bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluctuations in acceleration during voluntary contractions lead to greater impairment of movement accuracy in old adults
Authors: Christou Evangelos A. , Shinohara Minoru , Enoka Roger M.
Published: July 2015

The purpose of the study was to assess the effect of movement velocity on the relation between fluctuations in acceleration and the ability to achieve a target velocity during voluntary contractions performed by young (29.5 ± 4.3 yr) and old (74.9 ± 6.2 yr) adults. Subjects performed concentric and eccentric contractions with the first dorsal interosseus muscle while lifting a submaximal load (15% of maximum) at six movement velocities (0.03–1.16 rad/s). Fluctuations in acceleration, the accuracy of matching the target velocity, and electromyographic (EMG) activity were determined from three trials for each contraction type and movement velocity. The fluctuations in acceleration increased with movement velocity for both concentric and eccentric contractions, but they were greatest during fast eccentric contractions (∼135%) when there was stronger modulation of acceleration in the 5- to 10-Hz bandwidth. Nonetheless, EMG amplitude for first dorsal interosseus increased with movement velocity only for concentric and not eccentric contractions. Consistent with the minimum variance theory, movement accuracy was related to the fluctuations in acceleration for both types of contractions in all subjects. For a given level of fluctuations in acceleration, however, old subjects were three times less accurate than young subjects. Although the EMG amplitude at each speed was similar for young and old adults, only the young adults modulated the power in the EMG spectrum with speed. Thus the fluctuations in acceleration during voluntary contractions had a more pronounced effect on movement accuracy for old adults compared with young adults, probably due to factors that influenced the frequency-domain characteristics of the EMG.
Evidence for altered α-adrenoreceptor responsiveness after a single bout of maximal exercise
Authors: Convertino Victor A.
Published: July 2015

We studied hemodynamic responses to α- and β-receptor agonists in eight men to test the hypothesis that adrenoreceptor responsiveness is altered within 24 h of the performance of maximal exercise. Adrenoreceptor responsiveness was tested under two experimental conditions (with and without maximal exercise). Adrenoreceptor tests were performed 24 h after each subject performed graded upright cycle ergometry to volitional exhaustion. The 2 test days (experimental conditions) were separated by at least 1 wk, and the order of exercise and no-exercise conditions was counterbalanced. Steady-state graded infusions of phenylephrine (PE) and isoproterenol (Iso) were used to assess α- and β-adrenoreceptor responsiveness, respectively. Slopes calculated from linear regressions between Iso and PE doses and changes in heart rate, blood pressure, and leg vascular resistance for each subject were used as an index of α- and β-adrenoreceptor responsiveness. The slope of the relationship between heart rate and Iso with maximal exercise was 1,773 ± 164 beats · μg–1· kg–1· min–1compared with 1,987 ± 142 beats · μg–1· kg–1· min–1without exercise ( P = 0.158), whereas the slopes of the relationship between vascular resistance to Iso were -438 ± 123 peripheral resistance units (PRU) · μg–1· kg–1· min–1with maximal exercise and -429 ± 105 ·μg–1·kg–1·min–1without exercise ( P = 0.904). Maximal exercise was associated with greater ( P < 0.05) vascular resistance (15.1 ± 2.8 PRU·μg–1·kg–1· min–1) and mean arterial blood pressure (15.8 ± 2.1 mmHg · μg–1· kg–1· min–1) responses to PE infusion compared with no exercise (9.0 ± 2.0 PRU · μg–1· kg–1· min–1and 10.9 ± 2.0 mmHg · μg–1· kg–1· min–1, respectively). These results provide evidence that a single bout of maximal exercise increases α1-adrenoreceptor responsiveness within 24 h without affecting β-cardiac and vascular adrenoreceptor responses.
Structure of slowly adapting pulmonary stretch receptors in the lung periphery
Authors: Yu J. , Wang Y. F. , Zhang J. W.
Published: July 2015

Pulmonary sensory receptors are the initiating sites for lung reflexes; however, little is known about their structure, especially the relationship between the structure and function of these receptors. Using a novel approach (combining electrophysiological and morphological techniques), we examined the structures of the typical slowly adapting pulmonary stretch receptors (SARs) located in the lung periphery. We recorded SAR activities in the cervical vagus nerve, identified the receptive field, dissected the SARs in blocks, fixed and processed these blocks for immunohistochemical staining using anti-Na+/K+-ATPase, and examined the blocks under a confocal microscope. These SAR structures have multiple endings that have terminal knobs. Some structures that are located in the airway walls have terminal knobs buried in smooth muscle. Others are in the most peripheral part of the lung, and their terminal knobs have no obvious relation to smooth muscle, suggesting that muscle contraction may not be a direct factor for SAR activation.
Androgen-mediated modulation of macrophage function after trauma-hemorrhage: central role of 5α-dihydrotestosterone
Authors: Schneider Christian P. , Schwacha Martin G. , Samy T. S. Anantha , Bland Kirby I. , Chaudry Irshad H.
Published: July 2015

Androgens have been implicated as the causative factor for the postinjury immune dysfunction in males; however, it remains unknown whether androgens directly affect macrophages. To study this, male mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (mean arterial pressure, 30 ± 5 mmHg for 90 min and then resuscitated). The mice received the 5α-reductase inhibitor 4-hydroxyandrostenedione (4-OHA) before resuscitation. Plasma TNF-α, IL-6, and IL-10 levels were elevated after trauma-hemorrhage and normalized by 4-OHA. TNF-α and IL-6 production by splenic macrophages was decreased after injury, whereas Kupffer cell production of these mediators was enhanced. 4-OHA normalized cytokine production. Androgens suppressed cytokine production by splenic macrophages from hemorrhaged mice, whereas it enhanced TNF-α and IL-6 production by Kupffer cells. The addition of 4-OHA in vitro normalized cytokine production by cells treated with testosterone, but it had no effect on dihydrotestosterone-treated cells. These results indicate that androgens directly affect macrophage function in males after trauma and hemorrhagic shock and that the intracellular conversion of testosterone to dihydrotestosterone is of particular importance in mediating the androgen-induced effects.
Kinetic analysis of pulmonary neutrophil retention in vivo using the multiple-indicator-dilution technique
Authors: Schwab Andreas J. , Salamand Agnés , Merhi Yahye , Simard André , Dupuis Jocelyn
Published: July 2015

Multiple-indicator-dilution experiments were performed in the lungs of 13 anesthetized dogs by simultaneous bolus injection of111In-labeled neutrophils,51Cr-labeled red blood cells, and Evans blue-labeled albumin. Concomitant counts of unlabeled neutrophils were similar in pulmonary artery and aortic blood samples, demonstrating a dynamic balance across the lungs in the physiological state. Outflow profiles of labeled neutrophils were analyzed on the basis of a recirculatory pharmacokinetic model of labeled albumin. The outflow profiles of the recovered neutrophils were composed of a throughput component of circulating neutrophils and a component of reversibly marginated neutrophils. They were interpreted by a model incorporating neutrophil margination (transfer coefficient = 0.195 ± 0.081 s-1), rapid demargination (0.054 ± 0.027 s-1), and transfer to a slow marginated pool (0.023 ± 0.018 s-1). It will be interesting to apply the analysis in future studies aimed at determining whether it could be a useful research tool to investigate the interactions between the pulmonary endothelium and neutrophils in physiological and diseased states.
Evaluation of musculotendinous stiffness in prepubertal children and adults, taking into account muscle activity
Authors: Lambertz Daniel , Mora Isabelle , Grosset Jean-Francois , Pérot Chantal
Published: July 2015

Musculotendinous (MT) stiffness of the triceps surae (TS) muscle group was quantified in 28 prepubertal children (7–10 yr) by using quick-release movements at different levels of submaximal contractions. Surface electromyograms (EMG) of each part of the TS and of the tibialis anterior were also recorded. A stiffness index, defined as the slope of the angular stiffness-torque relationship (SIMT-Torque), was used to quantify changes in MT stiffness with age. Results showed a significant decrease in SIMT-Torque with age, ranging from 4.02 ± 0.29 to 2.88 ± 0.31 rad-1 for the youngest to the oldest children. Because an increase in stiffness with age was expected due to the maturation of elastic tissues, overactivation of the TS was suspected to contribute to the higher SIMT-Torque values found in the youngest children. TS EMG-torque analyses confirmed that neuromuscular efficiency was significantly lower for the 7- or 8-yr-old children compared with 10-yr-old children, notably due to a higher degree of tibialis anterior coactivation found in the youngest children. Thus the stiffness index originally defined as the slope of the angular stiffness-EMG relationship increased significantly with age toward adult values. The results underlined the necessity to take into account the capacities of muscle activation to quantify changes in elastic properties of muscles, when those capacities are suspected to be altered.
Small airway morphology and lung function in the transition from normality to chronic airway obstruction
Authors: Corsico Angelo , Milanese Manlio , Baraldo Simonetta , Casoni Gian Luca , Papi Alberto , Riccio Anna Maria , Cerveri Isa , Saetta Marina , Brusasco Vito
Published: July 2015

This study investigated the relationships between pathological changes in small airways (<6 mm perimeter) and lung function in 22 nonasthmatic subjects (20 smokers) undergoing lung resection for peripheral lesions. Preoperative pulmonary function tests revealed airway obstruction [ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) < 70%] in 12 subjects and normal lung function in 10. When all subjects were considered together, total airway wall thickness was significantly correlated with FEV1/FVC ( r2 = 0.25), reactivity to methacholine ( r2 = 0.26), and slope of linear regression of FVC against FEV1 values recorded during the methacholine challenge ( r2 = 0.56). Loss of peribronchiolar alveolar attachments was significantly associated ( r2 = 0.25) with a bronchoconstrictor effect of deep inhalation, as assessed from a maximal-to-partial expiratory flow ratio <1, but not with airway responses to methacholine. No significant correlation was found between airway smooth muscle thickness and lung function measurements. In conclusion, this study suggests that thickening of the airway wall is a major mechanism for airway closure, whereas loss of airway-to-lung interdependence may contribute to the bronchoconstrictor effect of deep inhalation in the transition from normal lung function to airway obstruction in nonasthmatic smokers.
Effects of different exercise modes on mineralization, structure, and biomechanical properties of growing bone
Authors: Huang T. H. , Lin S. C. , Chang F. L. , Hsieh S. S. , Liu S. H. , Yang R. S.
Published: July 2015

Weight bearing during exercise plays an important role in improving the mechanical properties of bone. The effect on bone of non-weight-bearing exercise such as swimming remains controversial. To investigate the effects of exercise mode on growing bone, 29 male Wistar rats (7 wk old) were randomly assigned to a running exercise group (Run, n = 9), a swimming exercise group (Swim, n = 10), or a nonexercise control group (Con, n = 10). During an 8-wk training session (20–60 min/day, 5 days/wk), the Run rats were trained at progressively increasing running speeds (12–22 m/min), and weights attached to the tail of the Swim rats were progressively increased from 0 to 2% of their body weight. The bone mineral density of the proximal tibiae of the Run rats was significantly higher than in the Swim ( P < 0.05). Femoral wet weights of the two exercise groups were significantly higher than in the control group ( P < 0.05). Interestingly, the percent difference between the tissue wet weight and dry weight (water content ratio), which is related to bone mechanical properties, was significantly higher in the tibiae of the Swim rats and the femora of both exercise groups compared with controls ( P < 0.05). Extrinsic as well as intrinsic biomechanical material properties were measured in a three-point bending test. Bone mechanical properties of the tibiae and femora of rats in the Swim and Run groups were significantly greater than those in the control group ( P < 0.05). In summary, different modes of exercise may benefit bone mechanical properties in different ways. The specific effects of swimming exercise (non-weight-bearing exercise) on bone require further study.
Augmentation of the push-pull effect by terminal aortic occlusion during head-down tilt
Authors: Hakeman Amy L. , Shepard Jami L. , Sheriff Don D.
Published: July 2015

Tolerance to positive vertical acceleration (Gz) gravitational stress is reduced when positive Gzstress is preceded by exposure to hypogravity, which is called the “push-pull effect.” The purpose of this study was to test the hypothesis that baroreceptor reflexes contribute to the push-pull effect by augmenting the magnitude of simulated hypogravity and thereby augmenting the stimulus to the baroreceptors. We used eye-level blood pressure as a measure of the effectiveness of the blood pressure regulatory systems. The approach was to augment the magnitude of the carotid hypertension (and the hindbody hypotension) when hypogravity was simulated by head-down tilt by mechanically occluding the terminal aorta and the inferior vena cava. Sixteen anesthetized Sprague-Dawley rats were instrumented with a carotid artery catheter and a pneumatic vascular occluder cuff surrounding the terminal aorta and inferior vena cava. Animals were restrained and subjected to a control gravitational (G) profile that consisted of rotation from 0 Gzto 90° head-up tilt (+1 Gz) for 10 s and a push-pull G profile consisting of rotation from 0 Gzto 90° head-down tilt (-1 Gz) for 2 s immediately preceding 10 s of +1 Gzstress. An augmented push-pull G profile consisted of terminal aortic vascular occlusion during 2 s of head-down tilt followed by 10 s of +1 Gzstress. After the onset of head-up tilt, the magnitude of the fall in eye-level blood pressure from baseline was -20 ± 1.3, -23 ± 0.7, and -28 ± 1.6 mmHg for the control, push-pull, and augmented push-pull conditions, respectively, with all three pairwise comparisons achieving statistically significant differences ( P < 0.01). Thus augmentation of negative Gzstress with vascular occlusion increased the magnitude of the push-pull effect in anesthetized rats subjected to tilting.
Hypercapnic duty cycle is an intermediate physiological phenotype linked to mouse chromosome 5
Authors: Schneider H. , Patil S. P. , Canisius S. , Gladmon E. A. , Schwartz A. R. , O'Donnell C. P. , Smith P. L. , Tankersley C. G.
Published: July 2015

We hypothesized that upper airway obstruction (UAO) leads to a compensatory increase in the duty cycle [ratio of inspiratory time to respiratory cycle length (Ti/Tt)], which is determined by genetic factors. We examined the compensatory Ti/Tt responses to 1) UAO and hypercapnia among normal individuals and 2) hypercapnia in different inbred strains, C3H/HeJ (C3) and C57BL/6J (B6), and their first- and second-generation (F2) offspring. 3) We then used the compensatory Ti/Tt response in the F2 to determine genetic linkage to the mouse genome. First, normal individuals exhibited a similar increase in the Ti/Tt during periods of hypercapnia (0.11 ± 0.07) and UAO (0.09 ± 0.06) compared with unobstructed breathing ( P < 0.01). Second, the F2 offspring of C3 and B6 progenitors showed an average Ti/Tt response to 3% CO2 (0.42 ± 0.005%) that was significantly ( P < 0.01) greater than that of the two progenitors. Third, with a peak log of the odds ratio score of 4.4, Ti/Tt responses of F2 offspring are genetically linked to an interval between 58 and 64 centimorgans (cM) on mouse chromosome 5. One gene in the interval, Dagk4 at 57 cM, is polymorphic for C3 and B6 mice. Two other genes, Adrbk2 at 60 cM and Nos1 at 65 cM, have biological plausibility in mechanisms of upper airway patency and chemosensitivity, respectively. In summary, Ti/Tt may serve as an intermediate physiological phenotype for compensatory neuromuscular response mechanisms for maintaining ventilation in the face of UAO and hypoventilation and to help target specific candidate genes that may play a role in the expression of sleep-disordered breathing.
Effects of gravity on lung diffusing capacity and cardiac output in prone and supine humans
Authors: Rohdin M. , Petersson J. , Sundblad P. , Mure M. , Glenny R. W. , Lindahl S. G. E. , Linnarsson D.
Published: July 2015

Both in normal subjects exposed to hypergravity and in patients with acute respiratory distress syndrome, there are increased hydrostatic pressure gradients down the lung. Also, both conditions show an impaired arterial oxygenation, which is less severe in the prone than in the supine posture. The aim of this study was to use hypergravity to further investigate the mechanisms behind the differences in arterial oxygenation between the prone and the supine posture. Ten healthy subjects were studied in a human centrifuge while exposed to 1 and 5 times normal gravity (1 G, 5 G) in the anterioposterior (supine) and posterioanterior (prone) direction. They performed one rebreathing maneuver after ∼5 min at each G level and posture. Lung diffusing capacity decreased in hypergravity compared with 1 G (ANOVA, P = 0.002); it decreased by 46% in the supine posture compared with 25% in the prone ( P = 0.01 for supine vs. prone). At the same time, functional residual capacity decreased by 33 and 23%, respectively ( P < 0.001 for supine vs. prone), and cardiac output by 40 and 31% ( P = 0.007 for supine vs. prone), despite an increase in heart rate of 16 and 28% ( P < 0.001 for supine vs. prone), respectively. The finding of a more impaired diffusing capacity in the supine posture compared with the prone at 5 G supports our previous observations of more severe arterial hypoxemia in the supine posture during hypergravity. A reduced pulmonary-capillary blood flow and a reduced estimated alveolar volume can explain most of the reduction in diffusing capacity when supine.
Modeling airflow-related shear stress during heterogeneous constriction and mechanical ventilation
Authors: Nucci Gianluca , Suki Béla , Lutchen Kenneth
Published: July 2015

Ventilator-induced lung injury has been proposed as being caused by overdistention and closure and reopening of small airways and alveoli. Here we investigate the possibility that heterogeneous constriction increases airflow-related shear stress to a dangerously high level that may be sufficient to cause injury to the epithelial cells during mechanical ventilation. We employed an anatomically consistent model of the respiratory system, based on Horsfield morphometric data, and solved for the time evolution of pressure and flow along the airway tree during mechanical ventilation. We simulated constant-flow ventilation with passive expiration in two different conditions: baseline and highly heterogeneous constriction. The constriction was applied with two strategies: establishing a simple diameter reduction or adding also a length shortening. The shear stress distribution on airway walls was analyzed for airways ranging from the trachea to the acini. Our results indicate that 1) heterogeneous constriction can amplify the maximal values of shear stress up to 50-fold, with peak values higher than 0.6 cmH2O; 2) the highest shear stress is found in pathways constricted by 60–80%; 3) simultaneous diameter reduction and shortening amplifies the shear stresses by three- to fourfold, with shear stresses reaching 2 cmH2O; and 4) there is a range of airways (diameters from 0.6 to 0.3 mm at baseline) that appear to be at risk of very high stresses. We conclude that elevated airflow-related shear stress on the epithelial cell layer can occur during heterogeneous constriction and conjecture that this may constitute a mechanism contributing to ventilator-induced lung injury.
Relationship between middle cerebral artery blood velocity and end-tidal PCO2 in the hypocapnic-hypercapnic range in humans
Authors: Ide Kojiro , Eliasziw Michael , Poulin Marc J.
Published: July 2015

This study examined the relationship between cerebral blood flow (CBF) and end-tidal Pco2 (PetCO2) in humans. We used transcranial Doppler ultrasound to determine middle cerebral artery peak blood velocity responses to 14 levels of PetCO2 in a range of 22 to 50 Torr with a constant end-tidal Po2 (100 Torr) in eight subjects. PetCO2 and end-tidal Po2 were controlled by using the technique of dynamic end-tidal forcing combined with controlled hyperventilation. Two protocols were conducted in which PetCO2 was changed by 2 Torr every 2 min from hypocapnia to hypercapnia ( protocol I) and vice-versa ( protocol D). Over the range of PetCO2 studied, the sensitivity of peak blood velocity to changes in PetCO2 (CBF-PetCO2 sensitivity) was nonlinear with a greater sensitivity in hypercapnia (4.7 and 4.0%/Torr, protocols I and D, respectively) compared with hypocapnia (2.5 and 2.2%/Torr). Furthermore, there was evidence of hysteresis in the CBF-PetCO2 sensitivity; for a given PetCO2, there was greater sensitivity during protocol I compared with protocol D. In conclusion, CBF-PetCO2 sensitivity varies depending on the level of PetCO2 and the protocol that is used. The mechanisms underlying these responses require further investigation.
TRP Channel Proteins and Signal Transduction
Authors: Minke Baruch , Cook Boaz
Published: July 2015

TRP channel proteins constitute a large and diverse family of proteins that are expressed in many tissues and cell types. This family was designated TRP because of a spontaneously occurring Drosophila mutant lacking TRP that responded to a continuous light with a transient receptor potential (hence TRP). In addition to responses to light, TRPs mediate responses to nerve growth factor, pheromones, olfaction, mechanical, chemical, temperature, pH, osmolarity, vasorelaxation of blood vessels, and metabolic stress. Furthermore, mutations in several members of TRP-related channel proteins are responsible for several diseases, such as several tumors and neurodegenerative disorders. TRP-related channel proteins are found in a variety of organisms, tissues, and cell types, including nonexcitable, smooth muscle, and neuronal cells. The large functional diversity of TRPs is also reflected in their diverse permeability to ions, although, in general, they are classified as nonselective cationic channels. The molecular domains that are conserved in all members of the TRP family constitute parts of the transmembrane domains and in most members also the ankyrin-like repeats at the NH2terminal of the protein and a “TRP domain” at the COOH terminal, which is a highly conserved 25-amino acid stretch with still unknown function. All of the above features suggest that members of the TRP family are “special assignment” channels, which are recruited to diverse signaling pathways. The channels' roles and characteristics such as gating mechanism, regulation, and permeability are determined by evolution according to the specific functional requirements.
Plastic Changes in the Central Auditory System After Hearing Loss, Restoration of Function, and During Learning
Authors: Syka Josef
Published: July 2015

Traditionally the auditory system was considered a hard-wired sensory system; this view has been challenged in recent years in light of the plasticity of other sensory systems, particularly the visual and somatosensory systems. Practical experience in clinical audiology together with the use of prosthetic devices, such as cochlear implants, contributed significantly to the present view on the plasticity of the central auditory system, which was originally based on data obtained in animal experiments. The loss of auditory receptors, the hair cells, results in profound changes in the structure and function of the central auditory system, typically demonstrated by a reorganization of the projection maps in the auditory cortex. These plastic changes occur not only as a consequence of mechanical lesions of the cochlea or biochemical lesions of the hair cells by ototoxic drugs, but also as a consequence of the loss of hair cells in connection with aging or noise exposure. In light of the aging world population and the increasing amount of noise in the modern world, understanding the plasticity of the central auditory system has its practical consequences and urgency. In most of these situations, a common denominator of central plastic changes is a deterioration of inhibition in the subcortical auditory nuclei and the auditory cortex. In addition to the processes that are elicited by decreased or lost receptor function, the function of nerve cells in the adult central auditory system may dynamically change in the process of learning. A better understanding of the plastic changes in the central auditory system after sensory deafferentation, sensory stimulation, and learning may contribute significantly to improvement in the rehabilitation of damaged or lost auditory function and consequently to improved speech processing and production.
Immunity, Inflammation, and Remodeling in the Airway Epithelial Barrier: Epithelial-Viral-Allergic Paradigm
Authors: Holtzman Michael J. , Morton Jeffrey D. , Shornick Laurie P. , Tyner Jeffrey W. , O'Sullivan Mary P. , Antao Aurita , Lo Mindy , Castro Mario , Walter Michael J.
Published: July 2015

The concept that airway inflammation leads to airway disease has led to a widening search for the types of cellular and molecular interactions responsible for linking the initial stimulus to the final abnormality in airway function. It has not yet been possible to integrate all of this information into a single model for the development of airway inflammation and remodeling, but a useful framework has been based on the behavior of the adaptive immune system. In that paradigm, an exaggeration of T-helper type 2 (Th2) over Th1 responses to allergic and nonallergic stimuli leads to airway inflammatory disease, especially asthma. In this review, we summarize alternative evidence that the innate immune system, typified by actions of airway epithelial cells and macrophages, may also be specially programmed for antiviral defense and abnormally programmed in inflammatory disease. Furthermore, this abnormality may be inducible by paramyxoviral infection and, in the proper genetic background, may persist indefinitely. Taken together, we propose a new model that highlights specific interactions between epithelial, viral, and allergic components and so better explains the basis for airway immunity, inflammation, and remodeling in response to viral infection and the development of long-term disease phenotypes typical of asthma and other hypersecretory airway diseases.
Dendritic Cells: Immune Regulators in Health and Disease
Authors: Lipscomb Mary F. , Masten Barbara J.
Published: July 2015

Dendritic cells (DCs) are bone marrow-derived cells of both lymphoid and myeloid stem cell origin that populate all lymphoid organs including the thymus, spleen, and lymph nodes, as well as nearly all nonlymphoid tissues and organs. Although DCs are a moderately diverse set of cells, they all have potent antigen-presenting capacity for stimulating naive, memory, and effector T cells. DCs are members of the innate immune system in that they can respond to dangers in the host environment by immediately generating protective cytokines. Most important, immature DCs respond to danger signals in the microenvironment by maturing, i.e., differentiating, and acquiring the capacity to direct the development of primary immune responses appropriate to the type of danger perceived. The powerful adjuvant activity that DCs possess in stimulating specific CD4 and CD8 T cell responses has made them targets in vaccine development strategies for the prevention and treatment of infections, allograft reactions, allergic and autoimmune diseases, and cancer. This review addresses the origins and migration of DCs to their sites of activity, their basic biology as antigen-presenting cells, their roles in important human diseases and, finally, selected strategies being pursued to harness their potent antigen-stimulating activity.
Electrolyte Transport in the Mammalian Colon: Mechanisms and Implications for Disease
Authors: Kunzelmann Karl , Mall Marcus
Published: July 2015

The colonic epithelium has both absorptive and secretory functions. The transport is characterized by a net absorption of NaCl, short-chain fatty acids (SCFA), and water, allowing extrusion of a feces with very little water and salt content. In addition, the epithelium does secret mucus, bicarbonate, and KCl. Polarized distribution of transport proteins in both luminal and basolateral membranes enables efficient salt transport in both directions, probably even within an individual cell. Meanwhile, most of the participating transport proteins have been identified, and their function has been studied in detail. Absorption of NaCl is a rather steady process that is controlled by steroid hormones regulating the expression of epithelial Na+channels (ENaC), the Na+-K+-ATPase, and additional modulating factors such as the serum- and glucocorticoid-regulated kinase SGK. Acute regulation of absorption may occur by a Na+feedback mechanism and the cystic fibrosis transmembrane conductance regulator (CFTR). Cl−secretion in the adult colon relies on luminal CFTR, which is a cAMP-regulated Cl−channel and a regulator of other transport proteins. As a consequence, mutations in CFTR result in both impaired Cl−secretion and enhanced Na+absorption in the colon of cystic fibrosis (CF) patients. Ca2+- and cAMP-activated basolateral K+channels support both secretion and absorption of electrolytes and work in concert with additional regulatory proteins, which determine their functional and pharmacological profile. Knowledge of the mechanisms of electrolyte transport in the colon enables the development of new strategies for the treatment of CF and secretory diarrhea. It will also lead to a better understanding of the pathophysiological events during inflammatory bowel disease and development of colonic carcinoma.
The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction
Authors: Glickman Michael H. , Ciechanover Aaron
Published: July 2015

Between the 1960s and 1980s, most life scientists focused their attention on studies of nucleic acids and the translation of the coded information. Protein degradation was a neglected area, considered to be a nonspecific, dead-end process. Although it was known that proteins do turn over, the large extent and high specificity of the process, whereby distinct proteins have half-lives that range from a few minutes to several days, was not appreciated. The discovery of the lysosome by Christian de Duve did not significantly change this view, because it became clear that this organelle is involved mostly in the degradation of extracellular proteins, and their proteases cannot be substrate specific. The discovery of the complex cascade of the ubiquitin pathway revolutionized the field. It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic pathways during cell life and death as well as in health and disease. With the multitude of substrates targeted and the myriad processes involved, it is not surprising that aberrations in the pathway are implicated in the pathogenesis of many diseases, certain malignancies, and neurodegeneration among them. Degradation of a protein via the ubiquitin/proteasome pathway involves two successive steps: 1) conjugation of multiple ubiquitin moieties to the substrate and 2) degradation of the tagged protein by the downstream 26S proteasome complex. Despite intensive research, the unknown still exceeds what we currently know on intracellular protein degradation, and major key questions have remained unsolved. Among these are the modes of specific and timed recognition for the degradation of the many substrates and the mechanisms that underlie aberrations in the system that lead to pathogenesis of diseases.
Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships
Authors: Szkudlinski Mariusz W. , Fremont Valerie , Ronin Catherine , Weintraub Bruce D.
Published: July 2015

This review focuses on recent advances in the structure-function relationships of thyroid-stimulating hormone (TSH) and its receptor. TSH is a member of the glycoprotein hormone family constituting a subset of the cystine-knot growth factor superfamily. TSH is produced by the pituitary thyrotrophs and released to the circulation in a pulsatile manner. It stimulates thyroid functions using specific membrane TSH receptor (TSHR) that belongs to the superfamily of G protein-coupled receptors (GPCRs). New insights into the structure-function relationships of TSH permitted better understanding of the role of specific protein and carbohydrate domains in the synthesis, bioactivity, and clearance of this hormone. Recent progress in studies on TSHR as well as studies on the other GPCRs provided new clues regarding the molecular mechanisms of receptor activation. Such advances are a result of extensive site-directed mutagenesis, peptide and antibody approaches, detailed sequence analyses, and molecular modeling as well as studies on naturally occurring gain- and loss-of-function mutations. This review integrates expanding information on TSH and TSHR structure-function relationships and summarizes current concepts on ligand-dependent and -independent TSHR activation. Special emphasis has been placed on TSH domains involved in receptor recognition, constitutive activity of TSHR, new insights into the evolution of TSH bioactivity, and the development of high-affinity TSH analogs. Such structural, physiological, pathophysiological, evolutionary, and therapeutic implications of TSH-TSHR structure-function studies are frequently discussed in relation to concomitant progress made in studies on gonadotropins and their receptors.
Microwave-Promoted Synthesis of Sulfonated Metallophthalocyanines and Aggregation in Different Solvents
Authors: Cheng Zhenhua , Cui Na , Jiang Shengjuan , Zhang Hongxiao , Zhu Lijun , Xia Daohong
Published: July 2015

Five metallosulfophthalocyanines (Fe, Ni, Zn, Co, and Cu) compounds were synthesized by microwave irradiation. Compared to the conventional method of synthesis in terms of reaction time and yields, the microwave-promoted synthesis is preferred with high product yield and short reaction time. All synthesized products were characterized with MALDI-TOF mass spectrum, Fourier transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV-Vis), and X-ray diffraction (XRD). Aggregation behavior of the five metallosulfophthalocyanines (MSPc) in different solvents was studied by UV-Vis spectroscopy separately in N,N-dimethyl formamide (DMF) and NaOH aqueous solution (5%wt). A redshift of maximum absorption wavelength and deviations from Lambert-Beer law with increasing the concentration were observed. The dimerization equilibrium constants (K) of the five MSPc were determined, respectively.
An Intensive Lifestyle Intervention Is an Effective Treatment of Morbid Obesity: The TRAMOMTANA Study—A Two-Year Randomized Controlled Clinical Trial
Authors: Burguera Bartolomé , Jesús Tur Juan , Escudero Antonio Jorge , Alos María , Pagán Alberto , Cortés Baltasar , González Xavier Francesc , Soriano Joan B.
Published: July 2015

Bariatric surgery is currently the most effective therapy to induce weight loss in morbidly obese patients.Objective. This controlled, clinical trial with a two-year intervention was aimed at comparing the efficacy of two nonsurgical approaches versus bariatric surgery, on body weight changes and metabolic parameters in morbidly obese patients.Methods. Patients were randomized to an Intensive Lifestyle Intervention (ILI) (n=60) or Conventional Obesity Therapy (COT) (n=46). The ILI group received behavioral therapy and nutritional counseling. The COT group received standard medical treatment. They were compared with a third group, Surgical Obesity Group (SOG) (n=37).Results. Patients who received ILI had a greater percentage of weight loss than patients receiving COT (−11.3% versus −1.6%;p<0.0044). Interestingly 31.4% of patients included in the ILI group were no longer morbidly obese after just six months of intervention, increasing to 44.4% after 24 months of intervention. The percentage weight loss in SOG was −29.6% after that same period of time.Conclusions. ILI was associated with significant weight loss when compared to COT, in a group of patients with obesity. An ILI approach could be an alternative therapy to patients with obesity, who are not candidates to undergo bariatric surgery. This trial is registered with EudraCT2009-013737-24.
A Tutorial on Optical Feeding of Millimeter-Wave Phased Array Antennas for Communication Applications
Authors: Aldaya Ivan , Campuzano Gabriel , Castañón Gerardo , Aragón-Zavala Alejandro
Published: July 2015

Given the interference avoidance capacity, high gain, and dynamical reconfigurability, phased array antennas (PAAs) have emerged as a key enabling technology for future broadband mobile applications. This is especially important at millimeter-wave (mm-wave) frequencies, where the high power consumption and significant path loss impose serious range constraints. However, at mm-wave frequencies the phase and amplitude control of the feeding currents of the PAA elements is not a trivial issue because electrical beamforming requires bulky devices and exhibits relatively narrow bandwidth. In order to overcome these limitations, different optical beamforming architectures have been presented. In this paper we review the basic principles of phased arrays and identify the main challenges, that is, integration of high-speed photodetectors with antenna elements and the efficient optical control of both amplitude and phase of the feeding current. After presenting the most important solutions found in the literature, we analyze the impact of the different noise sources on the PAA performance, giving some guidelines for the design of optically fed PAAs.
Analytical Model of Random Variation in Drain Current of FGMOSFET
Authors: Banchuin Rawid
Published: July 2015

The analytical model of random variation in drain current of the Floating Gate MOSFET (FGMOSFET) has been proposed in this research. The model is composed of two parts for triode and saturation region of operation where the process induced device level random variations of each region and their statistical correlations have been taken into account. The nonlinearity of floating gate voltage and dependency on drain voltage of the coupling factors of FGMOSFET have also been considered. The model has been found to be very accurate since it can accurately fit the SPICE BSIM3v3 based reference obtained by using Monte-Carlo SPICE simulation and FGMOSFET simulation technique with SPICE. It can fit the BSIM4 based reference if desired by using the optimally extracted parameters. By using the proposed model, the variability analysis of FGMOSFET and the analytical modeling of the variation in the circuit level parameter of any FGMOSFET based circuit can be performed. So, this model has been found to be an efficient tool for the variability aware analysis and design of FGMOSFET based circuit.
Effect of Simvastatin on Arterial Stiffness in Patients with Statin Myalgia
Authors: Ballard Kevin D. , Lorson Lindsay , White C. Michael , Thompson Paul D. , Taylor Beth A.
Published: July 2015

Statins reduce arterial stiffness but are also associated with mild muscle complaints. It is unclear whether individuals with muscle symptoms experience the same vascular benefit or whether statins affect striated and smooth muscle cells differently. We examined the effect of simvastatin treatment on arterial stiffness in patients who did versus those who did not exhibit muscle symptoms. Patients with a history of statin-related muscle complaints (n=115) completed an 8 wk randomized, double-blind, cross-over trial of daily simvastatin 20 mg and placebo. Serum lipids and pulse wave velocity (PWV) were assessed before and after each treatment. Muscle symptoms with daily simvastatin treatment were reported by 38 patients (33%). Compared to baseline, central PWV decreased (P=0.01) following simvastatin treatment but not placebo (drug ∗ time interaction:P=0.047). Changes in central PWV with simvastatin treatment were not influenced by myalgia status or time on simvastatin (P≥0.15). Change in central PWV after simvastatin treatment was inversely correlated with age (r=-0.207,P=0.030), suggesting that advancing age is associated with enhanced statin-mediated arterial destiffening. In patients with a history of statin-related muscle complaints, the development of myalgia with short-term simvastatin treatment did not attenuate the improvement in arterial stiffness.
Safety and Efficacy Endpoints for Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients
Authors: Bank J. R. , Rabelink T. J. , de Fijter J. W. , Reinders M. E. J.
Published: July 2015

Despite excellent short-term graft survival after renal transplantation, the long-term graft outcome remains compromised. It has become evident that a combination of sustained alloreactivity and calcineurin-inhibitor- (CNI-) related nephrotoxicity results in fibrosis and consequently dysfunction of the graft. New immunosuppressive regimens that can minimize or eliminate side effects, while maintaining efficacy, are required to improve long-term graft survival. In this perspective mesenchymal stromal cells (MSCs) are an interesting candidate, since MSCs have immunosuppressive and regenerative properties. The first clinical trials with MSCs in renal transplantation showed safety and feasibility and displayed promising results. Recently, the first phase II studies have been started. One of the most difficult and challenging aspects in those early phase trials is to define accurate endpoints that can measure safety and efficacy of MSC treatment. Since both graft losses and acute rejection rates declined, alternative surrogate markers such as renal function, histological findings, and immunological markers are used to measure efficacy and to provide mechanistic insight. In this review, we will discuss the current status of MSCs in renal transplantation with a focus on the endpoints used in the different experimental and clinical studies.
Alterations in the Secretome of Clinically Relevant Preparations of Adipose-Derived Mesenchymal Stem Cells Cocultured with Hyaluronan
Authors: Succar Peter , Breen Edmond J. , Kuah Donald , Herbert Benjamin R.
Published: July 2015

Osteoarthritis (OA) can be a debilitating degenerative disease and is the most common form of arthritic disease. There is a general consensus that current nonsurgical therapies are insufficient for younger OA sufferers who are not candidates for knee arthroplasties. Adipose-derived mesenchymal stem cells (MSCs) therapy for the treatment of OA can slow disease progression and lead to neocartilage formation. The mechanism of action is secretion driven. Current clinical preparations from adipose tissue for the treatment of OA include autologous stromal vascular fraction (SVF), SVF plus mature adipocytes, and culture-purified MSCs. Herein we have combined these human adipose-derived preparations with Hyaluronan (Hylan G-F 20: Synvisc)in vitroand measured alterations in cytokine profile. SVF plus mature adipocytes showed the greatest decreased in the proinflammatory cytokines IL-1β, IFN-γ, and VEGF. MCP-1 and MIP-1αdecreased substantially in the SVF preparations but not the purified MSCs. The purified MSC preparation was the only one to show increase in MIF. Overall the SVF plus mature adipocytes preparation may be most suited of all the preparations for combination with HA for the treatment of OA, based on the alterations of heavily implicated cytokines in OA disease progression. This will require further validation usingin vivomodels.
Extraction of Iron from the Rabbit Anterior Chamber with Reverse Iontophoresis
Authors: Sun Shoubin , Diao Huijie , Zhao Fali , Bai Jianhai , Zhou Yuan , Cui Hao , Zhang Liqiong
Published: July 2015

Ocular siderosis is a common eye disease caused by retention of an iron-containing intraocular foreign body in the eye. Iron-containing intraocular foreign bodies may cause severe inflammatory reaction and affect visual function. Currently the optimal treatment method of ocular siderosis is a moot point. This study used the reverse iontophoresis technique to noninvasively extract iron from the rabbit anterior chamber. By slit lamp observation and histological examination, reverse iontophoresis treatment has a good effect on ocular siderosis. Reverse iontophoresis seems to be a noninvasive and promising approach to extract iron from the anterior chamber to treat ocular siderosis.
Sepsis: From Pathophysiology to Individualized Patient Care
Authors: László Ildikó , Trásy Domonkos , Molnár Zsolt , Fazakas János
Published: July 2015

Sepsis has become a major health economic issue, with more patients dying in hospitals due to sepsis related complications compared to breast and colorectal cancer together. Despite extensive research in order to improve outcome in sepsis over the last few decades, results of large multicenter studies were by-and-large very disappointing. This fiasco can be explained by several factors, but one of the most important reasons is the uncertain definition of sepsis resulting in very heterogeneous patient populations, and the lack of understanding of pathophysiology, which is mainly based on the imbalance in the host-immune response. However, this heroic research work has not been in vain. Putting the results of positive and negative studies into context, we can now approach sepsis in a different concept, which may lead us to new perspectives in diagnostics and treatment. While decision making based on conventional sepsis definitions can inevitably lead to false judgment due to the heterogeneity of patients, new concepts based on currently gained knowledge in immunology may help to tailor assessment and treatment of these patients to their actual needs. Summarizing where we stand at present and what the future may hold are the purpose of this review.