NO rebinding to myoglobin: a reactive molecular dynamics study.

The rebinding of NO to myoglobin after photolysis is studied using the 'reactive molecular dynamics' method. In this approach the energy of the system is evaluated on two potential energy surfaces that include the heme-ligand interactions which change between liganded and unliganded myoglobin. This makes it possible to take into account in a simple way, the high dimensionality of the transition seam connecting the reactant and product states. The dynamics of the dissociated NO molecules are examined, and the geometrical and energetic properties of the transition seam are studied. Analysis of the frequency of recrossing shows that the height of the effective rebinding barrier is dependent on the time after photodissociation. This effect is due mainly to protein relaxation and may contribute to the experimentally observed non-exponential rebinding rate of NO, as has been suggested previously.

Latest Miocene - Pliocene Larger Foraminifera and depositional environments of the carbonate bank of La Désirade Island, Guadeloupe (French Antilles)

In this paper we present first results of the study of planktonic Foraminifera, large benthic Foraminifera and carbonate facies of La Désirade, aiming at a definition of the age and depositional environments of the Neogene carbonates of this island. The study of planktonic Foraminifera from the Detrital Offshore Limestones (DOL) of the Anciènne Carrière allows to constrain the biochronology of this formation to the lower Zone N19 and indicates a latest Miocene to early Pliocene (5.48 - 4.52 Ma) age. Large benthic Foraminifera were studied both as isolated and often naturally split specimens from the DOL, and in thin sections of limestones from the DOL and the Limestone Table (LT). The assemblages of Foraminifera include Nummulitidae, Amphisteginidae, Asterigerinidae, Peneroplidae, Soritidae, Rotalidae (Globigerinidae: Globigerinoides, Sphaeroidenellopsis, Orbulina) and incrusting Foraminifera (Homotrema and Sporadotrema). The genera Amphistegina, Archaias and Operculina are discussed. Concerning the Nummulitidae we include both "Paraspiroclypeus" chawneri and "Nummulites" cojimarensis, as well as a newly described species, Operculina desiradensis new species, in the genus Operculina, because the differences between these 3 species are rather on the specific than the generic level, while their morphology, studied by SEM, is compatible with the definition of the genus Operculina (D'Orbigny1826, emend. Hottinger 1977). The three species can be easily distinguished on the basis of their differences in spiral growth: while O. desiradensis has an overall logarithmic spiral growth, O. cojimarensis and especially O. chawneri show a tighter and more geometric spiral growth. O. cojimarensis and O. chawneri were originally described from Cuba in outcrops originally dated as Oligocene and later redated as early Pliocene. Therefore, O. chawneri was considered until now as restricted to the early Pliocene. However, in the absence of a detailed morphometric and biostratigraphic study of the Caribbean Neogene nummulitids, it is difficult to evaluate the biochronologic range of these species.The history of the carbonates begins with the initial tectonic uplift and erosion of the Jurassic igneous basement of La Désirade, that must have occurred at latest in late Miocene times, when sea-level oscillated around a long term stable mean. The rhythmic deposition of the Désirade Limestone Table (LT) can be explained by synsedimentary subsidence in a context of rapidly oscillating sea-level due to precession-driven (19-21 kyr) glacio-eustatic sea-level changes during the latest Miocene- Pliocene. Except for a thin reef cap present at the eastern edge of the LT, no other in-place reefal constructions have been observed in the LT. The DOL of western Désirade are interpreted as below wave base gravity deposits that accumulated beneath a steep fore-reef slope. They document the mobilisation of carbonate material (including Larger Foraminifera) from an adjacent carbonate platform by storms and their gravitational emplacement as debris and grain flows. The provenance of both the reefal carbonate debris and the tuffaceous components redeposited in the carbonates of La Désirade must be to the west, i. e. the carbonate platforms of Marie Galante and Grande Terre.

Wandering, verbally and physically abusive behaviour and their relation with pain in nursing homes residents

Backgrounds:¦Behavioural and psychological symptoms of dementia (BPSD) include, among others, hallucinations, delusions, depression, euphoria, agitation, aggression, sexual desinhibition, sleep disturbances, and apathy (1). To our knowledge, surprisingly few studies looked into the possible association between pain and BPSD in nursing home residents. Given this dearth of studies, we wondered whether or not there is an association, in nursing home residents, between pain and BPSD, in particular wandering as well as verbally and physically abusive behaviour, and whether or not this possible association changes with the degree of cognitive impairment.¦Method:¦All nursing home residents in the three Swiss cantons Aargau, Basel-City, and Solothurn (corresponding to 13.5%¦of the total Swiss population) receive a Resident Assessment Instrument Minimum Data Set (RAI-MDS)¦assessment within the first two weeks upon entry. This yielded a total sample of 16'430 nursing home residents considering that the residents' assessment took place between 1997 and 2007 and that we only took into account the admission RAI-MDS assessment. Only residents for whom data on pain was recorded were included in the study (n = 16'183).¦Results:¦Wandering correlated significantly with pain although the effect size was small (Spearman correlation coefficient = 0.052; p = 0.000), a result very similar to that found for VAB (Spearman correlation coefficient = 0.034; p = 0.000) and PAB (Spearman correlation coefficient = 0.043; p = 0.000). Likewise, using linear regression analyses, pain was very significantly associated with any of the three BPSD considered, but it predicted astonishingly little of the¦variance observed (wandering: B = 0.036; p = 0.000; R2 = 0.002; VAB: B = 0.021; p = 0.000; R2 = 0.001 PAB: B = 0.012; p = 0.000; R2 = 0.001). The interaction of pain and cognition had a significant effect on the three BPSD, suggesting that cognition was a moderator of the relationship between pain and all three behaviours.¦Conclusion:¦Wandering behaviours, VAB and PAB seem to be predicted by many factors. Although pain predicts only a small part of variance of these behaviours, it still remains important to recognise and treat pain in order to reduce these behaviours at least a little both in intensity and frequency. Given the dearth of studies and their somewhat contradictory results, further studies ought to investigate the role, the type and localisation of pain might play on the expression of different BPSD or how residents suffering from dementia perceive pain.

Iron overload, an immunosuppression marker in HIV-infected patients.

Purpose: Iron overload (IO) has been associated with increased cardiovascular risk (CVR) and metabolic syndrome (MS) in the general population; both elevated CVR and MS are frequent in HIV- patients. Our aim was to analyze the prevalence of IO in a cohort of asymptomatic patients with HIV infection, and related factors. Methods: Cross-sectional study of a cohort of HIV outpatients in regular follow-up. Demographic, epidemiological, clinical, analytical and therapeutic data were collected. Patients completed a questionnaire about CVR factors and 10-year CV disease risk estimation (Framingham score), underwent a physical exam, and a fasting blood analysis. IO was defined as a plasma ferritin level higher than 200 m/L in women and 300 m/L in men. Results: 571 patients (446 men, 125 women), with a mean age of 43.2 years, sexual transmission of HIV in 68.5%, median CD4 count 474 cell/μL (IQR: 308-666), and 36.3% Aids cases 86.2% were on antiretroviral therapy (ART), and 74.8% of them had undetectable HIV viral load 14.6% met MS criteria, and mean CVR at 10 years was 6.67%. IO was detected in 11% of cases. Patients with IO were more immunosuppressed (CD4 count 369 vs 483/μL, p<0.0001), presented a higher prevalence of detectable HIV viral load (17.6% vs 8.9%; p<0.005), and of Aids cases (14.9% vs 8.7%; p<0.023), and lower plasma levels of cholesterol, HDLc and LDLc (154 vs 183, 34 vs 43, 93 vs 110 mg/dL, respectively; p<0.0001. In the multivariate analysis, the only related factor was CD4 count <350 cell/μL (OR 2.86, 95% CI 1.6-4.9; p<0.0001). IO was not associated with CVR nor with MS. Conclusions: IO is not uncommon in HIV patients, and it is only related with immunosuppression defined as CD4 count <350 cell/ mL, and in contrast to general population, it is not related with increased CVR nor with MS.

Stringent V beta requirement for the development of NK1.1+ T cell receptor-alpha/beta+ cells in mouse liver.

The liver of C57BL/6 mice contains a major subset of CD4+8- and CD4-8- T cell receptor (TCR)-alpha/beta+ cells expressing the polymorphic natural killer NK1.1 surface marker. Liver NK1.1+TCR-alpha/beta+ (NK1+ T) cells require interaction with beta2-microglobulin-associated, major histocompatibility complex I-like molecules on hematopoietic cells for their development and have a TCR repertoire that is highly skewed to Vbeta8.2, Vbeta7, and Vbeta2. We show here that congenic C57BL/6.Vbeta(a) mice, which lack Vbeta8- expressing T cells owing to a genomic deletion at the Vbeta locus, maintain normal levels of liver NK1+ T cells owing to a dramatic increase in the proportion of cells expressing Vbeta7 and Vbeta2 (but not other Vbetas). Moreover, in C57BL/6 congenic TCR-V Vbeta3 and -Vbeta8.1 transgenic mice (which in theory should not express other Vbeta, owing to allelic exclusion at the TCR-beta locus), endogenous TCR-Vbeta8.2, Vbeta7, and Vbeta2 (but not other Vbetas) are frequently expressed on liver NK1+T cells but absent on lymph node T cells. Finally, when endogenous V beta expression is prevented in TCR-Vbeta3 and Vbeta8.1 transgenic mice (by introduction of a null allele at the C beta locus), the development of liver NK1+T cells is totally abrogated. Collectively, our data indicate that liver NK1+T cells have a stringent requirement for expression of TCR-Vbeta8.2, Vbeta7, or Vbeta2 for their development.

Urological surgery and antiplatelet drugs after cardiac and cerebrovascular accidents.

PURPOSE: The perioperative treatment of patients on dual antiplatelet therapy after myocardial infarction, cerebrovascular event or coronary stent implantation represents an increasingly frequent issue for urologists and anesthesiologists. We assess the current scientific evidence and propose strategies concerning treatment of these patients. MATERIALS AND METHODS: A MEDLINE and PubMed search was conducted for articles related to antiplatelet therapy after myocardial infarction, coronary stents and cerebrovascular events, as well as the use of aspirin and/or clopidogrel in the context of surgery. RESULTS: Early discontinuation of antiplatelet therapy for secondary prevention is associated with a high risk of coronary thrombosis, which is further increased by the hypercoagulable state induced by surgery. Aspirin has recently been recommended as a lifelong therapy. Clopidogrel is mandatory for 6 weeks after myocardial infarction and bare metal stents, and for 12 months after drug-eluting stents. Surgery must be postponed beyond these waiting periods or performed with patients receiving dual antiplatelet therapy because withdrawal therapy increases 5 to 10 times the risk of postoperative myocardial infarction, stent thrombosis or death. The shorter the waiting period between revascularization and surgery the greater the risk of adverse cardiac events. The risk of surgical hemorrhage is increased approximately 20% by aspirin and 50% by clopidogrel. CONCLUSIONS: The risk of coronary thrombosis when antiplatelet agents are withdrawn before surgery is generally higher than the risk of surgical hemorrhage when antiplatelet agents are maintained. However, this issue has not yet been sufficiently evaluated in urological patients and in many instances during urological surgery the risk of bleeding can be dangerous. A thorough dialogue among surgeon, cardiologist and anesthesiologist is essential to determine all risk factors and define the best possible strategy for each patient.

Influencia de la angina preinfarto en la semana previa en la morbimortalidad cardiovascular tardía tras el alta hospitalaria.

The occurrence of angina in the week preceding myocardial infarction is associated with a reduction in cardiovascular complications in the acute phase. However, little is known about it relationship with prognosis after hospitalization (e.g., cardiovascular death and the development of heart failure or ischemic cardiomyopathy). The study included 290 consecutive patients admitted for a first myocardial infarction: 107 (36.9%) had preceding angina while 183 did not. Those with a history of ischemic cardiomyopathy of more than 1 week or structural cardiopathy were excluded. There was no difference in baseline characteristics between the two groups. Moreover, there was no difference in the rates of cardiovascular complications after hospital discharge: cardiovascular death (7% vs. 12.6%; P=.3), heart failure (7.4% vs. 11.6%; P=.2), and myocardial ischemia, including myocardial infarction and unstable angina, requiring hospitalization (41.2% vs. 31.3%; P=.3). The occurrence of angina in the week before a first myocardial infarction did not influence cardiovascular complications after hospital discharge (odds ratio = 0.75 [0.51-1.11]; P=.15).

Predictive value of Glasgow Coma Scale after brain trauma: change in trend over the past ten years.

BACKGROUND: Age and the Glasgow Coma Scale (GCS) score on admission are considered important predictors of outcome after traumatic brain injury. We investigated the predictive value of the GCS in a large group of patients whose computerised multimodal bedside monitoring data had been collected over the previous 10 years. METHODS: Data from 358 subjects with head injury, collected between 1992 and 2001, were analysed retrospectively. Patients were grouped according to year of admission. Glasgow Outcome Scores (GOS) were determined at six months. Spearman's correlation coefficients between GCS and GOS scores were calculated for each year. RESULTS: On average 34 (SD: 7) patients were monitored every year. We found a significant correlation between the GCS and GOS for the first five years (overall 1992-1996: r = 0.41; p<0.00001; n = 183) and consistent lack of correlations from 1997 onwards (overall 1997-2001: r = 0.091; p = 0.226; n = 175). In contrast, correlations between age and GOS were in both time periods significant and similar (r = -0.24 v r = -0.24; p<0.002). CONCLUSIONS: The admission GCS lost its predictive value for outcome in this group of patients from 1997 onwards. The predictive value of the GCS should be carefully reconsidered when building prognostic models incorporating multimodality monitoring after head injury.

Cytotoxic T cells deficient in both functional fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease.

Graft-versus-host disease (GVHD) is the main complication after allogeneic bone marrow transplantation. Although the tissue damage and subsequent patient mortality are clearly dependent on T lymphocytes present in the grafted inoculum, the lethal effector molecules are unknown. Here, we show that acute lethal GVHD, induced by the transfer of splenocytes from C57BL/6 mice into sensitive BALB/c recipients, is dependent on both perforin and Fas ligand (FasL)-mediated lytic pathways. When spleen cells from mutant mice lacking both effector molecules were transferred to sublethally irradiated allogeneic recipients, mice survived. Delayed mortality was observed with grafted cells deficient in only one lytic mediator. In contrast, protection from lethal acute GVHD in resistant mice was exclusively perforin dependent. Perforin-FasL-deficient T cells failed to lyse most target cells in vitro. However, they still efficiently killed tumor necrosis factor alpha-sensitive fibroblasts, demonstrating that cytotoxic T cells possess a third lytic pathway.

Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study.

BACKGROUND: Treatment strategies for acute basilar artery occlusion (BAO) are based on case series and data that have been extrapolated from stroke intervention trials in other cerebrovascular territories, and information on the efficacy of different treatments in unselected patients with BAO is scarce. We therefore assessed outcomes and differences in treatment response after BAO. METHODS: The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO between November 1, 2002, and October 1, 2007. Stroke severity at time of treatment was dichotomised as severe (coma, locked-in state, or tetraplegia) or mild to moderate (any deficit that was less than severe). Outcome was assessed at 1 month. Poor outcome was defined as a modified Rankin scale score of 4 or 5, or death. Patients were divided into three groups according to the treatment they received: antithrombotic treatment only (AT), which comprised antiplatelet drugs or systemic anticoagulation; primary intravenous thrombolysis (IVT), including subsequent intra-arterial thrombolysis; or intra-arterial therapy (IAT), which comprised thrombolysis, mechanical thrombectomy, stenting, or a combination of these approaches. Risk ratios (RR) for treatment effects were adjusted for age, the severity of neurological deficits at the time of treatment, time to treatment, prodromal minor stroke, location of the occlusion, and diabetes. FINDINGS: 619 patients were entered in the registry. 27 patients were excluded from the analyses because they did not receive AT, IVT, or IAT, and all had a poor outcome. Of the 592 patients who were analysed, 183 were treated with only AT, 121 with IVT, and 288 with IAT. Overall, 402 (68%) of the analysed patients had a poor outcome. No statistically significant superiority was found for any treatment strategy. Compared with outcome after AT, patients with a mild-to-moderate deficit (n=245) had about the same risk of poor outcome after IVT (adjusted RR 0.94, 95% CI 0.60-1.45) or after IAT (adjusted RR 1.29, 0.97-1.72) but had a worse outcome after IAT compared with IVT (adjusted RR 1.49, 1.00-2.23). Compared with AT, patients with a severe deficit (n=347) had a lower risk of poor outcome after IVT (adjusted RR 0.88, 0.76-1.01) or IAT (adjusted RR 0.94, 0.86-1.02), whereas outcomes were similar after treatment with IAT or IVT (adjusted RR 1.06, 0.91-1.22). INTERPRETATION: Most patients in the BASICS registry received IAT. Our results do not support unequivocal superiority of IAT over IVT, and the efficacy of IAT versus IVT in patients with an acute BAO needs to be assessed in a randomised controlled trial. FUNDING: Department of Neurology, University Medical Center Utrecht.

Iowa Department of Commerce - Credit Union Division, Agency Performance Plan

Annual Report, Agency Performance Plan