Improved detection of amnestic MCI by means of discriminative vector quantization of single-trial cognitive ERP responses

Cognitive event-related potentials (ERPs) are widely employed in the study of dementive disorders. The morphology of averaged response is known to be under the influence of neurodegenerative processes and exploited for diagnostic purposes. This work is built over the idea that there is additional information in the dynamics of single-trial responses. We introduce a novel way to detect mild cognitive impairment (MCI) from the recordings of auditory ERP responses. Using single trial responses from a cohort of 25 amnestic MCI patients and a group of age-matched controls, we suggest a descriptor capable of encapsulating single-trial (ST) response dynamics for the benefit of early diagnosis. A customized vector quantization (VQ) scheme is first employed to summarize the overall set of ST-responses by means of a small-sized codebook of brain waves that is semantically organized. Each ST-response is then treated as a trajectory that can be encoded as a sequence of code vectors. A subject's set of responses is consequently represented as a histogram of activated code vectors. Discriminating MCI patients from healthy controls is based on the deduced response profiles and carried out by means of a standard machine learning procedure. The novel response representation was found to improve significantly MCI detection with respect to the standard alternative representation obtained via ensemble averaging (13% in terms of sensitivity and 6% in terms of specificity). Hence, the role of cognitive ERPs as biomarker for MCI can be enhanced by adopting the delicate description of our VQ scheme.

Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice

The immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P1 and S1P3, but not S1P2, receptor internalization as a result of receptor activation. Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNFα-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNFα-mediated downregulation of PECAM-1 mRNA expression. In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes and significantly reduced the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice comparable to FTY720 either by prophylactic or therapeutic treatment. In parallel to the reduced clinical symptoms, infiltration of immune cells in the brain was strongly reduced, and in isolated tissues of brain and spinal cord, the mRNA and protein expressions of ICAM-1 and VCAM-1, as well as of matrix metalloproteinase-9 were reduced by all compounds, whereas PECAM-1 and tissue inhibitor of metalloproteinase TIMP-1 were upregulated. In summary, the data suggest that these novel butterfly derivatives of FTY720 could have considerable implication for future therapies of multiple sclerosis and other autoimmune diseases.

4-year clinical outcomes and predictors of repeat revascularization in patients treated with new-generation drug-eluting stents: a report from the RESOLUTE All-Comers trial (A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention)

OBJECTIVES The aim of the study was to investigate 4-year outcomes and predictors of repeat revascularization in patients treated with the Resolute zotarolimus-eluting stent (R-ZES) (Medtronic, Minneapolis, Minnesota) and XIENCE V everolimus-eluting stent (EES) (Abbott Vascular, Abbott Park, Illinois) in the RESOLUTE (A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention) All-Comers trial. BACKGROUND Data on long-term outcomes of new-generation drug-eluting stents are limited, and predictors of repeat revascularization due to restenosis and/or progression of disease are largely unknown. METHODS Patients were randomly assigned to treatment with the R-ZES (n = 1,140) or the EES (n = 1,152). We assessed pre-specified safety and efficacy outcomes at 4 years including target lesion failure and stent thrombosis. Predictors of revascularization at 4 years were identified by Cox regression analysis. RESULTS At 4 years, the rates of target lesion failure (15.2% vs. 14.6%, p = 0.68), cardiac death (5.4% vs. 4.7%, p = 0.44), and target vessel myocardial infarction (5.3% vs. 5.4%, p = 1.00), clinically-indicated target lesion revascularization (TLR) (7.0% vs. 6.5%, p = 0.62), and definite/probable stent thrombosis (2.3% vs. 1.6%, p = 0.23) were similar with the R-ZES and EES. Independent predictors of TLR were age, insulin-treated diabetes, SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score, treatment of saphenous vein grafts, ostial lesions, and in-stent restenosis. Independent predictors of any revascularization were age, diabetes, previous percutaneous coronary intervention, absence of ST-segment elevation myocardial infarction, smaller reference vessel diameter, SYNTAX score, and treatment of left anterior descending, right coronary artery, saphenous vein grafts, ostial lesions, or in-stent restenosis. CONCLUSIONS R-ZES and EES demonstrated similar safety and efficacy throughout 4 years. TLR represented less than one-half of all repeat revascularization procedures. Patient- and lesion-related factors predicting the risk of TLR and any revascularization showed considerable overlap. (A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention [RESOLUTE-AC]; NCT00617084).

Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following resolute zotarolimus-eluting stent implantation.

AIM The optimal duration of dual antiplatelet therapy (DAPT) following the use of new generation drug-eluting stents is unknown. METHODS AND RESULTS The association between DAPT interruption and the rates of stent thrombosis (ST) and cardiac death/target-vessel myocardial infarction (CD/TVMI) in patients receiving a Resolute zotarolimus-eluting stent (R-ZES) was analysed in 4896 patients from the pooled RESOLUTE clinical programme. Daily acetylsalicylate (ASA) and a thienopyridine for 6-12 months were prescribed. A DAPT interruption was defined as any interruption of ASA and/or a thienopyridine of >1 day; long interruptions were >14 days. Three groups were analysed: no interruption, interruption during the first month, and >1-12 months. There were 1069 (21.83%) patients with a DAPT interruption and 3827 patients with no interruption. Among the 166 patients in the 1-month interruption group, 6 definite/probable ST events occurred (3.61%; all long DAPT interruptions), and among the 903 patients in the >1-12 months (60% occurred between 6 and 12 months) interruption group, 1 ST event occurred (0.11%; 2-day DAPT interruption). Among patients with no DAPT interruption, 32 ST events occurred (0.84%). Rates of CD/TVMI were 6.84% in the 1-month long interruption group, 1.41% in the >1-12 months long interruption group, and 4.08% in patients on continuous DAPT. CONCLUSION In a pooled population of patients receiving an R-ZES, DAPT interruptions within 1 month are associated with a high risk of adverse outcomes. Dual antiplatelet therapy interruptions between 1 and 12 months were associated with low rates of ST and adverse cardiac outcomes. Randomized clinical trials are needed to determine whether early temporary or permanent interruption of DAPT is truly safe. CLINICAL TRIALSGOV IDENTIFIERS NCT00617084; NCT00726453; NCT00752128; NCT00927940.

Safety of Prasugrel Loading Doses in Patients Pre-Loaded With Clopidogrel in the Setting of Primary Percutaneous Coronary Intervention: Results of a Nonrandomized Observational Study.

OBJECTIVES The aim of this study was to assess the safety of the concurrent administration of a clopidogrel and prasugrel loading dose in patients undergoing primary percutaneous coronary intervention. BACKGROUND Prasugrel is one of the preferred P2Y12 platelet receptor antagonists for ST-segment elevation myocardial infarction patients. The use of prasugrel was evaluated clinically in clopidogrel-naive patients. METHODS Between September 2009 and October 2012, a total of 2,023 STEMI patients were enrolled in the COMFORTABLE (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI]) and the SPUM-ACS (Inflammation and Acute Coronary Syndromes) studies. Patients receiving a prasugrel loading dose were divided into 2 groups: 1) clopidogrel and a subsequent prasugrel loading dose; and 2) a prasugrel loading dose. The primary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding in hospital at 30 days. RESULTS Of 2,023 patients undergoing primary percutaneous coronary intervention, 427 (21.1%) received clopidogrel and a subsequent prasugrel loading dose, 447 (22.1%) received a prasugrel loading dose alone, and the remaining received clopidogrel only. At 30 days, the primary safety endpoint was observed in 1.9% of those receiving clopidogrel and a subsequent prasugrel loading dose and 3.4% of those receiving a prasugrel loading dose alone (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.25 to 1.30, p = 0.18). The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) bleeding score tended to be higher in prasugrel-treated patients (p = 0.076). The primary safety endpoint results, however, remained unchanged after adjustment for these differences (clopidogrel and a subsequent prasugrel loading dose vs. prasugrel only; HR: 0.54 [95% CI: 0.23 to 1.27], p = 0.16). No differences in the composite of cardiac death, myocardial infarction, or stroke were observed at 30 days (adjusted HR: 0.66, 95% CI: 0.27 to 1.62, p = 0.36). CONCLUSIONS This observational, nonrandomized study of ST-segment elevation myocardial infarction patients suggests that the administration of a loading dose of prasugrel in patients pre-treated with a loading dose of clopidogrel is not associated with an excess of major bleeding events. (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI] [COMFORTABLE]; NCT00962416; and Inflammation and Acute Coronary Syndromes [SPUM-ACS]; NCT01000701).

Sphingosine kinase 2 deficient mice exhibit reduced experimental autoimmune encephalomyelitis: Resistance to FTY720 but not ST-968 treatments

The immunomodulatory drug FTY720 is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that requires activation by sphingosine kinase 2 (SK-2) to induce T cell homing to secondary lymphoid tissue. In this study, we have investigated the role of SK-2 in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. We show that SK-2 deficiency reduced clinical symptoms of EAE. Furthermore, in SK-2-deficient mice, the protective effect of FTY720 on EAE was abolished, while the non-prodrug FTY720-derivative ST-968 was still fully active. Protection was paralleled by reduced numbers of T-lymphocytes in blood and a reduced blood-brain-barrier leakage. This correlated with reduced mRNA expression of ICAM-1, VCAM-1, but enhanced expression of PECAM-1. A similar regulation of permeability and of PECAM-1 was seen in primary cultures of isolated mouse brain vascular endothelial cells and in a human immortalized cell line upon SK-2 knockdown. In summary, these data demonstrated that deletion of SK-2 exerts a protective effect on the pathogenesis of EAE in C57BL/6 mice and that SK-2 is essential for the protective effect of FTY720 but not of ST-968. Thus, ST-968 is a promising novel immunomodulatory compound that may be a valuable alternative to FTY720 under conditions where SK-2 activity is limited.

In German gaols : a narrative of two years' captivity in German East Africa

by Ernest F. Spanton, priest of the Universities Mission to Central Africa, pricipal of St. Andrew's College, Zanzibar. With a prefatory note by Harry Hamilton Johnston

Systematic review of interventions designed to reduce screen time in children and adolescents

This descriptive systematic review describes intervention trials for children and youth that targeted screen time (ST) as a way to prevent or control obesity and measured ST, and at least one of the following: physical activity, dietary intake, and adiposity. Both “hands-on” (e.g., video games) and “hands free” (e.g., television viewing) ST were included. Published, completed intervention trials (k=12), not-yet-published, completed trials (k=6), and in-progress trials (k=11) were identified through searches of electronic databases, including trial registries and bibliographies of eligible study reports. Study characteristics of the 29 identified trials were coded and presented in evidence tables. Considerable attention was paid to the type of ST addressed, measures used, and the type of interventions. Based on the number of in-progress and not-yet-published trials, the number of completed, published reports will double in the next three years. Most of the studies were funded by federal sources. General populations, not restricted by race, gender, or weight status, were targets of most interventions with children ages 9-12 yeas as the modal age group. Most trials used randomized control trials in which the majority of control or comparison group received an intervention. The mean number of participants was 242.8 (SD=314.7) and interventions were delivered over an average of 10.5 months and consisted of approximately 16 sessions, with a total time of about eight hours. The majority of completed trials evaluate each of the four constructs, however, most studies have more than one measure to assess each construct (e.g., BMI and tricep skinfold thickness to evaluate adiposity) and rarely did studies use the same measures. This is likely why the majority of studies produced at least one significant intervention effect on each outcome that was assessed. The four major outcomes should be evaluated in all interventions attempting to reduce screen time in order to determine the mechanisms involved that may contribute to obesity. More importantly researchers should work together to determine the best measures to evaluate the four main constructs to allow studies to be compared. Another area for consensus is the definition of ST. ^

Isotope geochemistry of Ninetyeast Ridge basalts

The Ninetyeast Ridge lavas have Sr and Nd isotopic ratios intermediate between those of Indian Ocean MORBs and those of the very enriched Kerguelen hot spot. In an Nd-Sr isotope diagram, they also plot close to the fields of St. Paul Island lavas and of the early magmatism on Kerguelen Archipelago. The Ninetyeast Ridge lavas were generated by mixing among at least three components: a depleted, MORB-type component, such as the one erupted today on the Southeast Indian Ridge; a very enriched, high- Sr/ Sr, low-epsilon-Nd, OIB-type component (the Kerguelen hot spot); and an OIB-type component comparable to that sampled from the St. Paul (and Amsterdam) lavas. The Ninetyeast Ridge lavas show a typical Dupal anomaly signature and Pb, Sr, and Nd isotopic systematics indicate that the Kerguelen hot spot was involved in the ridge's formation as the Indian plate moved northward. The different sites cored during ODP Leg 121 show a trend in their isotopic compositions, from less radiogenic Pb/ Pb ratios and intermediate 87Sr/86Sr and 143Nd/**Nd ratios in the oldest lavas (Site 758) toward more radiogenic 206Pb/204Pb, higher epsilon-Nd, and lower 87Sr/86Sr values in the youngest lavas (Site 756). The lavas from Site 757 have 206Pb/204Pb ratios intermediate between those of the lavas from Sites 756 and 758 and higher 87Sr/86Sr and lower epsilon-Nd values. The relative proportions of the hot spot(s) and MORB component have evolved with time, reflecting differences of tectonic setting: the relative proportion of the Kerguelen hot spot component appears lower in the younger Site 756 lavas than in the older lavas from Sites 757 and 758. Site 756 coincides with the beginning of rifting at the Southeast Indian Ridge, about 43 Ma ago. The formation of the early Kerguelen Archipelago lavas may have drained most of the plume-derived material toward the Antarctic plate. Alternatively, the proximity of the spreading-ridge axis may account for the isotopic similarity of the Site 756 lavas to young lavas erupted on the Southeast Indian Ridge, from 33? to 37?S. The older lavas of Ninetyeast Ridge may have formed when the hot spot and ridge axis did not exactly coincide. The involvement of the third component, a St. Paul hot spot, in the genesis of the Ninetyeast Ridge lavas, especially for the Site 756 lavas, is clearly indicated by Sr, Pb, and Nd isotope systematics and also by trace element ratios. These data, together with those from the Kerguelen Plateau, indicate that the Kerguelen hot spot has been active more or less continuously in the South Indian Ocean for at least 115 Ma. This could indicate that the plume, and by inference the Dupal anomaly, is deep seated in origin.

Reconstruction of sea-surface conditions at middle to high latitudes of the Northern Hemisphere

A new calibration database of census counts of organic-walled dinoflagellate cyst (dinocyst) assemblages has been developed from the analyses of surface sediment samples collected at middle to high latitudes of the Northern Hemisphere after standardisation of taxonomy and laboratory procedures. The database comprises 940 reference data points from the North Atlantic, Arctic and North Pacific oceans and their adjacent seas, including the Mediterranean Sea, as well as epicontinental environments such as the Estuary and Gulf of St. Lawrence, the Bering Sea and the Hudson Bay. The relative abundance of taxa was analysed to describe the distribution of assemblages. The best analogue technique was used for the reconstruction of Last Glacial Maximum (LGM) sea-surface temperature and salinity during summer and winter, in addition to sea-ice cover extent, at sites from the North Atlantic (n=63), Mediterranean Sea (n=1) and eastern North Pacific (n=1). Three of the North Atlantic cores, from the continental margin of eastern Canada, revealed a barren LGM interval, probably because of quasi-permanent sea ice. Six other cores from the Greenland and Norwegian seas were excluded from the compilation because of too sparse assemblages and poor analogue situation. At the remaining sites (n= 54), relatively close modern analogues were found for most LGM samples, which allowed reconstructions. The new LGM results are consistent with previous reconstructions based on dinocyst data, which show much cooler conditions than at present along the continental margins of Canada and Europe, but sharp gradients of increasing temperature offshore. The results also suggest low salinity and larger than present contrasts in seasonal temperatures with colder winters and more extensive sea-ice cover, whereas relatively warm conditions may have prevailed offshore in summer. From these data, we hypothesise low thermal inertia in a shallow and low-density surface water layer.