Inferring neural activity from BOLD signals through nonlinear optimization

The blood oxygen level-dependent (BOLD) fMRI signal does not measure neuronal activity directly. This fact is a key concern for interpreting functional imaging data based on BOLD. Mathematical models describing the path from neural activity to the BOLD response allow us to numerically solve the inverse problem of estimating the timing and amplitude of the neuronal activity underlying the BOLD signal. In fact, these models can be viewed as an advanced substitute for the impulse response function. In this work, the issue of estimating the dynamics of neuronal activity from the observed BOLD signal is considered within the framework of optimization problems. The model is based on the extended "balloon" model and describes the conversion of neuronal signals into the BOLD response through the transitional dynamics of the blood flow-inducing signal, cerebral blood flow, cerebral blood volume and deoxyhemoglobin concentration. Global optimization techniques are applied to find a control input (the neuronal activity and/or the biophysical parameters in the model) that causes the system to follow an admissible solution to minimize discrepancy between model and experimental data. As an alternative to a local linearization (LL) filtering scheme, the optimization method escapes the linearization of the transition system and provides a possibility to search for the global optimum, avoiding spurious local minima. We have found that the dynamics of the neural signals and the physiological variables as well as the biophysical parameters can be robustly reconstructed from the BOLD responses. Furthermore, it is shown that spiking off/on dynamics of the neural activity is the natural mathematical solution of the model. Incorporating, in addition, the expansion of the neural input by smooth basis functions, representing a low-pass filtering, allows us to model local field potential (LFP) solutions instead of spiking solutions.     

Relationship between pain and upper limb movement in patients with chronic sternal instability following cardiac surgery

Physiotherapists routinely prescribe upper limb exercises for patients who have undergone a median sternotomy during cardiac surgery. It is not currently known whether upper limb exercises should be unilateral or bilateral and conducted with or without additional loading to minimise pain and further sternal separation in patients with sternal instability. Eight patients who had chronic sternal instability after cardiac surgery were included in this study. During a selected regimen of upper limb exercises, the amount of sternal separation at different vertical points on the sternum was measured by ultrasound. The amount of sternal separation was not related to type of upper limb activity, but both unilateral and unilateral loaded positions were found to be significantly associated with sternal pain (p = 0.009). In this group of patients with chronic sternal instability, bilateral upper limb movements were significantly less associated with sternal pain than unilateral movements.     

Comparative Evaluation of Piperacillin in Vitro

The minimal inhibitory concentrations of piperacillin and seven other betalactam antibiotics were determined against 407 bacterial isolates. Piperacillin was found to be more active than ampicillin against susceptible gram-negative bacilli and more active than either carbenicillin or ticarcillin against Pseudomonas aeruginosa and streptococci. Although piperacillin was active against Klebsiella pneumoniae, this activity was less than that of the cephalosporins. Piperacillin was not active against penicillin-resistant Staphylococcus aureus and Enterobacteriaceae that were resistant to the other test antibiotics.     

Protection of Pseudomonas aeruginosa against ciprofloxacin and beta-lactams by homologous alginate.

Pseudomonas aeruginosa-derived alginate but no other neutral and negatively charged polysaccharides protected mucoid and nonmucoid strains of that organism against ciprofloxacin, gentamicin, ticarcillin, and ceftazidime. Data indicate that alginate has an intrinsic protective effect which is independent of diffusion, charge, or biofilm phenomena.     

Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial

OBJECTIVE: To assess morbidity in patients with severe sepsis managed with and without drotrecogin alfa (activated). DESIGN: Analysis of secondary end points in a prospective, randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (PROWESS). SETTING: A total of 164 medical institutions in 11 countries. PATIENTS: A total of 1,690 consecutive adult patients with severe sepsis. INTERVENTIONS: A 96-hr infusion of drotrecogin alfa (activated) (human recombinant activated protein C) or placebo. MEASUREMENTS AND MAIN RESULTS: Sequential Organ Failure Assessment (SOFA) scores for cardiovascular, respiratory, renal, hematologic, and hepatic organ systems were measured for 28 days. Mean cardiovascular SOFA scores were significantly lower for patients treated with drotrecogin alfa (activated) compared with placebo patients over this time period (p = .022). Drotrecogin alfa (activated)-treated patients also showed significantly faster resolution of cardiovascular (p = .009) and respiratory (p = .009) dysfunction and significantly slower onset of hematologic organ dysfunction (p = .041) compared with placebo patients for days 1 to 7. No significant differences in morbidity were observed between treatment groups among 28-day survivors. CONCLUSION: Drotrecogin alfa (activated) demonstrated significant improvements in organ function compared with placebo in a large phase 3 clinical trial that has shown a mortality benefit in patients with severe sepsis.     

Further development of biomarkers in amyotrophic lateral sclerosis

Introduction: Amyotrophic lateral sclerosis (ALS) is an idiopathic neurodegenerative disease usually fatal in less than three years. Even if standard guidelines are available to diagnose ALS, the mean diagnosis delay is more than one year. In this context, biomarker discovery is a priority. Research has to focus on new diagnostic tools, based on combined explorations.

Areas covered: In this review, we specifically focus on biology and imaging markers. We detail the innovative field of ‘omics’ approach and imaging and explain their limits to be useful in routine practice. We describe the most relevant biomarkers and suggest some perspectives for biomarker research.

Expert commentary: The successive failures of clinical trials in ALS underline the need for new strategy based on innovative tools to stratify patients and to evaluate their responses to treatment. Biomarker data may be useful to improve the designs of clinical trials. Biomarkers are also needed to better investigate disease pathophysiology, to identify new therapeutic targets, and to improve the performance of clinical assessments for diagnosis and prognosis in the clinical setting. A consensus on the best management of neuroimaging and ‘omics’ methods is necessary and a systematic independent validation of findings may add robustness to future studies.     

Prehospital management of pediatric SVT

Accurate prehospital diagnosis and early initiation of emergency medical treatment for pediatric patients found to have supraventricular tachycardia is a reasonable task to accomplish and one that does not have to be anxiety-provoking. The most important point to remember is that the standard approach to resuscitation and stabilization for pediatric patients with narrow complex tachycardias (and those with aberrant or wide complexes identifiable as WPW) applies to all variations of SVT; thus, it is not necessary to precisely diagnose the variant prior to initiation of treatment, except for WPW, in which adenosine administration is contraindicated. Once the dysrhythmia is identified as SVT, the patient must rapidly be categorized as stable or unstable, which will then lead the EMS provider down the correct branch of the treatment algorithm. Every attempt should be made to perform a 12-lead ECG pre- and post-resuscitation, as well at to administer sedation prior to emergent synchronized cardioversion. Dosages of medications need not be memorized, provided that a readily available guide, such as a Broselow tape or regional tertiary care center laminated resuscitation card, is at hand. Finally, while termination of pediatric SVT, whether spontaneous or by EMS intervention, will also likely terminate the EMS provider's own palpitations, it is essential that these patients be seen in an emergency department immediately in order to accurately diagnose their medical condition and provide the patient and family with an appropriate disposition based on the events surrounding the incident.     

Comparative Clinical Pharmacology of Amoxicillin and Ampicillin Administered Orally

Ampicillin and amoxicillin (alpha-amino-p-hydroxybenzyl penicillin) were administered orally in 500-mg doses to eight fasting volunteers in a comparative study in which pharmacokinetic techniques were used. The absorption of amoxicillin was significantly better, as demonstrated by a higher mean peak serum concentration of 7.6 mug/ml as compared to 3.2 mug/ml for ampicillin, an average "area under the curve" that was approximately double that of ampicillin, and an 8-hr urinary recovery for amoxicillin of 60% as compared to 34% for ampicillin. Serum half-lives were the same for the two antibiotics, with values of 60.3 (+/-3.3) min for ampicillin and 61.3 (+/-5.6) min for amoxicillin. The latter drug gave measurable concentrations in the blood at 8 hr in all of eight volunteers, as compared to only three of eight with ampicillin.