Dynamic 1^1H Imaging of Hyperpolarized [1-13^{13}C]Lactate In Vivo Using a Reverse INEPT Experiment

$\textbf{Purpose:}$ Dynamic magnetic resonance spectroscopic imaging of hyperpolarized $^{13}$C-labeled cell substrates has enabled the investigation of tissue metabolism in vivo. Currently observation of these hyperpolarized substrates is limited mainly to $^{13}$C detection. We describe here an imaging pulse sequence that enables proton observation by using polarization transfer from the hyperpolarized $^{13}$C nucleus to spin-coupled protons. $\textbf{Methods:}$ The pulse sequence transfers $^{13}$C hyperpolarization to $^1$H using a modified reverse insensitive nuclei enhanced by polarization transfer (INEPT) sequence that acquires a fully refocused echo. The resulting hyperpolarized $^1$H signal is acquired using a 2D echo-planar trajectory. The efficiency of polarization transfer was investigated using simulations with and without T$_1$ and T$_2$ relaxation of both the $^1$H and $^{13}$C nuclei. $\textbf{Results:}$ Simulations showed that $^1$H detection of the hyperpolarized $^{13}$C nucleus in lactate should increase significantly the signal-to-noise ratio when compared with direct $^{13}$C detection at 3T. However the advantage of $^1$H detection is expected to disappear at higher fields. Dynamic $^1$H images of hyperpolarized [1-$^{13}$C]lactate, with a spatial resolution of 1.25 × 1.25 mm$^2$, were acquired from a phantom injected with hyperpolarized [1-$^{13}$C]lactate and from tumors in vivo following injection of hyperpolarized [1-$^{13}$C]pyruvate. $\textbf{Conclusions:}$ The sequence allows $^1$H imaging of hyperpolarized $^{13}$C-labeled substrates in vivo.Grant sponsor: Cancer Research UK Programme; Grant number: 17242; Grant sponsor: CRUK-EPSRC Imaging Centre in Cambridge and Manchester; Grant number: 16465; Grant sponsor: Danish Strategic Research Council (LIFE-DNP: Hyperpolarized magnetic resonance for in vivo quantification of lipid, sugar and amino acid metabolism in lifestyle related diseases); Grant sponsor: Marie Curie ITN studentship (EUROPOL); Grant number: 642773

Tuning of Human Modulation Filters Is Carrier-Frequency Dependent

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Socioeconomic predictors and consequences of depression among primary care attenders with non-communicable diseases in the Western Cape, South Africa:Cohort study within a randomised trial

Background: Socioeconomic predictors and consequences of depression and its treatment were investigated in 4393 adults with specified non-communicable diseases attending 38 public sector primary care clinics in the Eden and Overberg districts of the Western Cape, South Africa.   Methods: Participants were interviewed at baseline in 2011 and 14 months later, as part of a randomised controlled trial of a guideline-based intervention to improve diagnosis and management of chronic diseases. The 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) was used to assess depression symptoms, with higher scores representing more depressed mood. Results: Higher CESD-10 scores at baseline were independently associated with being less educated (p=0.004) and having lower income (p=0.003). CESD-10 scores at follow-up were higher in participants with less education (p=0.010) or receiving welfare grants (p=0.007) independent of their baseline scores. Participants with CESD-10 scores of 10 or more at baseline (56% of all participants) had 25% higher odds of being unemployed at follow-up (p=0.016), independently of baseline CESD-10 score and treatment status. Among participants with baseline CESD-10 scores of 10 or more, antidepressant medication at baseline was independently more likely in participants who had more education (p=0.002), higher income (p<0.001), or were unemployed (p=0.001). Antidepressant medication at follow up was independently more likely in participants with higher income (p=0.023), and in clinics with better access to pharmacists (p=0.053) and off-site drug delivery (p=0.013).  Conclusions: Socioeconomic disadvantage appears to be both a cause and consequence of depression, and may also be a barrier to treatment. There are opportunities for improving the prevention, diagnosis and treatment of depression in primary care in inequitable middle income countries like South Africa.  Trial registration: The trial is registered with Current Controlled Trials (ISRCTN20283604) and the Office for Human Research Protections Database (IRB00001938, FWA00001637)

Reduced sensitivity for visual textures affects judgments of shape-from-shading and step climbing behaviour in older adults

Falls on stairs are a major hazard for older adults. Visual decline in normal aging can affect step climbing ability, altering gait and reducing toe clearance. Here we show that a loss of fine-grained visual information associated with age can affect the perception of surface undulations in patterned surfaces. We go on to show that such cues affect the limb trajectories of young adults, but due to their lack of sensitivity, not that of older adults. Interestingly neither the perceived height of a step nor conscious awareness are altered by our visual manipulation but stepping behaviour is: suggesting that the influence of shape perception on stepping behaviour is via the unconscious, action-centred, dorsal visual pathway

PKQuest: a general physiologically based pharmacokinetic model. Introduction and application to propranolol

BACKGROUND: A "physiologically based pharmacokinetic" (PBPK) approach uses a realistic model of the animal to describe the pharmacokinetics. Previous PBPKs have been designed for specific solutes, required specification of a large number of parameters and have not been designed for general use. METHODS: This new PBPK program (PKQuest) includes a "Standardhuman" and "Standardrat" data set so that the user input is minimized. It has a simple user interface, graphical output and many new features: 1) An option that uses the measured plasma concentrations to solve for the time course of the gastrointestinal, intramuscular, intraperotineal or skin absorption and systemic availability of a drug – for a general non-linear system. 2) Capillary permeability limitation defined in terms of the permeability-surface area products. 4) Saturable plasma and tissue protein binding. 5) A lung model that includes perfusion-ventilation mismatch. 6) A general optimization routine using either a global (simulated annealing) or local (Powell) minimization applicable to all model parameters. RESULTS: PKQuest was applied to measurements of human propranolol pharmacokinetics and intestinal absorption. A meal has two effects: 1) increases portal blood flow by 50%; and 2) decreases liver metabolism by 20%. There is a significant delay in the oval propranolol absorption in fasting subjects that is absent in fed subjects. The oral absorption of the long acting form of propranolol continues for a period of more than 24 hours. CONCLUSIONS: PKQuest provides a new general purpose, easy to use, freely distributed and physiologically rigorous PBPK software routine

Terahertz underdamped vibrational motion governs protein-ligand binding in solution

Low-frequency collective vibrational modes in proteins have been proposed as being responsible for efficiently directing biochemical reactions and biological energy transport. However, evidence of the existence of delocalized vibrational modes is scarce and proof of their involvement in biological function absent. Here we apply extremely sensitive femtosecond optical Kerr-effect spectroscopy to study the depolarized Raman spectra of lysozyme and its complex with the inhibitor triacetylchitotriose in solution. Underdamped delocalized vibrational modes in the terahertz frequency domain are identified and shown to blue-shift and strengthen upon inhibitor binding. This demonstrates that the ligand-binding coordinate in proteins is underdamped and not simply solvent-controlled as previously assumed. The presence of such underdamped delocalized modes in proteins may have significant implications for the understanding of the efficiency of ligand binding and protein–molecule interactions, and has wider implications for biochemical reactivity and biological function

Quantum Correlations in NMR systems

In conventional NMR experiments, the Zeeman energy gaps of the nuclear spin ensembles are much lower than their thermal energies, and accordingly exhibit tiny polarizations. Generally such low-purity quantum states are devoid of quantum entanglement. However, there exist certain nonclassical correlations which can be observed even in such systems. In this chapter, we discuss three such quantum correlations, namely, quantum contextuality, Leggett-Garg temporal correlations, and quantum discord. In each case, we provide a brief theoretical background and then describe some results from NMR experiments.Comment: 21 pages, 7 figure

Colostomy closure: how to avoid complications

Purpose: Colostomy is an operation frequently performed in pediatric surgery. Despite its benefits, it can produce significant morbidity. In a previous publication we presented our experience with the errors and complications that occurred during cases of colostomy creation. We now have focused in the morbidity related to the colostomy closure. The technical details that might have contributed to the minimal morbidity we experienced are described. Methods: The medical records of 649 patients who underwent colostomy closure over a 28-year period were retrospectively reviewed looking for complications following these procedures. Our perioperative protocol for colostomy closure consisted in: clear fluids by mouth and repeated proximal stoma irrigations 24 h prior to the operation. Administration of IV antibiotics during anesthesia induction and continued for 48 h. Meticulous surgical technique that included: packing of the proximal stoma, plastic drape to immobilize the surgical field, careful hemostasis, emphasis in avoiding contamination, cleaning the edge of the stomas to allow a good 2-layer, end-to-end anastomosis with separated long-term absorbable sutures, generous irrigation of the peritoneal cavity and subsequent layers with saline solution, closure by layers to avoid dead space, and avoidance of hematomas. No drains and no nasogastric tubes were used. Oral fluids were started the day after surgery and patients were discharged 48-72 h after the operation. Results: The original diagnoses of the patients were: anorectal malformation (583), Hirschsprung\u27s disease (53), and others (13). 10 patients (1.5%) had complications: 6 had intestinal obstruction (5 due to small bowel adhesions, 1 had temporary delay of the function of the anastomosis due to a severe size discrepancy between proximal and distal stoma with a distal microcolon) and 4 incisional hernias. There were no anastomotic dehiscences or wound infection. There was no bleeding, no anastomotic stricture and no mortality. Conclusion: Based on this experience we believe that colostomy closure can be performed with minimal morbidity provided a meticulous technique is observed. © 2010 The Author(s)

Seasonality in depressive and anxiety symptoms among primary care patients and in patients with depressive and anxiety disorders; results from the Netherlands Study of Depression and Anxiety

<p>Abstract</p> <p>Background</p> <p>Little is known about seasonality of specific depressive symptoms and anxiety symptoms in different patient populations. This study aims to assess seasonal variation of depressive and anxiety symptoms in a primary care population and across participants who were classified in diagnostic groups 1) healthy controls 2) patients with a major depressive disorder, 3) patients with any anxiety disorder and 4) patients with a major depression and any anxiety disorder.</p> <p>Methods</p> <p>Data were used from the Netherlands Study of Depression and Anxiety (NESDA). First, in 5549 patients from the NESDA primary care recruitment population the Kessler-10 screening questionnaire was used and data were analyzed across season in a multilevel linear model. Second, in 1090 subjects classified into four groups according to psychiatric status according to the Composite International Diagnostic Interview, overall depressive symptoms and atypical versus melancholic features were assessed with the Inventory of Depressive Symptoms. Anxiety and fear were assessed with the Beck Anxiety Inventory and the Fear questionnaire. Symptom levels across season were analyzed in a linear regression model.</p> <p>Results</p> <p>In the primary care population the severity of depressive and anxiety symptoms did not show a seasonal pattern. In the diagnostic groups healthy controls and patients with any anxiety disorder, but not patients with a major depressive disorder, showed a small rise in depressive symptoms in winter. Atypical and melancholic symptoms were both elevated in winter. No seasonal pattern for anxiety symptoms was found. There was a small gender related seasonal effect for fear symptoms.</p> <p>Conclusions</p> <p>Seasonal differences in severity or type of depressive and anxiety symptoms, as measured with a general screening instrument and symptom questionnaires, were absent or small in effect size in a primary care population and in patient populations with a major depressive disorder and anxiety disorders.</p

The dipolar endofullerene HF@C60

The cavity inside fullerenes provides a unique environment for the study of isolated atoms and molecules. We report encapsulation of hydrogen fluoride inside C60 using molecular surgery to give the endohedral fullerene HF@C60. The key synthetic step is the closure of the open fullerene cage while minimizing escape of HF. The encapsulated HF molecule moves freely inside the cage and exhibits quantization of its translational and rotational degrees of freedom, as revealed by inelastic neutron scattering and infrared spectroscopy. The rotational and vibrational constants of the encapsulated HF molecules were found to be redshifted relative to free HF. The NMR spectra display a large 1H-19F J coupling typical of an isolated species. The dipole moment of HF@C60 was estimated from the temperature-dependence of the dielectric constant at cryogenic temperatures and showed that the cage shields around 75% of the HF dipole