bluuebunny/crossref_metadata_2025 huggingface dataset:
Significant improvement in cardiometabolic health in healthy nonobese individuals during caloric restriction-induced weight loss and weight loss maintenance
Authors: Most Jasper , Gilmore L. Anne , Smith Steven R. , Han Hongmei , Ravussin Eric , Redman Leanne M.
Published: January 2018

Calorie restriction (CR) triggers benefits for healthspan including decreased risk of cardiometabolic disease (CVD). In an ancillary study to CALERIE 2, a 24-mo 25% CR study, we assessed the cardiometabolic effects of CR in 53 healthy, nonobese (BMI: 22–28 kg/m2) men ( n = 17) and women ( n = 36). The aim of this study was to investigate whether CR can reduce risk factors for CVD and insulin resistance in nonobese humans and, moreover, to assess whether improvements are exclusive to a period of weight loss or continue during weight maintenance. According to the energy balance method, the 25% CR intervention ( n = 34) produced 16.5 ± 1.5% (mean ± SE) and 14.8 ± 1.5% CR after 12 and 24 mo (M12, M24), resulting in significant weight loss (M12 −9 ± 0.5 kg, M24 −9 ± 0.5 kg, P < 0.001). Weight was maintained in the group that continued their habitual diet ad libitum (AL, n = 19). In comparison to AL, 24 mo of CR decreased visceral (−0.5 ± 0.01 kg, P < 0.0001) and subcutaneous abdominal adipose tissue (−1.9 ± 0.2kg, P < 0.001) as well as intramyocellular lipid content (−0.11 ± 0.05%, P = 0.031). Furthermore, CR decreased blood pressure (SBP −8 ± 3 mmHg, P = 0.005; DBP −6 ± 2 mmHg, P < 0.001), total cholesterol (−13.6 ± 5.3 mg/dl, P = 0.001), and LDL-cholesterol (−12.9 ± 4.4 mg/dl, P = 0.005), and the 10-yr risk of CVD-disease was reduced by 30%. Homeostasis model assessment of insulin resistance (HOMA-IR) decreased during weight loss in the CR group (−0.46 ± 0.15, P = 0.003), but this decrease was not maintained during weight maintenance (−0.11 ± 0.15, P = 0.458). In conclusion, sustained CR in healthy, nonobese individuals is beneficial in improving risk factors for cardiovascular and metabolic disease such as visceral adipose tissue mass, ectopic lipid accumulation, blood pressure, and lipid profile, whereas improvements in insulin sensitivity were only transient.
Contribution of parasympathetic muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia
Authors: Rickels Michael R. , Perez Elys M. , Peleckis Amy J. , Alshehabi Erica , Nguyen Huong-Lan , Stefanovski Darko , Rickels Karl , Teff Karen L.
Published: January 2018

Atypical antipsychotic drugs have been associated with the development of obesity and diabetes. In particular, olanzapine can induce peripheral insulin resistance and compensatory hyperinsulinemia independent of weight gain or psychiatric disease. To determine if this compensatory increase in insulin is mediated by parasympathetic muscarinic stimulation, we randomized 15 healthy subjects 2:1 to receive double-blind olanzapine or placebo for 9 days under diet- and activity-controlled inpatient conditions. Before and after 7 days of study drug administration, subjects underwent frequently sampled intravenous glucose tolerance tests with either saline or atropine infused on subsequent days to assess insulin secretion and hepatic insulin extraction in the absence or presence of muscarinic blockade. We found that olanzapine led to an increase in the acute insulin response to glucose, which was not seen with placebo, and was attenuated in the olanzapine group by atropine. Deconvolution of C-peptide data confirmed an increase in insulin secretion with olanzapine, which was blocked by atropine, with a modest reduction in hepatic insulin extraction with olanzapine. These results support the contribution of muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia, and provide a mechanism for the compensatory hyperinsulinemia that normally serves to prevent deterioration of glucose tolerance under conditions of metabolic challenge.
Measurement of postprandial glucose fluxes in response to acute and chronic endurance exercise in healthy humans
Authors: Morrison Dale J. , Kowalski Greg M. , Grespan Eleonora , Mari Andrea , Bruce Clinton R. , Wadley Glenn D.
Published: January 2018

The effect of endurance exercise on enhancing insulin sensitivity and glucose flux has been well established with techniques such as the hyperinsulinemic clamp. Although informative, such techniques do not emulate the physiological postprandial state, and it remains unclear how exercise improves postprandial glycaemia. Accordingly, combining mixed-meal tolerance testing and the triple-stable isotope glucose tracer approach, glucose fluxes [rates of meal glucose appearance (Ra), disposal (Rd), and endogenous glucose production (EGP)] were determined following acute endurance exercise (1 h cycling; ~70% V̇o2max) and 4 wk of endurance training (cycling 5 days/wk). Training was associated with a modest increase in V̇o2max (~7%, P < 0.001). Postprandial glucose and insulin responses were reduced to the same extent following acute and chronic training. Interestingly, this was not accompanied by changes to rates of meal Ra, Rd, or degree of EGP suppression. Glucose clearance (Rd relative to prevailing glucose) was, however, enhanced with acute and chronic exercise. Furthermore, the duration of EGP suppression was shorter with acute and chronic exercise, with EGP returning toward fasting levels more rapidly than pretraining conditions. These findings suggest that endurance exercise influences the efficiency of the glucoregulatory system, where pretraining rates of glucose disposal and production were achieved at lower glucose and insulin levels. Notably, there was no influence of chronic training over and above that of a single exercise bout, providing further evidence that glucoregulatory benefits of endurance exercise are largely attributed to the residual effects of the last exercise bout.
Young mice expel the tapeworm Hymenolepis diminuta and are protected from colitis by triggering a memory response with worm antigen
Authors: Arai Toshio , Lopes Fernando , Shute Adam , Wang Arthur , McKay Derek M.
Published: January 2018

Infection with helminth parasites reduces the severity of concomitant inflammatory disease in adult mice. There is an alarming increase of inflammatory bowel disease (IBD) in children. It is important to determine whether helminth therapy would be of value in pediatric IBD and whether triggering immunological memory to the worm would be anticolitic. Three-week-old (young) and eight-week-old (adult) Balb/c mice were infected with H. diminuta, and infectivity and T helper 2 (Th2) immunity were assessed. Other mice received H. diminuta with or without a crude worm extract ( HdE) 28–42 days postinfection (dpi) with or without dinitrobenzene sulphonic acid [DNBS, 1.5 mg (young) or 3 mg (adults), ir], and colitis was assessed 72 h later. Infected young mice developed Th2 immunity and expelled H. diminuta; expulsion was delayed by ~2 days compared with adult mice. Colitis, as gauged by macroscopic disease and histopathology scores, was less severe in young mice infected 10 days, but not 8 days, before DNBS. Protection against DNBS-induced colitis was accompanied by an increased capacity to make interleukin (IL)-4 and IL-10. Mice infected with H. diminuta were not protected from DNBS-colitis when challenged 28 days later; however, injection of these mice with HdE coincident with DNBS resulted in less disease and increased splenic IL-4 and IL-10. Using a boost (500 μg HdE, 28 dpi) and repeat HdE (100 μg, 42 dpi) regimen with infected mice suppressed DNBS-colitis, as did adoptive transfer of splenic CD4+ T cells from infected mice with low-dose HdE challenge. Should these data translate to IBD, then helminth therapy could be of value in pediatric-onset IBD, and defining the antigen(s) that elicit antihelminth immunological memory could serve as an anticolitic approach in previously infected individuals.

NEW & NOTEWORTHY This study demonstrates that juvenile mice are protected from colitis by infection with the tapeworm Hymenolepis diminuta and that using worm antigen to trigger an immunological memory response in previously infected mice can be used to limit the severity of colitis.
Macrophage-dependent impairment of α2-adrenergic autoreceptor inhibition of Ca2+channels in sympathetic neurons from DOCA-salt but not high-fat diet-induced hypertensive rats
Authors: Mui Ryan K. , Fernandes Roxanne N. , Garver Hannah G. , Van Rooijen Nico , Galligan James J.
Published: January 2018

DOCA-salt and obesity-related hypertension are associated with inflammation and sympathetic nervous system hyperactivity. Prejunctional α2-adrenergic receptors (α2ARs) provide negative feedback to norepinephrine release from sympathetic nerves through inhibition of N-type Ca2+channels. Increased neuronal norepinephrine release in DOCA-salt and obesity-related hypertension occurs through impaired α2AR signaling; however, the mechanisms involved are unclear. Mesenteric arteries are resistance arteries that receive sympathetic innervation from the superior mesenteric and celiac ganglia (SMCG). We tested the hypothesis that macrophages impair α2AR-mediated inhibition of Ca2+channels in SMCG neurons from DOCA-salt and high-fat diet (HFD)-induced hypertensive rats. Whole cell patch-clamp methods were used to record Ca2+currents from SMCG neurons maintained in primary culture. We found that DOCA-salt, but not HFD-induced, hypertension caused macrophage accumulation in mesenteric arteries, increased SMCG mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-α, and impaired α2AR-mediated inhibition of Ca2+currents in SMCG neurons. α2AR dysfunction did not involve changes in α2AR expression, desensitization, or downstream signaling factors. Oxidative stress impaired α2AR-mediated inhibition of Ca2+currents in SMCG neurons and resulted in receptor internalization in human embryonic kidney-293T cells. Systemic clodronate-induced macrophage depletion preserved α2AR function and lowered blood pressure in DOCA-salt rats. HFD caused hypertension without obesity in Sprague-Dawley rats and hypertension with obesity in Dahl salt-sensitive rats. HFD-induced hypertension was not associated with inflammation in SMCG and mesenteric arteries or α2AR dysfunction in SMCG neurons. These results suggest that macrophage-mediated α2AR dysfunction in the mesenteric circulation may only be relevant to mineralocorticoid-salt excess.

NEW & NOTEWORTHY Here, we identify a contribution of macrophages to hypertension development through impaired α2-adrenergic receptor (α2AR)-mediated inhibition of sympathetic nerve terminal Ca2+channels in DOCA-salt hypertensive rats. Impaired α2AR function may involve oxidative stress-induced receptor internalization. α2AR dysfunction may be unique to mineralocorticoid-salt excess, as it does not occur in obesity-related hypertension.
Cub domain-containing protein 1 negatively regulates TGF-β signaling and myofibroblast differentiation
Authors: Noskovičová Nina , Heinzelmann Katharina , Burgstaller Gerald , Behr Jürgen , Eickelberg Oliver
Published: January 2018

Fibroblasts are thought to be the prime cell type for producing and secreting extracellular matrix (ECM) proteins in the connective tissue. The profibrotic cytokine transforming growth factor-β1 (TGF-β1) activates and transdifferentiates fibroblasts into α-smooth muscle actin (α-SMA)-expressing myofibroblasts, which exhibit increased ECM secretion, in particular collagens. Little information, however, exists about cell-surface molecules on fibroblasts that mediate this transdifferentiation process. We recently identified, using unbiased cell-surface proteome analysis, Cub domain-containing protein 1 (CDCP1) to be strongly downregulated by TGF-β1. CDCP1 is a transmembrane glycoprotein, the expression and role of which has not been investigated in lung fibroblasts to date. Here, we characterized, in detail, the effect of TGF-β1 on CDCP1 expression and function, using immunofluorescence, FACS, immunoblotting, and siRNA-mediated knockdown of CDCP1. CDCP1 is present on interstitial fibroblasts, but not myofibroblasts, in the normal and idiopathic pulmonary fibrosis lung. In vitro, TGF-β1 decreased CDCP1 expression in a time-dependent manner by impacting mRNA and protein levels. Knockdown of CDCP1 enhanced a TGF-β1-mediated cell adhesion of fibroblasts. Importantly, CDCP1-depleted cells displayed an enhanced expression of profibrotic markers, such as collagen V or α-SMA, which was found to be independent of TGF-β1. Our data show, for the very first time that loss of CDCP1 contributes to fibroblast to myofibroblast differentiation via a potential negative feedback loop between CDCP1 expression and TGF-β1 stimulation.
Fourth ventricular thyrotropin induces satiety and increases body temperature in rats
Authors: Smedh Ulrika , Scott Karen A. , Moran Timothy H.
Published: January 2018

Besides its well-known action to stimulate thyroid hormone release, thyrotropin mRNA is expressed within the brain, and thyrotropin and its receptor have been shown to be present in brain areas that control feeding and gastrointestinal function. Here, the hypothesis that thyrotropin acts on receptors in the hindbrain to alter food intake and/or gastric function was tested. Fourth ventricular injections of thyrotropin (0.06, 0.60, and 6.00 µg) were given to rats with chronic intracerebroventricular cannulas aimed at the fourth ventricle. Thyrotropin produced an acute reduction of sucrose intake (30 min). The highest dose of thyrotropin caused inhibition of overnight solid food intake (22 h). In contrast, subcutaneous administration of corresponding thyrotropin doses had no effect on nutrient intake. The highest effective dose of fourth ventricular thyrotropin (6 µg) did not produce a conditioned flavor avoidance in a standardized two-bottle test, nor did it affect water intake or gastric emptying of glucose. Thyrotropin injected in the fourth ventricle produced a small but significant increase in rectal temperature and lowered plasma levels of tri-iodothyronin but did not affect plasma levels of thyroxine. In addition, there was a tendency toward a reduction in blood glucose 2 h after fourth ventricular thyrotropin injection ( P = 0.056). In conclusion, fourth ventricular thyrotropin specifically inhibits food intake, increases core temperature, and lowers plasma levels of tri-iodothyronin but does not affect gastromotor function.
Body mass-specific Na+-K+-ATPase activity in the medullary thick ascending limb: implications for species-dependent urine concentrating mechanisms
Authors: Aw Mun , Armstrong Tamara M. , Nawata C. Michele , Bodine Sarah N. , Oh Jeeeun J. , Wei Guojun , Evans Kristen K. , Shahidullah Mohammad , Rieg Timo , Pannabecker Thomas L.
Published: January 2018

In general, the mammalian whole body mass-specific metabolic rate correlates positively with maximal urine concentration (Umax) irrespective of whether or not the species have adapted to arid or mesic habitat. Accordingly, we hypothesized that the thick ascending limb (TAL) of a rodent with markedly higher whole body mass-specific metabolism than rat exhibits a substantially higher TAL metabolic rate as estimated by Na+-K+-ATPase activity and Na+-K+-ATPase α1-gene and protein expression. The kangaroo rat inner stripe of the outer medulla exhibits significantly higher mean Na+-K+-ATPase activity (~70%) compared with two rat strains (Sprague-Dawley and Munich-Wistar), extending prior studies showing rat activity exceeds rabbit. Furthermore, higher expression of Na+-K+-ATPase α1-protein (~4- to 6-fold) and mRNA (~13-fold) and higher TAL mitochondrial volume density (~20%) occur in the kangaroo rat compared with both rat strains. Rat TAL Na+-K+-ATPase α1-protein expression is relatively unaffected by body hydration status or, shown previously, by dietary Na+, arguing against confounding effects from two unavoidably dissimilar diets: grain-based diet without water (kangaroo rat) or grain-based diet with water (rat). We conclude that higher TAL Na+-K+-ATPase activity contributes to relationships between whole body mass-specific metabolic rate and high Umax. More vigorous TAL Na+-K+-ATPase activity in kangaroo rat than rat may contribute to its steeper Na+and urea axial concentration gradients, adding support to a revised model of the urine concentrating mechanism, which hypothesizes a leading role for vigorous active transport of NaCl, rather than countercurrent multiplication, in generating the outer medullary axial osmotic gradient.
Role of TRPV1 in acupuncture modulation of reflex excitatory cardiovascular responses
Authors: Guo Zhi-Ling , Fu Liang-Wu , Su Hou-Fen , Tjen-A-Looi Stephanie C. , Longhurst John C.
Published: January 2018

We have shown that acupuncture, including manual and electroacupuncture (MA and EA), at the P5–6 acupoints stimulates afferent fibers in the median nerve (MN) to modulate sympathoexcitatory cardiovascular reflexes through central regulation of autonomic function. However, the mechanisms underlying acupuncture activation of these sensory afferent nerves and their cell bodies in the dorsal root ganglia (DRG) are unclear. Transient receptor potential vanilloid type 1 (TRPV1) is present in sensory nerve fibers distributed in the general region of acupoints like ST36 and BL 40 located in the hindlimb. However, the contribution of TRPV1 to activation of sensory nerves by acupuncture, leading to modulation of pressor responses, has not been studied. We hypothesized that TRPV1 participates in acupuncture’s activation of sensory afferents and their associated cell bodies in the DRG to modulate pressor reflexes. Local injection of iodoresiniferatoxin (Iodo-RTX; a selective TRPV1 antagonist), but not 5% DMSO (vehicle), into the P6 acupoint on the forelimb reversed the MA’s inhibition of pressor reflexes induced by gastric distension (GD). Conversely, inhibition of GD-induced sympathoexcitatory responses by EA at P5–6 was unchanged after administration of Iodo-RTX into P5–6. Single-unit activity of Group III or IV bimodal afferents sensitive to both mechanical and capsaicin stimuli responded to MA stimulation at P6. MA-evoked activity was attenuated significantly ( P < 0.05) by local administration of Iodo-RTX ( n = 12) but not by 5% DMSO ( n = 12) into the region of the P6 acupoint in rats. Administration of Iodo-RTX into P5–6 did not reduce bimodal afferent activity evoked by EA stimulation ( n = 8). Finally, MA at P6 and EA at P5–6 induced phosphorylation of extracellular signal-regulated kinases (ERK; an intracellular signaling messenger involved in cellular excitation) in DRG neurons located at C7–8 spinal levels receiving MN inputs. After TRPV1 was knocked down in the DRG at these spinal levels with intrathecal injection of TRPV1-siRNA, expression of phosphorylated ERK in the DRG neuron was reduced in MA-treated, but not EA-treated animals. These data suggest that TRPV1 in Group III and IV bimodal sensory afferent nerves contributes to acupuncture inhibition of reflex increases in blood pressure and specifically plays an important role during MA but not EA.
N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenous antioxidant responses
Authors: Small David M. , Sanchez Washington Y. , Roy Sandrine F. , Morais Christudas , Brooks Heddwen L. , Coombes Jeff S. , Johnson David W. , Gobe Glenda C.
Published: January 2018

Oxidative stress and mitochondrial dysfunction exacerbate acute kidney injury (AKI), but their role in any associated progress to chronic kidney disease (CKD) remains unclear. Antioxidant therapies often benefit AKI, but their benefits in CKD are controversial since clinical and preclinical investigations often conflict. Here we examined the influence of the antioxidant N-acetyl-cysteine (NAC) on oxidative stress and mitochondrial function during AKI (20-min bilateral renal ischemia plus reperfusion/IR) and progression to chronic kidney pathologies in mice. NAC (5% in diet) was given to mice 7 days prior and up to 21 days post-IR (21d-IR). NAC treatment resulted in the following: prevented proximal tubular epithelial cell apoptosis at early IR (40-min postischemia), yet enhanced interstitial cell proliferation at 21d-IR; increased transforming growth factor-β1 expression independent of IR time; and significantly dampened nuclear factor-like 2-initiated cytoprotective signaling at early IR. In the long term, NAC enhanced cellular metabolic impairment demonstrated by increased peroxisome proliferator activator-γ serine-112 phosphorylation at 21d-IR. Intravital multiphoton microscopy revealed increased endogenous fluorescence of nicotinamide adenine dinucleotide (NADH) in cortical tubular epithelial cells during ischemia, and at 21d-IR that was not attenuated with NAC. Fluorescence lifetime imaging microscopy demonstrated persistent metabolic impairment by increased free/bound NADH in the cortex at 21d-IR that was enhanced by NAC. Increased mitochondrial dysfunction in remnant tubular cells was demonstrated at 21d-IR by tetramethylrhodamine methyl ester fluorimetry. In summary, NAC enhanced progression to CKD following AKI not only by dampening endogenous cellular antioxidant responses at time of injury but also by enhancing persistent kidney mitochondrial and metabolic dysfunction.
Chest wall strapping increases expiratory airflow and detectable airway segments in computer tomographic scans of normal and obstructed lungs
Authors: Taher Hisham , Bauer Christian , Abston Eric , Kaczka David W. , Bhatt Surya P. , Zabner Joseph , Brower Roy G. , Beichel Reinhard R. , Eberlein Michael
Published: January 2018

Chest wall strapping (CWS) induces breathing at low lung volumes but also increases parenchymal elastic recoil. In this study, we tested the hypothesis that CWS dilates airways via airway-parenchymal interdependence. In 11 subjects (6 healthy and 5 with mild to moderate COPD), pulmonary function tests and lung volumes were obtained in control (baseline) and the CWS state. Control and CWS-CT scans were obtained at 50% of control (baseline) total lung-capacity (TLC). CT lung volumes were analyzed by CT volumetry. If control and CWS-CT volumetry did not differ by more than 25%, airway dimensions were analyzed via automated airway segmentation. CWS-TLC was reduced on average to 71% of control-TLC in normal subjects and 79% of control-TLC in subjects with COPD. CWS increased expiratory airflow at 50% of control-TLC by 41% (3.50 ± 1.6 vs. 4.93 ± 1.9 l/s, P = 0.04) in normals and 316% in COPD(0.25 ± 0.05 vs 0.79 ± 0.39 l/s, P = 0.04). In 10 subjects (5 normals and 5 COPD), control and CWS-CT scans at 50% control-TLC did not differ more than 25% on CT volumetry and were included in the airway structure analysis. CWS increased the mean number of detectable airways with a diameter of ≤2 mm by 32.5% (65 ± 10 vs. 86 ± 124, P = 0.01) in normal subjects and by 79% (59 ± 19 vs. 104 ± 16, P = 0.01) in subjects with COPD. There was no difference in the number of detectable airways with diameters 2–4 mm and >4 mm in normal or in COPD subjects. In conclusion, CWS enhances the detection of small airways via automated CT airway segmentation and increases expiratory airflow in normal subjects as well as in subjects with mild to moderate COPD.

NEW & NOTEWORTHY In normal and COPD subjects, chest wall strapping(CWS) increased the number of detectable small airways using automated CT airway segmentation. The concept of dysanapsis expresses the physiological variation in the geometry of the tracheobronchial tree and lung parenchyma based on development. We propose a dynamic concept to dysanapsis in which CWS leads to breathing at lower lung volumes with a corresponding increase in the size of small airways, a potentially novel, nonpharmacological treatment for COPD.
The effect of muscle-tendon unit vs. fascicle analyses on vastus lateralis force-generating capacity during constant power output cycling with variable cadence
Authors: Brennan Scott F. , Cresswell Andrew G. , Farris Dominic J. , Lichtwark Glen A.
Published: January 2018

The maximum force-generating capacity of a muscle is dependent on the lengths and velocities of its contractile apparatus. Muscle-tendon unit (MTU) length changes can be estimated from joint kinematics; however, contractile element length changes are more difficult to predict during dynamic contractions. The aim of this study was to compare vastus lateralis (VL) MTU and fascicle level force-length and force-velocity relationships, and dynamic muscle function while cycling at a constant submaximal power output (2.5 W/kg) with different cadences. We hypothesized that manipulating cadence at a constant power output would not affect VL MTU shortening, but significantly affect VL fascicle shortening. Furthermore, these differences would affect the predicted force capacity of the muscle. Using an isokinetic dynamometer and B-mode ultrasound (US), we determined the force-length and force-velocity properties of the VL MTU and its fascicles. In addition, three-dimensional kinematics and kinetics of the lower limb, as well as US images of VL fascicles were collected during submaximal cycling at cadences of 40, 60, 80, and 100 rotations per minute. Ultrasound measures revealed a significant increase in fascicle shortening as cadence decreased (84% increase across all conditions, P < 0.01), whereas there were no significant differences in MTU lengths across any of the cycling conditions (maximum of 6%). The MTU analysis resulted in greater predicted force capacity across all conditions relative to the force-velocity relationship ( P < 0.01). These results reinforce the need to determine muscle mechanics in terms of separate contractile element and connective tissue length changes during isokinetic contractions, as well as dynamic movements like cycling.

NEW & NOTEWORTHY We demonstrate that vastus lateralis (VL) muscle tendon unit (MTU) length changes do not adequately reflect the underlying fascicle mechanics during cycling. When examined across different pedaling cadence conditions, the force-generating potential measured only at the level of MTU (or joint) overestimated the maximum force capacity of VL compared with analysis using fascicle level data.
Parathyroid hormone-(1–34) ameliorated knee osteoarthritis in rats via autophagy
Authors: Chen Chung-Hwan , Ho Mei-Ling , Chang Ling-Hua , Kang Lin , Lin Yi-Shan , Lin Sung-Yen , Wu Shun-Cheng , Chang Je-Ken
Published: January 2018

Anterior cruciate ligament (ACL) tear can lead to osteoarthritis (OA). However, parathyroid hormone (PTH)-(1–34) was found to alleviate OA progression in a papain-induced OA model. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with chondrocyte death and OA. Thus we examined the roles of autophagy in PTH treatment in OA after ACL transection (ACLT). Thirty-six rats were randomized into three groups: control group, ACLT-induced OA (OA) group, and OA with intra-articular PTH-(1–34) treatment (OA+PTH) group. Weight-bearing and treadmill tests were evaluated. Cartilage matrix was determined by a histological evaluation of glycosaminoglycan (GAG), Osteoarthritis Research Society International (OARSI) score, chondrocyte apoptosis, and immunohistochemistry. Rats in the OA group had significantly decreased weight bearing and running endurance. The histological results indicated that GAG, collagen type II, and chondrocyte autophagy had decreased but that the OARSI score, terminal differentiation markers (collagen type X and Indian hedgehog), and chondrocyte apoptosis had increased in the OA group. Additionally, PTH-(1–34) treatment significantly improved weight bearing and treadmill endurance, preserved GAG and collagen type II, and reduced the OARSI score and terminal differentiation markers. Finally, PTH-(1–34) ameliorated chondrocyte apoptosis by regulating the expression of autophagy-related proteins, through reducing mechanistic target of rapamycin (mTOR) and p62 and enhancing microtubule-associated protein-1 light chain 3 (LC3) and beclin-1. Reconstructive surgery after ACL rupture cannot prevent OA occurrence. Intra-articular PTH-(1–34) treatment can alleviate OA progression after ACLT and histological molecular changes. Possible mechanisms are reducing chondrocyte terminal differentiation and apoptosis, with increasing autophagy.

NEW & NOTEWORTHY Anterior cruciate ligament (ACL) tear can lead to osteoarthritis (OA). Intra-articular parathyroid hormone (PTH)-(1–34) significantly improved weight bearing and treadmill endurance, preserved glycosaminoglycan and collagen type II, and reduced Osteoarthritis Research Society International (OARSI) score and terminal differentiation. Finally, PTH-(1–34) ameliorated chondrocyte apoptosis by regulating the expression of autophagy-related proteins, through reducing mechanistic target of rapamycin (mTOR) and p62 and enhancing microtubule-associated protein-1 light chain 3 (LC3) and beclin-1. PTH-(1–34) can alleviate OA progression after ACL transection. Possible mechanisms are reducing chondrocyte terminal differentiation and apoptosis, with increasing autophagy.
Beetroot juice ingestion during prolonged moderate-intensity exercise attenuates progressive rise in O2 uptake
Authors: Tan Rachel , Wylie Lee J. , Thompson Christopher , Blackwell Jamie R. , Bailey Stephen J. , Vanhatalo Anni , Jones Andrew M.
Published: January 2018

Nitrate-rich beetroot juice (BR) supplementation has been shown to increase biomarkers of nitric oxide availability with implications for the physiological responses to exercise. We hypothesized that BR supplementation before and during prolonged moderate-intensity exercise would maintain an elevated plasma nitrite concentration ([[Formula: see text]]), attenuate the expected progressive increase in V̇o2 over time, and improve performance in a subsequent time trial (TT). In a double-blind, randomized, crossover design, 12 men completed 2 h of moderate-intensity cycle exercise followed by a 100-kJ TT in three conditions: 1) BR before and 1 h into exercise (BR + BR); 2) BR before and placebo (PL) 1 h into exercise (BR + PL); and 3) PL before and 1 h into exercise (PL + PL). During the 2-h moderate-intensity exercise bout, plasma [[Formula: see text]] declined by ~17% in BR + PL but increased by ~8% in BR + BR such that, at 2 h, plasma [[Formula: see text]] was greater in BR + BR than both BR + PL and PL + PL ( P < 0.05). V̇o2 was not different among conditions over the first 90 min of exercise but was lower at 120 min in BR + BR (1.73 ± 0.24 l/min) compared with BR + PL (1.80 ± 0.21 l/min; P = 0.08) and PL + PL (1.83 ± 0.27 l/min; P < 0.01). The decline in muscle glycogen concentration over the 2-h exercise bout was attenuated in BR + BR (~28% decline) compared with BR + PL (~44% decline) and PL + PL (~44% decline; n = 9, P < 0.05). TT performance was not different among conditions ( P > 0.05). BR supplementation before and during prolonged moderate-intensity exercise attenuated the progressive rise in V̇o2 over time and appeared to reduce muscle glycogen depletion but did not enhance subsequent TT performance.

NEW & NOTEWORTHY We show for the first time that ingestion of nitrate during exercise preserves elevated plasma [nitrite] and negates the progressive rise in O2 uptake during prolonged moderate-intensity exercise.
Nonsinusoidal neuronal oscillations: bug or feature?
Authors: Lozano-Soldevilla Diego
Published: January 2018

There is compiling evidence suggesting that independent neuronal ensembles are coordinated in time and space through cross-frequency coupling (CFC). However, recent studies have convincingly demonstrated that nonsinusoidal oscillations produce serious biases in state of the art CFC metrics. Although most of studies treat nonsinusoidal waves as a nuisance or just ignore them, fortunately some scientists are starting to exploit their neurophysiological relevance opening new research vistas with critical implications.
Network disruption following mild traumatic brain injury: clinical and experimental research implications
Authors: Swick Casey , Andersen Tiffany , Flores Ana-Mercedes
Published: January 2018

Illuminating the pathophysiological mechanisms that underlie persistent postconcussive symptoms following mild traumatic brain injury (mTBI) is a growing area of study. Alhourani et al. ( J Neurophysiol 116: 1840–1847, 2016) added to this emerging body of literature with their study examining default mode network disruption in mTBI using magnetoencephalography. The findings provided enhanced insight into the neural underpinnings of mTBI, which can be applied to future clinical and experimental research in this area.
Existence and Attractivity for Fractional Evolution Equations
Authors: Zhou Yong , He Jia Wei , Ahmad Bashir , Alsaedi Ahmed
Published: January 2018

We study the existence and attractivity of solutions for fractional evolution equations with Riemann-Liouville fractional derivative. We establish sufficient conditions for the global attractivity of mild solutions for the Cauchy problems in the case that semigroup is compact.
Protected Turning Movements of Noncooperative Automated Vehicles: Geometrics, Trajectories, and Saturation Flow
Authors: Liu Xiaobo , Lai Lijuan , Kong You , Le Vine Scott
Published: January 2018

This study is the first to quantify throughput (saturation flow) of noncooperative automated vehicles when performing turning maneuvers, which are critical bottlenecks in arterial road networks. We first develop a constrained optimization problem based on AVs’ kinematic behavior during a protected signal phase which considers both ABS-enabled and wheels-locked braking, as well as avoiding encroaching into oncoming traffic or past the edge-of-receiving-lane. We analyze noncooperative (“defensive”) behavior, in keeping with the Assured Clear Distance Ahead legal standard to which human drivers are held and AVs will likely also be for the foreseeable future. We demonstrate that, under plausible behavioral parameters, AVs appear likely to have positive impacts on throughput of turning traffic streams at intersections, in the range of +0.2% (under the most conservative circumstances) to +43% for a typical turning maneuver. We demonstrate that the primary mechanism of impact of turning radius is its effect on speed, which is likely to be constrained by passenger comfort. We show heterogeneous per-lane throughput in the case of “double turn lanes.” Finally, we demonstrate limited sensitivity to crash-risk criterion, with a 4% difference arising from a change from 1 in 10,000 to 1 in 100,000,000. The paper concludes with a brief discussion of policy implications and future research needs.
Phytochemical Screening and Biological Activity of Mentha × piperita L. and Lavandula angustifolia Mill. Extracts
Authors: Alexa Ersilia , Danciu Corina , Radulov Isidora , Obistioiu Diana , Sumalan Renata Maria , Morar Adriana , Dehelean Cristina Adriana
Published: January 2018

The present study aimed to investigate the phytochemical composition of Mentha × piperita L. (MP) and Lavandula angustifolia Mill. (LA) extracts in terms of hydroxycinnamic acid (HCAs) content, in particular, caffeic (CA), p-cumaric (CU), ferulic (FE), and rosmarinic (RS) acids using LC-MS. Also, the in vitro antimicrobial effect against Staphylococcus aureus and the antiproliferative activity against two cancerous cell lines (A375 and MDA-MB-231) using the MTT assay were tested. The extracts were prepared using aromatic water which resulted from the extraction of oils from plants as extraction medium, with/without acid. The results showed that RS and FE represent the majority of HCAs compounds; the highest content of FE is found in LA (7.47 mg·g–1d.m.), and the maximum content of RS in MP (6.36 mg·g–1d.m.). Regarding the antimicrobial effect against Staphylococcus aureus, the two extracts showed a simulative role on the growth rate of Staphyloccocus aureus, but a slightly inhibitory effect (69.12%) can be attributed to the acidic environment. In terms of biological activity against MDA-MB-231 breast carcinoma cell line, and A375 human melanoma cell line, at the highest employed concentration, 150 μg·mL–1, the tested extracts present a weak antiproliferative effect.
The New Era of Transplant Oncology: Liver Transplantation for Nonresectable Colorectal Cancer Liver Metastases
Authors: Gorgen Andre , Muaddi Hala , Zhang Wei , McGilvray Ian , Gallinger Steven , Sapisochin Gonzalo
Published: January 2018

Colorectal cancer (CRC) is the third most incident cancer worldwide. Most of CRC patients will develop distant metastases, mainly to the liver, and liver resection is the only potential chance for cure. On the other hand, only a small proportion of patients with hepatic CRC metastasis are candidates for upfront liver resection. Liver transplantation (LT) is an attractive option for patients with nonresectable CRC liver metastases (NRCLM) without extrahepatic involvement. Initial experiences with LT for NRCLM achieved very poor outcomes, with a 5-year overall survival (OS) lower than 20%. However, these initial studies did not have a standardized patient selection or neoadjuvant or adjuvant therapies. With recent advances in the surgical and medical oncology fields, the landscape has changed. Recent studies from Norway have shown an encouraging 5-year OS of 50% when transplanting patients with NRCLM. Nevertheless, the main concern when expanding the indications for LT is organ shortage. To manage this organ shortage, strategies utilizing live donor liver transplantation are gaining favor. A few ongoing trials are assessing the impact of LT in NRCLM patient survival. Therefore, the aim of this paper is to review the current status of LT for NRCLM.
Ecological Approaches to Dental Caries Prevention: Paradigm Shift or Shibboleth?
Authors: Philip Nebu , Suneja Bharat , Walsh Laurence J.
Published: January 2018

Contemporary paradigms of dental caries aetiology focus on the ecology of the dental plaque biofilm and how local environmental factors can modulate this to cause disease. The crucial role that a healthy oral microbiome plays in preventing caries and promoting oral health is also being increasingly recognized. Based on these concepts, several ecological preventive approaches have been developed that could potentially broaden the arsenal of currently available caries-preventive measures. Many of these ecological approaches aim for long-term caries control by either disrupting cariogenic virulence factors without affecting bacterial viability, or include measures that can enhance the growth of health-associated, microbially diverse communities in the oral microbiome. This paper argues for the need to develop ecological preventive measures that go beyond conventional caries-preventive methods, and discusses whether these ecological approaches can be effective in reducing the severity of caries by promoting stable, health-associated oral biofilm communities.
Electronic Nose in the Detection of Wound Infection Bacteria from Bacterial Cultures: A Proof-of-Principle Study
Authors: Saviauk Taavi , Kiiski Juha P. , Nieminen Maarit K. , Tamminen Nelly N. , Roine Antti N. , Kumpulainen Pekka S. , Hokkinen Lauri J. , Karjalainen Markus T. , Vuento Risto E. , Aittoniemi Janne J. , Lehtimäki Terho J. , Oksala Niku K.
Published: January 2018

Background: Soft tissue infections, including postoperative wound infections, result in a significant burden for modern society. Rapid diagnosis of wound infections is based on bacterial stains, cultures, and polymerase chain reaction assays, and the results are available earliest after several hours, but more often not until days after. Therefore, antibiotic treatment is often administered empirically without a specific diagnosis. Methods: We employed our electronic nose (eNose) system for this proof-of-concept study, aiming to differentiate the most relevant bacteria causing wound infections utilizing a set of clinical bacterial cultures on identical blood culture dishes, and established bacterial lines from the gaseous headspace. Results: Our eNose system was capable of differentiating both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, and Clostridium perfringens with an accuracy of 78% within minutes without prior sample preparation. Most importantly, the system was capable of differentiating MRSA from MSSA with a sensitivity of 83%, a specificity of 100%, and an overall accuracy of 91%. Conclusions: Our results support the concept of rapid detection of the most relevant bacteria causing wound infections and ultimately differentiating MRSA from MSSA utilizing gaseous headspace sampling with an eNose.
Audio-Based Melody Categorization: Exploring Signal Representations and Evaluation Strategies
Authors: Kroher Nadine , Díaz-Báñez José-Miguel
Published: January 2018

Melody categorization refers to the task of grouping a set of melodies into categories of similar items that originate from the same melodic contour. From a computational perspective, automatic melody categorization is of crucial importance for the automatic organization of databases, as well as for large-scale musicological studies—in particular, in the context of folk music and non-Western music traditions. We investigate methods starting from the raw audio file. For each recording contained in a collection, we extract a pitch sequence representing the main melodic line. We then estimate pairwise similarities and evaluate the discriminative power of the resulting similarity matrix with respect to ground-truth annotations. We propose novel evaluation methodologies, compare melody representations, and explore the potential of our approach in the context of two applications: interstyle and intrastyle categorization of flamenco music and tune-family recognition of folk-song recordings.
Revisiting the ENSO–SSW Relationship
Authors: Song Kanghyun , Son Seok-Woo
Published: January 2018

Stratospheric sudden warming (SSW) events exhibit pronounced interannual variability. Based on zonal wind reversals at 60°N and 10 hPa, it has been suggested that SSW events occur more preferentially during El Niño–Southern Oscillation (ENSO) winters (both El Niño and La Niña winters) than during ENSO-neutral winters. This relationship is reevaluated here by considering seven different SSW definitions. For all definitions, SSW events are detected more frequently during El Niño winters than during ENSO-neutral winters, in agreement with a strengthened planetary-scale wave activity. However, such a systematic relationship is not found during La Niña winters. While three SSW definitions, including the wind-reversal definition, show a higher SSW frequency during La Niña winters than during ENSO-neutral winters, other definitions show no difference or even lower SSW frequency during La Niña winters. This result, which is qualitatively insensitive to the choice of reanalysis datasets, ENSO indices, and SST datasets, indicates that the reported ENSO–SSW relationship is dependent on the details of the SSW definition. This result is interpreted in terms of different background wind, latitudinal extent of wind reversal, and planetary-scale wave activity during El Niño and La Niña winter SSW events.
Impacts of Broad-Scale Surface Freshening of the Southern Ocean in a Coupled Climate Model
Authors: Purich Ariaan , England Matthew H. , Cai Wenju , Sullivan Arnold , Durack Paul J.
Published: January 2018

The Southern Ocean surface has freshened in recent decades, increasing water column stability and reducing upwelling of warmer subsurface waters. The majority of CMIP5 models underestimate or fail to capture this historical surface freshening, yet little is known about the impact of this model bias on regional ocean circulation and hydrography. Here experiments are performed using a global coupled climate model with additional freshwater applied to the Southern Ocean to assess the influence of recent surface freshening. The simulations explore the impact of persistent and long-term broad-scale freshening as a result of processes including precipitation minus evaporation changes. Thus, unlike previous studies, the freshening is applied as far north as 55°S, beyond the Antarctic ice margin. It is found that imposing a large-scale surface freshening causes a surface cooling and sea ice increase under preindustrial conditions, because of a reduction in ocean convection and weakened entrainment of warm subsurface waters into the surface ocean. This is consistent with intermodel relationships between CMIP5 models and the simulations, suggesting that models with larger surface freshening also exhibit stronger surface cooling and increased sea ice. Additional experiments are conducted with surface salinity restoration applied to capture observed regional salinity trends. Remarkably, without any mechanical wind trend forcing, these simulations accurately represent the spatial pattern of observed surface temperature and sea ice trends around Antarctica. This study highlights the importance of accurately simulating changes in Southern Ocean salinity to capture changes in ocean circulation, sea surface temperature, and sea ice.
Risedronate Sodium and Tirofiban Hydrochloride
Authors: Levien Terri , Baker Danial E.
Published: January 2018

Each month, subscribers to The Formulary® receive print and electronic versions of at least six monographs reviewing new drug entities or related drugs within a category. Some reviews take a second look at currently available drugs, whereas other preliminarily evaluate agents about to be released—just in time for use with your Pharmacy and Therapeutics Committee or for counter detailing. The monographs are prepared by clinical and drug-information pharmacists and are reviewed by expert pharmacists and physicians. Through the cooperation of The Formulary, Hospital Pharmacy has arranged to publish selected reviews in this column. If you would like more information about The Formulary or its related electronic bulletin board, known as the F.I.X.® (Formulary Information Exchange, write to: The Formulary, 33971 Selva Road, Suite 250, Dana Point CA 92629; or call 1-800-322–4349.
New Products and New Indications
Authors: Gatto Rose Ellen A.
Published: January 2018

Keeping abreast of new product trends is important to hospital pharmacists. This monthly feature is designed to help readers keep current on new drug products and new indications in the pharmaceutical industry. It is also interesting from a historic perspective to note the time and ori-
Remeron Tablet Strengths Easy to Confuse Safety Alert: Versed Syrup Reducing Errors with IV Insulin
Authors: Cohen Michael R.
Published: January 2018

These medication errors have occurred in health care facilities at least once. They will happen again–perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them in your inservice training programs.

Your assistance is required to continue this feature. The reports described here were received through the USP Medication Errors Reporting Program, which is presented in cooperation with the Institute of Safe Medication Practices. If you have encountered medication errors and would like to report them, you may call USP tool-free, 24 hours a day, at 1-800-233-7767 (1-800-23-ERROR).

Any reports published by ISMP will be anonymous. Comments are also invited; the writer's names will be published if desired. ISMP may be contacted at the address shown below.
Medicare Reimbursement: Entering the Era of Prospective Payment for Geriatric Care (Part 1)
Authors: Vogenberg F. Randy
Published: January 2018

Managed health care has changed the way health services are provided and paid for. It is still evolving. Many pharmacists have already felt the impact of these changes. This continuing feature illuminates the many facets of managed care with special emphasis on how these changes may affect pharmacists working in health systems. The expertise provided by pharmacists will be needed to fulfill the potential of affordable, comprehensive, and quality health care as promised by managed care. Pharmacists must understand what is happening, why it is happening, and what is likely to happen in the future. To be an active and effective player, you must understand what is happening on the field.