Expanding the evidence base in transplantation: the complementary roles of randomized controlled trials and outcomes research

Transplantation offers a unique opportunity to demonstrate the complementary roles of randomized controlled trials and outcome research. The surgery and collaboration necessary for the transplant procedure makes randomization and blinding difficult. Because essentially every recipient is included in a transplant registry, sampling bias is minimized. Regulatory agencies generally do not consider outcomes research when assessing efficacy of new drugs or medical interventions. This workgroup summary examines the suitability of outcomes research to complement results of randomized controlled trials and related issues: efficacy versus effectiveness, internal versus external validity, data types, limitations, and analysis methodologies. Many advances in outcomes research have been pioneered in transplantation. A case is made for regulatory and reimbursement authorities to use outcomes research when making efficacy, effectiveness, and coverage decisions in transplantation.     

Dissection of the recognition properties of p38 MAP kinase. Determination of the binding mode of a new pyridinyl-heterocycle inhibitor family

The main recognition characteristics of the ATP binding site of p38 mitogen activated protein kinase alpha (p38alpha MAPK) have been explored by a combination of modeling and bioinformatics techniques, making special emphasis in the characteristics of the site that justifies binding specificity with respect to other MAP kinases. Particularly, we have analyzed the binding mode of a new family of p38 MAPK inhibitors based on the pyridinyl-heterocycle core. This family of compounds has a marked pseudosymmetry and can exist in different tautomeric forms, which makes the determination of the binding mode especially challenging. A combination of homology modeling, quantum mechanics, classical docking, and molecular dynamics calculations allowed us to determine the main characteristics defining the binding mode of this new scaffold in the ATP binding site of p38alpha. A set of free energy calculations allowed us to verify the binding mode proposed, giving an overall excellent agreement with the experimental values. Finally, the binding mode of this new family of compounds was compared to that of other members of the pyridinyl and pyrimidinyl heterocycle class.     

Linear Morphea Mimicking Lichen Striatus in Its Early Presentation

Linear morphea and lichen striatus are distinct conditions that have been linked in only one previous case report. We describe two patients with facial lichen striatus preceding linear morphea at the same site. A possible pathogenic relationship is discussed.     

Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model

Background  

Experimental and clinical studies on sepsis have demonstrated activation of the innate immune response following the initial host–bacterial interaction. In addition, mechanical ventilation (MV) can induce a pulmonary inflammatory response. How these two responses interact when present simultaneously remains to be elucidated. We hypothesized that MV modulates innate host response during sepsis by influencing Toll-like receptor (TLR) signaling.     

Brain dynamics sustaining rapid rule extraction from speech

Language acquisition is a complex process that requires the synergic involvement of different cognitive functions, which include extracting and storing the words of the language and their embedded rules for progressive acquisition of grammatical information. As has been shown in other fields that study learning processes, synchronization mechanisms between neuronal assemblies might have a key role during language learning. In particular, studying these dynamics may help uncover whether different oscillatory patterns sustain more item-based learning of words and rule-based learning from speech input. Therefore, we tracked the modulation of oscillatory neural activity during the initial exposure to an artificial language, which contained embedded rules. We analyzed both spectral power variations, as a measure of local neuronal ensemble synchronization, as well as phase coherence patterns, as an index of the long-range coordination of these local groups of neurons. Synchronized activity in the gamma band (20-40 Hz), previously reported to be related to the engagement of selective attention, showed a clear dissociation of local power and phase coherence between distant regions. In this frequency range, local synchrony characterized the subjects who were focused on word identification and was accompanied by increased coherence in the theta band (4-8 Hz). Only those subjects who were able to learn the embedded rules showed increased gamma band phase coherence between frontal, temporal, and parietal regions.     

Is there an anatomical substrate for idiopathic paroxysmal atrial fibrillation? A case-control echocardiographic study.

AIM: Idiopathic paroxysmal atrial fibrillation (AF) occurs in patients with apparently normal heart. Its mechanisms may be complex and are poorly understood. The aim of the study was to evaluate whether patients with idiopathic AF have any structural abnormality that may explain the occurrence of AF. METHODS AND RESULTS: A case-control study was undertaken including 60 consecutive patients (mean age 48 +/- 12 years; 75% men) with idiopathic AF admitted to the emergency department. Sixty sex- and age-matched healthy volunteers made up the control group. An echocardiogram was performed in all patients and volunteers to assess the left atrial (LA) and ventricular (LV) dimensions and valvular function. LV diastolic function was also evaluated by analysis of the LV inflow and pulmonary vein flow velocity patterns and tissue Doppler imaging of the mitral annulus. All AF patients showed normal echocardiographic studies with similar LV dimensions, ejection fraction, and diastolic function when compared with normal controls. However, patients with AF had larger LA dimensions (27 +/- 3 vs. 24 +/- 3 mm/m(2)), LA area (10 +/- 2 vs. 8 +/- 2 mm(2)/m(2)), and LA volume (27 +/- 9 vs. 19 +/- 6 mL/m(2)) (P < 0.05 for all). Among patients with AF, there were no differences in LA size between patients with a first episode or recurrent paroxysmal episodes. CONCLUSION: Patients with idiopathic AF showed larger left atria when compared with controls, there being no differences between patients with a first episode or a recurrence. This suggests the presence of an enhanced substrate to develop idiopathic lone AF.     

Ischemic stroke in patients with intermittent claudication: a clinical study of 142 cases

The clinical features, risk factors, neuroimaging findings, and outcome of acute ischemic stroke were assessed in patients with intermittent claudication. Data from 142 patients with ischemic stroke and intermittent claudication were collected from a prospective hospital-based stroke registry in which 2500 consecutive acute stroke patients attended over a 12-year period. Ischemic stroke in patients with intermittent claudication accounted for 7.7% of all ischemic strokes (n = 1840). Ischemic stroke with and without intermittent claudication showed a similar in-hospital mortality rate (16% vs 14%) and absence of functional limitation at hospital discharge (20.5% vs 18.5%). Ischemic stroke patients with intermittent claudication showed a significantly shorter length of stay than patients without symptomatic peripheral arterial disease (14.6 vs 18.8 days, p < 0.05). Ischemic heart disease, transient ischemic attack (TIA), renal dysfunction, and watershed infarct were significant independent predictors of ischemic stroke in patients with intermittent claudication. Although cerebral infarction in patients with intermittent claudication showed a clinical profile suggestive of poor outcome, the prognosis was similar to that of ischemic stroke without intermittent claudication.