Bacteriophage Lysin Mediates the Binding of Streptococcus mitis to Human Platelets through Interaction with Fibrinogen

The binding of bacteria to human platelets is a likely central mechanism in the pathogenesis of infective endocarditis. We have previously found that platelet binding by Streptococcus mitis SF100 is mediated by surface components encoded by a lysogenic bacteriophage, SM1. We now demonstrate that SM1-encoded lysin contributes to platelet binding via its direct interaction with fibrinogen. Far Western blotting of platelets revealed that fibrinogen was the major membrane-associated protein bound by lysin. Analysis of lysin binding with purified fibrinogen in vitro confirmed that these proteins could bind directly, and that this interaction was both saturable and inhibitable. Lysin bound both the Aα and Bβ chains of fibrinogen, but not the γ subunit. Binding of lysin to the Bβ chain was further localized to a region within the fibrinogen D fragment. Disruption of the SF100 lysin gene resulted in an 83±3.1% reduction (mean ± SD) in binding to immobilized fibrinogen by this mutant strain (PS1006). Preincubation of this isogenic mutant with purified lysin restored fibrinogen binding to wild type levels. When tested in a co-infection model of endocarditis, loss of lysin expression resulted in a significant reduction in virulence, as measured by achievable bacterial densities (CFU/g) within vegetations, kidneys, and spleens. These results indicate that bacteriophage-encoded lysin is a multifunctional protein, representing a new class of fibrinogen-binding proteins. Lysin appears to be cell wall-associated through its interaction with choline. Once on the bacterial surface, lysin can bind fibrinogen directly, which appears to be an important interaction for the pathogenesis of endocarditis

Cognitive and cognitive-motor interventions affecting physical functioning: A systematic review

Background Several types of cognitive or combined cognitive-motor intervention types that might influence physical functions have been proposed in the past: training of dual-tasking abilities, and improving cognitive function through behavioral interventions or the use of computer games. The objective of this systematic review was to examine the literature regarding the use of cognitive and cognitive-motor interventions to improve physical functioning in older adults or people with neurological impairments that are similar to cognitive impairments seen in aging. The aim was to identify potentially promising methods that might be used in future intervention type studies for older adults. Methods A systematic search was conducted for the Medline/Premedline, PsycINFO, CINAHL and EMBASE databases. The search was focused on older adults over the age of 65. To increase the number of articles for review, we also included those discussing adult patients with neurological impairments due to trauma, as these cognitive impairments are similar to those seen in the aging population. The search was restricted to English, German and French language literature without any limitation of publication date or restriction by study design. Cognitive or cognitive-motor interventions were defined as dual-tasking, virtual reality exercise, cognitive exercise, or a combination of these. Results 28 articles met our inclusion criteria. Three articles used an isolated cognitive rehabilitation intervention, seven articles used a dual-task intervention and 19 applied a computerized intervention. There is evidence to suggest that cognitive or motor-cognitive methods positively affects physical functioning, such as postural control, walking abilities and general functions of the upper and lower extremities, respectively. The majority of the included studies resulted in improvements of the assessed functional outcome measures. Conclusions The current evidence on the effectiveness of cognitive or motor-cognitive interventions to improve physical functioning in older adults or people with neurological impairments is limited. The heterogeneity of the studies published so far does not allow defining the training methodology with the greatest effectiveness. This review nevertheless provides important foundational information in order to encourage further development of novel cognitive or cognitive-motor interventions, preferably with a randomized control design. Future research that aims to examine the relation between improvements in cognitive skills and the translation to better performance on selected physical tasks should explicitly take the relation between the cognitive and physical skills into account.ISSN:1471-231

Association of anemia and long-term survival in patients with pulmonary hypertension.

BACKGROUND: Anemia is a marker of worsened clinical outcome in patients with heart failure from left ventricular dysfunction. Pulmonary hypertension often results in right ventricular dysfunction. Accordingly we sought to examine the association of hemoglobin levels and long-term all-cause mortality in a cohort of patients with pulmonary hypertension. METHODS: Baseline demographic information, clinical characteristics and fasting blood work were obtained in a cohort of 145 patients with pulmonary hypertension referred for pulmonary vasodilator testing. Data was retrospectively analyzed with Cox-proportional hazards analysis. RESULTS: Baseline characteristics of the cohort included age (mean±SD) 55.8±14.6 years, 75% women, 50% with idiopathic pulmonary hypertension, mean pulmonary artery pressure 46.1±14.2 mm Hg and arterial O(2) saturation 91±6 %. The most commonly utilized pulmonary hypertension specific therapeutic agents in descending order of frequency were epoprostenol (27%), sildenafil (21%), bosentan (17%), and treprostinil (6%). Over a median follow-up of 2.1 years, there were 39 deaths (26.9%). Patients who died had significantly lower hemoglobin levels than those survived (12.2±2.3 vs. 13.7±2.0, p<0.001). After adjustment for known predictors of death and pulmonary hypertension etiology, anemic patients were 3.3 times more likely to die than non-anemic patients (95% CI [1.43-7.51], p=0.005). CONCLUSIONS: Hemoglobin levels closely parallel survival in pulmonary hypertension. Modification of anemia in this disorder could alter the clinical course and calls for further research in this area

Pulmonary hypertension and elevated transpulmonary gradient in patients with mitral stenosis.

BACKGROUND AND AIM OF THE STUDY: Pulmonary hypertension frequently complicates mitral stenosis, with a subset of these patients exhibiting pressures well in excess of their mitral valve hemodynamics. The prevalence of this condition and its impact on clinical outcome following percutaneous balloon mitral commissurotomy (PBMC) is unknown. METHODS: The transpulmonary gradient (TPG) was measured in 317 patients undergoing PBMC; patients were subsequently defined as having either an appropriate or excessive TPG (< or =15 mmHg or >15 mmHg, respectively). Twenty-two patients were excluded due to valvuloplasty-related significant mitral regurgitation. The remaining 295 patients (250 females, 45 males; mean age 52 +/- 13 years) were prospectively followed up, with each patient underwent serial echocardiography. RESULTS: Among the patients, 214 (73%) had pulmonary hypertension (pulmonary artery pressure >25 mmHg) and 55 (19%) also had an elevated TPG. Females were almost fivefold more likely than males to have an elevated TPG (p = 0.003). Patients with an elevated TPG had a worse mean NYHA functional class than those with a normal TPG (3.0 +/- 0.5 versus 2.7 +/- 0.6, p = 0.01), while the mitral valve area (MVA) was slightly smaller in patients with an elevated TPG (1.0 +/- 0.2 versus 1.1 +/- 0.2 cm2, p = 0.003). All patients demonstrated a significant increase in MVA after commissurotomy (final MVA 1.7 +/- 0.6 cm2, p < 0.001 for elevated TPG; 1.8 +/- 0.4 cm2, p < 0.001 for normal TPG), and the NYHA class at six months was improved for all patients (2.8 +/- 0.6 versus 1.6 +/- 0.7, p < 0.001). The improvements in NYHA class, TPG and MVA were sustained at 36 months. CONCLUSION: Pulmonary hypertension with elevated TPG occurs in patients with mitral stenosis, and is significantly more common in females. Despite worse symptoms and higher right-sided pressures, PBMC is equally successful in patients with a normal TPG, and provides sustained benefit for up to 36 months after the procedure