse, number of relapse-free patients and neutralizing antibodies did not show any significant differences (all p values >0.1). Transient elevations of liver enzymes were more frequent with atorvastatin (p = 0.02). In conclusion, atorvastatin 40 mg/day in addition to interferon beta-1b did not have a beneficial effect on relapsing-remitting MS compared to interferon beta-1b monotherapy over a 12-month period.

The CCR2/CCL2 interaction mediates the transendothelial recruitment of intravascularly delivered neural stem cells to the ischemic brain

The inflammatory response is a critical component of ischemic stroke. In addition to its physiological role, the mechanisms behind transendothelial recruitment of immune cells also offer a unique therapeutic opportunity for translational stem cell therapies. Recent reports have demonstrated homing of neural stem cells (NSC) into the injured brain areas after intravascular delivery. However, the mechanisms underlying the process of transendothelial recruitment remain largely unknown. Here we describe the critical role of the chemokine CCL2 and its receptor CCR2 in targeted homing of NSC after ischemia.

Airway remodelling and its relationship to inflammation in cystic fibrosis

Pulmonary disease is the most important cause of morbidity and mortality in cystic fibrosis (CF). Most patients with CF die from respiratory failure with extensive airway destruction. Airway remodelling, defined as structural airway wall changes, begins early in life in CF but the sequence of remodelling events in the disease process is poorly understood. Airway remodelling in CF has traditionally been thought to be solely the consequence of repeated cycles of inflammation and infection. However, new evidence obtained from developmental, physiological and histopathological studies suggests that there might instead be multiple mechanisms leading to airway remodelling in CF including (1) changes related to infection and inflammation; (2) changes specific to CF as a result of CF transmembrane conductance regulator (CFTR) dysfunction in the airway wall, independent of infection and inflammation; and (3) protective responses to (1) and/or (2). Recent advances in bronchoscopic techniques have allowed airway mucosal (endobronchial) biopsies to be taken in children and even infants. Endobronchial biopsy studies may provide insight into the role and relative contribution of the different mechanisms of airway remodelling in CF, with the main limitation that they assess only changes in proximal large airways and not in peripheral small airways from where CF disease is thought to originate. Findings from biopsy studies could encourage the development of novel therapeutic strategies targeting structural changes in addition to infection and inflammation.

Sensitivity of pelagic calcification to ocean acidification

Ocean acidification might reduce the ability of calcifying plankton to produce and maintain their shells of calcite, or of aragonite, the more soluble form of CaCO3. In addition to possibly large biological impacts, reduced CaCO3 production corresponds to a negative feedback on atmospheric CO2. In order to explore the sensitivity of the ocean carbon cycle to increasing concentrations of atmospheric CO2, we use the new biogeochemical Bern3D/PISCES model. The model reproduces the large scale distributions of biogeochemical tracers. With a range of sensitivity studies, we explore the effect of (i) using different parameterizations of CaCO3 production fitted to available laboratory and field experiments, of (ii) letting calcite and aragonite be produced by auto- and heterotrophic plankton groups, and of (iii) using carbon emissions from the range of the most recent IPCC Representative Concentration Pathways (RCP). Under a high-emission scenario, the CaCO3 production of all the model versions decreases from ~1 Pg C yr−1 to between 0.36 and 0.82 Pg C yr−1 by the year 2100. The changes in CaCO3 production and dissolution resulting from ocean acidification provide only a small feedback on atmospheric CO2 of −1 to −11 ppm by the year 2100, despite the wide range of parameterizations, model versions and scenarios included in our study. A potential upper limit of the CO2-calcification/dissolution feedback of −30 ppm by the year 2100 is computed by setting calcification to zero after 2000 in a high 21st century emission scenario. The similarity of feedback estimates yielded by the model version with calcite produced by nanophytoplankton and the one with calcite, respectively aragonite produced by mesozooplankton suggests that expending biogeochemical models to calcifying zooplankton might not be needed to simulate biogeochemical impacts on the marine carbonate cycle. The changes in saturation state confirm previous studies indicating that future anthropogenic CO2 emissions may lead to irreversible changes in ΩA for several centuries. Furthermore, due to the long-term changes in the deep ocean, the ratio of open water CaCO3 dissolution to production stabilizes by the year 2500 at a value that is 30–50% higher than at pre-industrial times when carbon emissions are set to zero after 2100.

Proteome remodelling during development from blood to insect-form Trypanosoma brucei quantified by SILAC and mass spectrometry

Trypanosoma brucei is the causative agent of human African sleeping sickness and Nagana in cattle. In addition to being an important pathogen T. brucei has developed into a model system in cell biology.

ImmunoChip study implicates antigen presentation to T cells in narcolepsy

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

A second generation radiation hybrid map to aid the assembly of the bovine genome sequence

BACKGROUND: Several approaches can be used to determine the order of loci on chromosomes and hence develop maps of the genome. However, all mapping approaches are prone to errors either arising from technical deficiencies or lack of statistical support to distinguish between alternative orders of loci. The accuracy of the genome maps could be improved, in principle, if information from different sources was combined to produce integrated maps. The publicly available bovine genomic sequence assembly with 6x coverage (Btau_2.0) is based on whole genome shotgun sequence data and limited mapping data however, it is recognised that this assembly is a draft that contains errors. Correcting the sequence assembly requires extensive additional mapping information to improve the reliability of the ordering of sequence scaffolds on chromosomes. The radiation hybrid (RH) map described here has been contributed to the international sequencing project to aid this process. RESULTS: An RH map for the 30 bovine chromosomes is presented. The map was built using the Roslin 3000-rad RH panel (BovGen RH map) and contains 3966 markers including 2473 new loci in addition to 262 amplified fragment-length polymorphisms (AFLP) and 1231 markers previously published with the first generation RH map. Sequences of the mapped loci were aligned with published bovine genome maps to identify inconsistencies. In addition to differences in the order of loci, several cases were observed where the chromosomal assignment of loci differed between maps. All the chromosome maps were aligned with the current 6x bovine assembly (Btau_2.0) and 2898 loci were unambiguously located in the bovine sequence. The order of loci on the RH map for BTA 5, 7, 16, 22, 25 and 29 differed substantially from the assembled bovine sequence. From the 2898 loci unambiguously identified in the bovine sequence assembly, 131 mapped to different chromosomes in the BovGen RH map. CONCLUSION: Alignment of the BovGen RH map with other published RH and genetic maps showed higher consistency in marker order and chromosome assignment than with the current 6x sequence assembly. This suggests that the bovine sequence assembly could be significantly improved by incorporating additional independent mapping information.

Comparative immunogenicity of a PreS/S hepatitis B vaccine in non- and low responders to conventional vaccine

Conventional hepatitis B vaccines do not elicit adequate antibody production in 5-10% vaccinees. This trial tests the ability of a third-generation vaccine, containing PreS1 and PreS2 antigens in addition to the S antigen, to elicit seroprotective titres in documented non- and low-responders, compared with those to a conventional vaccine. In the primary population of non-responders (<10 IU/l anti-HBs antibodies after > or = 4 previous injections of conventional vaccine) an enhanced antibody response was seen to additional injections of the third-generation vaccine compared with a conventional vaccine (absolute difference 14.9%; P = 0.006). Enhanced antibody responses were also found in a population that included low responders.

Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis

Autophagy-related gene (Atg) 5 is a gene product required for the formation of autophagosomes. Here, we report that Atg5, in addition to the promotion of autophagy, enhances susceptibility towards apoptotic stimuli. Enforced expression of Atg5-sensitized tumour cells to anticancer drug treatment both in vitro and in vivo. In contrast, silencing the Atg5 gene with short interfering RNA (siRNA) resulted in partial resistance to chemotherapy. Apoptosis was associated with calpain-mediated Atg5 cleavage, resulting in an amino-terminal cleavage product with a relative molecular mass of 24,000 (Mr 24K). Atg5 cleavage was observed independent of the cell type and the apoptotic stimulus, suggesting that calpain activation and Atg5 cleavage are general phenomena in apoptotic cells. Truncated Atg5 translocated from the cytosol to mitochondria, associated with the anti-apoptotic molecule Bcl-xL and triggered cytochrome c release and caspase activation. Taken together, calpain-mediated Atg5 cleavage provokes apoptotic cell death, therefore, represents a molecular link between autophagy and apoptosis--a finding with potential importance for clinical anticancer therapies.

Discontinuation of maintenance therapy against toxoplasma encephalitis in AIDS patients with sustained response to anti-retroviral therapy

Discontinuation of maintenance therapy against toxoplasma encephalitis (TE) for individuals infected with human immunodeficiency virus (HIV) who are receiving successful anti-retroviral therapy is considered safe. Nevertheless, there are few published studies concerning this issue. Within the setting of the Swiss HIV Cohort Study, this report describes a prospective study of discontinuation of maintenance therapy against TE in patients with a sustained increase of CD4 counts to > 200 cells/microL and 14% of total lymphocytes, and no active lesions on cerebral magnetic resonance imaging (MRI). In addition to clinical evaluation, cerebral MRI was performed at baseline, and 1 and 6 months following discontinuation. Twenty-six AIDS patients with a history of TE agreed to participate, but three patients (11%) could not be enrolled because they still showed enhancing cerebral lesions without a clinical correlate. One patient refused MRI after 6 months while clinically asymptomatic. Among the remaining 22 patients who discontinued maintenance therapy, one relapsed after 3 months. During a total follow-up of 58 patient-years, there was no TE relapse among the patients who had remained clinically and radiologically free of relapse during the study. Thus, discontinuation of maintenance therapy against TE was generally safe, but may fail in a minority of patients. Patients who remain clinically and radiologically free of relapse at 6 months after discontinuation are unlikely to experience a relapse of TE.

Doxycycline reduces mortality and injury to the brain and cochlea in experimental pneumococcal meningitis

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 microM in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats.

Air bells of water spiders are an extended phenotype modified in response to gas composition

The water spider Argyroneta aquatica (Clerck) is the only spider that spends its whole life under water. Water spiders keep an air bubble around their body for breathing and build under-water air bells, which they use for shelter and raising offspring, digesting and consuming prey, moulting, depositing eggs and sperm, and copulating. It is unclear whether these bells are an important oxygen reservoir for breathing under water, or whether they serve mainly to create water-free space for feeding and reproduction. In this study, we manipulated the composition of the gas inside the bell of female water spiders to test whether they monitor the quality of this gas, and replenish oxygen if required. We exchanged the entire gas in the bell either with pure O(2), pure CO(2), or with ambient air as control, and monitored behavioural responses. The test spiders surfaced and replenished air more often in the CO(2) treatment than in the O(2) treatment, and they increased bell building behaviour. In addition to active oxygen regulation, they monitored and adjusted the bells by adding silk. These results show that water spiders use the air bell as an oxygen reservoir, and that it functions as an external lung, which renders it essential for living under water permanently. A. aquatica is the only animal that collects, transports, and stores air, and monitors its property for breathing, which is an adaptive response of a terrestrial animal to the colonization of an aquatic habitat. J. Exp. Zool. 307A:549-555, 2007. (c) 2007 Wiley-Liss, Inc.

Blood donor screening: how to decrease the risk of transfusion-transmitted hepatitis B virus?

QUESTIONS UNDER STUDY: The risk of transfusion-transmitted HBV remains significant in Switzerland, where routine screening for hepatitis B virus (HBV) in blood donations relies solely on serological hepatitis B surface antigen (HBsAg) testing. This study was designed to determine the prevalence of anti-hepatitis B core (anti-HBc) and HBV nucleic acid testing (NAT) positive donations in two different Swiss donor populations, to help in deciding whether supplemental testing may bring additional safety to blood products. METHODS: In a first population of donors, 18143 consecutive donations were screened initially for HBsAg, anti-HBc (with one EIA assay) and with HBV NAT in minipools of 24 donations. The screening repeatedly reactive anti-HBc donations were then "confirmed" with two supplemental anti-HBc assays, an anti-hepatitis B surface assay (anti-HBs) and with single donation HBV NAT. In a second population of donors, 4186 consecutive donations were screened initially with two different anti-HBc assays in addition to the mandatory HBsAg screening test. The screening repeatedly reactive donations with at least one anti-HBc assay were tested for anti-HBs. RESULTS: In the first subset of 18143 donations, 17593 (97.0%) were negative for HBsAg, anti-HBc and HBV NAT in minipools. 549 (3.0%) were HBsAg and HBV NAT negative, but repeatedly reactive for anti-HBc. Of these 549 donations, 287 could not be "confirmed" with two additional anti-HBc assays and were negative with an anti-HBs assay, as well as with single donation HBV NAT. Only 211 (1.2% of the total screened donations) were "confirmed" positive with at least one of two supplemental anti-HBc assays. One repeatedly reactive HBsAg donation, from a first-time donor, was confirmed positive for HBsAg and anti-HBc, as well as with single donation HBV NAT. In the second subset of 4186 donations, 4014 (95.9%) were screened negative for HBsAg and for anti-HBc, tested with two independent anti-HBc assays. 172 donations (4.1%) were HBsAg negative but repeatedly reactive with at least one of the two anti-HBc assays. Of these 172 samples, 86 were reactive with the first anti-HBc assay only, 13 were reactive with the second anti-HBc assay only and 73 (1.7% of the total screened donations) were "confirmed" positive with both anti-HBc assays. CONCLUSION: The prevalence of anti-HBc "confirmed" positive donations in the two Swiss blood donor populations studied was low (<2%) and we found only one HBV NAT positive (HBsAg positive) donation among more than 18000. Concerning blood product safety, an increase in the deferral rate of less than 2% of anti-HBc positive, potentially infectious donors, would in our opinion make routine anti-HBc testing of blood donations cost-effective. There is however still a need for more specific assays to avoid an unacceptably high deferral rate of "false" positive donors. In contrast, the introduction of HBV NAT in minipools gives minimal benefit due to the inadequate sensitivity of the assay. It remains to evaluate more extensively the value of individual donation NAT, alone or in addition to anti-HBc, as supplemental testing in the context of several Swiss blood donor populations.

Automated, compliant, high-flow common carotid to middle cerebral artery bypass

The authors describe the use of the Cardica C-Port xA Distal Anastomosis System to perform an automated, high-flow extracranial-intracranial bypass. The C-Port system has been developed and tested in coronary artery bypass surgery for rapid distal coronary artery anastomoses. Air-powered, it performs an automated end-to-side anastomosis within seconds by nearly simultaneously making an arteriotomy and inserting 13 microclips into the graft and recipient vessel. Intracranial use of the device was first simulated in a cadaver prepared for microsurgical anatomical dissection. The authors used this system in a 43-year-old man who sustained a subarachnoid hemorrhage after being assaulted and was found to have a traumatic pseudoaneurysm of the proximal intracranial internal carotid artery. The aneurysm appeared to be enlarging on serial imaging studies and it was anticipated that a bypass would probably be needed to treat the lesion. An end-to-side bypass was performed with the C-Port system using a saphenous vein conduit extending from the common carotid artery to the middle cerebral artery. The bypass was demonstrated to be patent on intraoperative and postoperative arteriography. The patient had a temporary hyperperfusion syndrome and subsequently made a good neurological recovery. The C-Port system facilitates the performance of a high-flow extracranial-intracranial bypass with short periods of temporary arterial occlusion. Because of the size and configuration of the device, its use is not feasible in all anatomical situations that require a high-flow bypass; however it is a useful addition to the armamentarium of the neurovascular surgeon.

PU.1 binding to the p53 family of tumor suppressors impairs their transcriptional activity

The transcription factor PU.1 is essential for terminal myeloid differentiation, B- and T-cell development, erythropoiesis and hematopoietic stem cell maintenance. PU.1 functions as oncogene in Friend virus-induced erythroleukemia and as tumor suppressor in acute myeloid leukemias. Moreover, Friend virus-induced erythroleukemia requires maintenance of PU.1 expression and the disruption of p53 function greatly accelerates disease progression. It has been hypothesized that p53-mediated expression of the p21(Cip1) cell cycle inhibitor during differentiation of pre-erythroleukemia cells promotes selection against p53 function. In addition to the blockage of erythroblast differentiation provided by increased levels of PU.1, we propose that PU.1 alters p53 function. We demonstrate that PU.1 reduces the transcriptional activity of the p53 tumor suppressor family and thus inhibits activation of genes important for cell cycle regulation and apoptosis. Inhibition is mediated through binding of PU.1 to the DNA-binding and/or oligomerization domains of p53/p73 proteins. Lastly, knocking down endogenous PU.1 in p53 wild-type REH B-cell precursor leukemia cells leads to increased expression of the p53 target p21(Cip1).