Selectin catch–slip kinetics encode shear threshold adhesive behavior of rolling leukocytes

The selectin family of leukocyte adhesion receptors is principally recognized for mediating transient rolling interactions during the inflammatory response. Recent studies using ultrasensitive force probes to characterize the force–lifetime relationship between P- and L-selectin and their endogenous ligands have underscored the ability of increasing levels of force to initially extend the lifetime of these complexes before disrupting bond integrity. This so-called “catch–slip” transition has provided an appealing explanation for shear threshold phenomena in which increasing levels of shear stress stabilize leukocyte rolling under flow. We recently incorporated catch–slip kinetics into a mechanical model for cell adhesion and corroborated this hypothesis for neutrophils adhering via L-selectin. Here, using adhesive dynamics simulations, we demonstrate that biomembrane force probe measurements of various P- and L-selectin catch bonds faithfully predict differences in cell adhesion patterns that have been described extensively in vitro. Using phenomenological parameters to characterize the dominant features of molecular force spectra, we construct a generalized phase map that reveals that robust shear-threshold behavior is possible only when an applied force very efficiently stabilizes the bound receptor complex. This criteria explains why only a subset of selectin catch bonds exhibit a shear threshold and leads to a quantitative relationship that may be used to predict the magnitude of the shear threshold for families of catch–slip bonds directly from their force spectra. Collectively, our results extend the conceptual framework of adhesive dynamics as a means to translate complex single-molecule biophysics to macroscopic cell behavior.     

The state diagram for cell adhesion under flow: leukocyte rolling and firm adhesion

Leukocyte adhesion under flow in the microvasculature is mediated by binding between cell surface receptors and complementary ligands expressed on the surface of the endothelium. Leukocytes adhere to endothelium in a two-step mechanism: rolling (primarily mediated by selectins) followed by firm adhesion (primarily mediated by integrins). Using a computational method called "Adhesive Dynamics," we have simulated the adhesion of a cell to a surface in flow, and elucidated the relationship between receptor-ligand functional properties and the dynamics of adhesion. We express this relationship in a state diagram, a one-to-one map between the biophysical properties of adhesion molecules and various adhesive behaviors. Behaviors that are observed in simulations include firm adhesion, transient adhesion (rolling), and no adhesion. We varied the dissociative properties, association rate, bond elasticity, and shear rate and found that the unstressed dissociation rate, k(r)(o), and the bond interaction length, gamma, are the most important molecular properties controlling the dynamics of adhesion. Experimental k(r)(o) and gamma values from the literature for molecules that are known to mediate rolling adhesion fall within the rolling region of the state diagram. We explain why L-selectin-mediated rolling, which has faster k(r)(o) than other selectins, is accompanied by a smaller value for gamma. We also show how changes in association rate, shear rate, and bond elasticity alter the dynamics of adhesion. The state diagram (which must be mapped for each receptor-ligand system) presents a concise and comprehensive means of understanding the relationship between bond functional properties and the dynamics of adhesion mediated by receptor-ligand bonds.     

Ectopic pro-opiomelanocortin syndrome.

Ectopic POMC syndrome remains one of the most challenging differential diagnoses in endocrinology. Recent progress in the understanding of the tissue specific regulation of POMC gene expression and new insights into the processing of the POMC peptide in nonpituitary tissues has helped elucidate some of the molecular events leading to ectopic expression and secretion of POMC peptides. Corticotropin and other POMC-derived peptides have diverse effects on adrenal steroidogenesis, growth, and extra-adrenal tissues. Differences in POMC gene regulation in the corticotrope versus ectopic POMC-producing tumors provides a scientific framework for the clinical distinction between eutopic and ectopic Cushing's syndrome. In an attempt to revisit recent basic and clinical advances in the diagnosis of ectopic POMC syndrome the authors undertook an extensive literature review of 530 cases in 197 published papers and provided a molecular biologic, demographic and diagnostic update. According to this review, the four most common causes of ectopic POMC syndrome are the small cell carcinoma of the lung (27%), bronchial carcinoids (21%), islet cell tumor of the pancreas (16%), and thymic carcinoids (10%). Although the clinical features of patients with ectopic POMC syndrome are similar to those with Cushing's disease, subgroup analysis reveals a broad spectrum of severity and progression of signs and symptoms of hypercortisolism. The endocrine workup of a patient with suspected ectopic POMC syndrome includes the establishment of pathologic hypercortisolism, diagnosis of corticotropin dependency, and the differential diagnosis of corticotropin-dependent Cushing's syndrome. The use of a variety of baseline endocrine values, dynamic endocrine testing, and invasive procedures leads to the correct diagnosis in the majority of patients with ectopic POMC syndrome. Diagnostic imaging, including conventional radiological techniques and somatostatin receptor scintigraphy, aids in the correct localization and eventual treatment of ectopic POMC production.     

Reliability of MRSI brain temperature mapping at 1.5 and 3 T

MRSI permits the non‐invasive mapping of brain temperature in vivo, but information regarding its reliability is lacking. We obtained MRSI data from 31 healthy male volunteers [age range, 22–40 years; mean ± standard deviation (SD), 30.5 ± 5.0 years]. Eleven subjects (age range, 23–40 years; mean ± SD, 30.5 ± 5.2 years) were invited to receive four point‐resolved spectroscopy MRSI scans on each of 3 days in both 1.5‐T (TR/TE = 1000/144 ms) and 3‐T (TR/TE = 1700/144 ms) clinical scanners; a further 20 subjects (age range, 22–40 years; mean ± SD, 30.5 ± 4.9 years) were scanned on a single occasion at 3 T. Data were fitted in the time domain to determine the water–N‐acetylaspartate chemical shift difference, from which the temperature was estimated. Temperature data were analysed using a linear mixed effects model to determine variance components and systematic temperature changes during the scanning sessions. To characterise the effects of instrumental drift on apparent MRSI brain temperature, a temperature‐controlled phantom was constructed and scanned on multiple occasions. Components of apparent in vivo temperature variability at 1.5 T/3 T caused by inter‐subject (0.18/0.17 °C), inter‐session (0.18/0.15 °C) and within‐session (0.36/0.14 °C) effects, as well as voxel‐to‐voxel variation (0.59/0.54 °C), were determined. There was a brain cooling effect during in vivo MRSI of 0.10 °C [95% confidence interval (CI): –0.110, –0.094 °C; p < 0.001] and 0.051 °C (95% CI: –0.054, –0.048 °C; p < 0.001) per scan at 1.5 T and 3 T, respectively, whereas phantom measurements revealed minimal drift in apparent MRSI temperature relative to fibre‐optic temperature measurements. The mean brain temperature at 3 T was weakly associated with aural (R = 0.55, p = 0.002) and oral (R = 0.62, p < 0.001) measurements of head temperature. In conclusion, the variability associated with MRSI brain temperature mapping was quantified. Repeatability was somewhat higher at 3 T than at 1.5 T, although subtle spatial and temporal variations in apparent temperature were demonstrated at both field strengths. Such data should assist in the efficient design of future clinical studies. © 2013 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.     

Religion as a means to assure paternity

The sacred texts of five world religions (Buddhism, Christianity, Hinduism, Islam, and Judaism) use similar belief systems to set limits on sexual behavior. We propose that this similarity is a shared cultural solution to a biological problem: namely male uncertainty over the paternity of offspring. Furthermore, we propose the hypothesis that religious practices that more strongly regulate female sexuality should be more successful at promoting paternity certainty. Using genetic data on 1,706 father-son pairs, we tested this hypothesis in a traditional African population in which multiple religions (Islam, Christianity, and indigenous) coexist in the same families and villages. We show that the indigenous religion enables males to achieve a significantly (P = 0.019) lower probability of cuckoldry (1.3% versus 2.9%) by enforcing the honest signaling of menstruation, but that all three religions share tenets aimed at the avoidance of extrapair copulation. Our findings provide evidence for high paternity certainty in a traditional African population, and they shed light on the reproductive agendas that underlie religious patriarchy.     

Sudden unexpected death in epilepsy in lamotrigine randomized‐controlled trials

Purpose: Nonrandomized studies of the relationship of antiepileptic drugs (AEDs) with sudden unexpected death in epilepsy (SUDEP) may be susceptible to confounding by tonic–clonic seizure frequency, polypharmacy, and other potential risk factors for SUDEP. We evaluated the risk of SUDEP with lamotrigine (LTG) compared to active comparators and placebo in randomized controlled clinical trials conducted by GlaxoSmithKline (GSK) between 1984 and 2009. Methods: Among 7,774 subjects in 42 randomized clinical trials, there were 39 all‐cause deaths. Ten deaths occurred >2 weeks after discontinuation of study medication and were excluded. Narrative summaries of deaths were independently reviewed by three clinical experts (TT, LH, DF), who were blinded to randomized treatment arm. The risk of definite or probable SUDEP was compared between treatment arms for each trial type (placebo‐controlled, active‐comparator, crossover), using exact statistical methods. Key Findings: Of 29 on‐treatment deaths, eight were definite/probable SUDEP, four were possible SUDEP, and 17 were non‐SUDEP. The overall, unadjusted rate of definite/probable SUDEP for LTG was 2.2 events per 1,000‐patient years (95% confidence interval [95% CI] 0.70–5.4). The odds ratios (OR) for on‐treatment, definite/probable SUDEP in LTG arms relative to comparator arms, adjusted for length of exposure and trial, were the following: placebo‐controlled, OR 0.22 (95% CI 0.00–3.14; p = 0.26); active‐comparator, OR 2.18 (95% CI 0.17–117; p = 0.89); and placebo‐controlled cross‐over, OR 1.08 (95% CI 0.00–42.2; p = 1.0). Significance: There was no statistically significant difference in rate of SUDEP between LTG and comparator groups. However, the CIs were wide and a clinically important effect cannot be excluded.     

Role of Ultrasound in Managing Rheumatoid Arthritis

Ultrasound (US) is a valid and reliable imaging tool for evaluation of joint and tendon inflammation as well as cartilage and erosions in patients with rheumatoid arthritis (RA). Synovitis is usually scored semiquantitatively for both gray scale synovitis and power Doppler activity, and use of an atlas for US scoring has shown excellent reliability. Several scores are shown to be responsive to medical treatment, but the optimal joint/tendon score is to be explored. Doppler activity may be quantified by use of pixel counts and flow may be examined by use of resistive index. US-guided injections are better tolerated and have increased efficacy, as compared with palpation guidance, and should thus be included in rheumatologic practice. Different methods such as three-dimensional US, contrast-enhanced US and fusion imaging methods are all possible US approaches that may be used in treatment of RA patients in the future.     

Reliability of assessing the coronal curvature of children with scoliosis by using ultrasound images

Purpose

To investigate the intra- and inter-observer reliability of the coronal curvature asymmetry of children with adolescent idiopathic scoliosis (AIS) using the center of lamina (COL) method on ultrasound (US) images.

Methods

A cadaver spinal column phantom which was manipulated to present 30 scoliotic curves of varying severity of scoliotic deformities was scanned using both the US and laser scanner (LS) systems. Three observers of varying experience and skill measured the coronal curvature using the Cobb method on the LS images and the COL method on the US images. All of the measurements were performed twice, with a 1-week interval to reduce memory bias. The intra-class correlation coefficient (ICC), the mean absolute differences (MAD), and the error index (EI) were calculated to determine the agreement on selecting the end vertebrae. In addition, five AIS subjects were scanned using the US system. One observer measured the coronal curvature on the US images twice, and the measurements were compared with the Cobb angle reported in the clinical records.

Results

In the phantom study, the COL method showed high intra- and inter-observer reliabilities, with all ICC values >0.88. The maximum MAD of the COL measurements between different sessions among all observers was <4.1°. The EI values of the US method had similar end-vertebra selections as the LS method. The results of the pilot study showed a high intra-reliability for the US measurements. The measured difference between the Cobb and COL methods was 0.7° ± 0.5°.

Conclusions

The COL method using US images appears to be a very reliable method for measuring the coronal curvature in AIS without the need to expose the patient to radiation.