bluuebunny/crossref_metadata_2025 huggingface dataset:
Somatostatin and its receptors contribute in a tissue-specific manner to the sex-dependent metabolic (fed/fasting) control of growth hormone axis in mice
Authors: Córdoba-Chacón José , Gahete Manuel D. , Castaño Justo P. , Kineman Rhonda D. , Luque Raul M.
Published: October 2010

Somatostatin (SST) inhibits growth hormone (GH) secretion and regulates multiple processes by signaling through its receptors sst1–5. Differential expression of SST/ssts may contribute to sex-specific GH pattern and fasting-induced GH rise. To further delineate the tissue-specific roles of SST and sst1–5 in these processes, their expression patterns were evaluated in hypothalamus, pituitary, and stomach of male and female mice under fed/fasted conditions in the presence (wild type) or absence (SST-knockout) of endogenous SST. Under fed conditions, hypothalamic/stomach SST/ssts expression did not differ between sexes, whereas male pituitary expressed more SST and sst2A/2B/3/5A/5TMD2/5TMD1 and less sst1, and male pituitary cell cultures were more responsive to SST inhibitory actions on GH release compared with females. This suggests that local pituitary SST/ssts can contribute to the sexually dimorphic pattern of GH release. Fasting (48 h) reduced stomach sst2A/B and hypothalamic SST/sst2A expression in both sexes, whereas it caused a generalized downregulation of pituitary sst subtypes in male and of sst2A only in females. Thus, fasting can reduce SST sensitivity across tissues and SST input to the pituitary, thereby jointly contributing to enhance GH release. In SST-knockout mice, lack of SST differentially altered sst subtype expression levels in both sexes, supporting an important role for SST in sex-dependent control of GH axis. Evaluation of SST, IGF-I, and glucocorticoid effects on hypothalamic and pituitary cell cultures revealed that these hormones could directly account for alterations in sst2/5 expression in the physiological states examined. Taken together, these results indicate that changes in SST output and sensitivity can contribute critically to precisely define, in a tissue-dependent manner, the sex-specific metabolic regulation of the GH axis.
Ionic mechanisms of cellular electrical and mechanical abnormalities in Brugada syndrome
Authors: Dong Min , Niklewski Paul J. , Wang Hong-Sheng
Published: October 2010

The Brugada syndrome (BrS) is a right ventricular (RV) arrhythmia that is responsible for up to 12% of sudden cardiac deaths. The aims of our study were to determine the cellular mechanisms of the electrical abnormality in BrS and the potential basis of the RV contractile abnormality observed in the syndrome. Tetrodotoxin was used to reduce cardiac Na+ current ( INa) to mimic a BrS-like setting in canine ventricular myocytes. Moderate reduction (<50%) of INa with tetrodotoxin resulted in all-or-none repolarization in a fraction of RV epicardial myocytes. Dynamic clamp and modeling show that reduction of INa shifts the action potential (AP) duration-transient outward current ( Ito) density curve to the left and has a biphasic effect on AP duration. In the presence of a large Ito, INa reduction either prolongs or collapses the AP, depending on the exact density of Ito. These repolarization changes reduce Ca2+ influx and sarcoplasmic reticulum load, resulting in marked attenuation of myocyte contraction and Ca2+ transient in RV epicardial myocytes. We conclude that INa reduction alters repolarization by reducing the threshold for Ito-induced all-or-none repolarization. These cellular electrical changes suppress myocyte excitation-contraction coupling and contraction and may be a contributing factor to the contractile abnormality of the RV wall in BrS.
Respiratory syncytial virus is associated with an inflammatory response in lungs and architectural remodeling of lung-draining lymph nodes of newborn lambs
Authors: Sow Fatoumata B. , Gallup Jack M. , Olivier Alicia , Krishnan Subramaniam , Patera Andriani C. , Suzich JoAnn , Ackermann Mark R.
Published: October 2010

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in children worldwide. The understanding of neonatal RSV pathogenesis depends on using an animal model that reproduces neonatal RSV disease. Previous studies from us and others demonstrated that the neonatal lamb model resembles human neonatal RSV infection. Here, we provide an extensive and detailed characterization of the histopathology, viral load, cellular infiltration, and cytokine production in lungs and tracheobronchial lymph nodes of lambs inoculated with human RSV strain A2 over the course of infection. In the lung, RSV titers were low at day 3 postinfection, increased significantly by day 6, and decreased to baseline levels at day 14. Infection in the lung was associated with an accumulation of macrophages, CD4+and CD8+T cells, and a transcriptional response of genes involved in inflammation, chemotaxis, and interferon response, characterized by increased IFNγ, IL-8, MCP-1, and PD-L1, and decreased IFNβ, IL-10, and TGF-β. Laser capture microdissection studies determined that lung macrophage-enriched populations were the source of MCP-1 but not IL-8. Immunoreactivity to caspase 3 occurred within bronchioles and alveoli of day 6-infected lambs. In lung-draining lymph nodes, RSV induced lymphoid hyperplasia, suggesting an ability of RSV to enhance lymphocytic proliferation and differentiation pathways. This study suggests that, in lambs with moderate clinical disease, RSV enhances the activation of caspase cell death and Th1-skewed inflammatory pathways, and complements previous observations that emphasize the role of inflammation in the pathogenesis of RSV disease.
A comparison of fixation methods on lung morphology in a murine model of emphysema
Authors: Braber S. , Verheijden K. A. T. , Henricks P. A. J. , Kraneveld A. D. , Folkerts G.
Published: October 2010

Emphysema is characterized by enlargement of the alveoli, which is the most important parameter to assess the presence and severity of this disease. Alveolar enlargement is primarily defined on morphological criteria; therefore, characterization of this disease with morphological parameters is a prerequisite to study the pathogenesis. For this purpose, different methods of lung fixation were evaluated in a murine model of LPS-induced lung emphysema. Five different methods of lung fixation were evaluated: intratracheal instillation of fixatives, in situ fixation, fixed-volume fixation, vascular whole body perfusion, and vacuum inflation. In addition, the effects of three different fixatives (10% formalin, Carnoy's, and agarose/10% formalin solution) and two embedding methods (paraffin and plastic) were investigated on the murine lung morphology. Mice received intranasal administration of LPS to induce alveolar wall destruction. Quantification of air space enlargement was determined by mean linear intercept analysis, and the histological sections were analyzed for the most optimal fixation method. Additionally, routine immunohistological staining was performed on lung tissue of PBS-treated mice. Intratracheal instillation of formalin or agarose/formalin solution, in situ fixation, and fixed-volume fixation provided a normal lung architecture, in contrast to the lungs fixed via whole body perfusion and vacuum inflation. Formalin-fixed lungs resulted in the most optimal lung morphology for lung emphysema analysis when embedded in paraffin, while for Carnoy's fixed lungs, plastic embedding was preferred. The histological findings, the mean linear intercept measurement, and the immunohistochemistry data demonstrated that fixation by intratracheal instillation of 10% formalin or in situ fixation with 10% formalin are the two most optimal methods to fix lungs for alveolar enlargement analysis to study lung emphysema.
Endothelins participate in the central and peripheral regulation of submandibular gland secretion in the rat
Authors: Ventimiglia Maria S. , Rodriguez Myrian R. , Morales Vanina P. , Elverdin Juan C. , Perazzo Juan C. , Castañeda Mauricio M. , Davio Carlos A. , Vatta Marcelo S. , Bianciotti Liliana G.
Published: October 2010

We previously reported that endothelins (ETs) are involved in the rat central and peripheral regulation of bile secretion. In this study we sought to establish whether ET-1 and ET-3 modulated submandibular gland secretion when locally or centrally applied. Animals were prepared with gland duct cannulation to collect saliva samples and jugular cannulation to administer sialogogues. ETs were given either into the submandibular gland or brain lateral ventricle. Intraglandularly administered ETs failed to elicit salivation per se. However, ET-1, but not ET-3, potentiated both cholinergic- and adrenergic-evoked salivation through ETAreceptors. ET-1 decreased cAMP content but increased phosphoinositide hydrolysis, whereas ET-3 attenuated both intracellular pathways. The expression of ETAand ETBreceptor mRNAs as well as that of ETs was revealed in the submandibular gland by RT-PCR. Immunohistochemical studies showed that ETAreceptor staining was localized around the interlobular ducts and acini, compatible with the myoepithelial cells' location, whereas ETBreceptor staining was restricted to small blood vessels. When applied to the brain, both ETs induced no salivation but enhanced cholinergic- and adrenergic-evoked salivary secretion through parasympathetic pathways. ET-1 response was mediated by brain ETAreceptors, whereas that of ET-3 was presumably through nonconventional ET receptors. Present findings show that ETs are involved in the brain regulation of cholinergic- and adrenergic-stimulated submandibular gland secretion through the activation of distinct brain ET receptors and parasympathetic pathways. However, when ETs were administered into the gland, only ET-1 enhanced cholinergic and adrenergic salivation likely through myopithelial cell contraction by activating ETAreceptors coupled to phospholipase C. The presence of ETs and ET receptors suggests the existence of an endothelinergic system in the submandibular gland.
HIF-1α response to hypoxia is functionally separated from the glucocorticoid stress response in the in vitro regenerating human skeletal muscle
Authors: Pirkmajer Sergej , Filipovic Dragana , Mars Tomaz , Mis Katarina , Grubic Zoran
Published: October 2010

Injury of skeletal muscle is followed by muscle regeneration in which new muscle tissue is formed from the proliferating mononuclear myoblasts, and by systemic response to stress that exposes proliferating myoblasts to increased glucocorticoid (GC) concentration. Because of its various causes, hypoxia is a frequent condition affecting skeletal muscle, and therefore both processes, which importantly determine the outcome of the injury, often proceed under hypoxic conditions. It is therefore important to identify and characterize in proliferating human myoblasts: 1) response to hypoxia which is generally organized by hypoxia-inducible factor-1α (HIF-1α); 2) response to GCs which is mediated through the isoforms of glucocorticoid receptors (GRs) and 11β-hydroxysteroid dehydrogenases (11β-HSDs), and 3) the response to GCs under the hypoxic conditions and the influence of this combination on the factors controlling myoblast proliferation. Using real-time PCR, Western blotting, and HIF-1α small-interfering RNA silencing, we demonstrated that cultured human myoblasts possess both, the HIF-1α-based response to hypoxia, and the GC response system composed of GRα and types 1 and 2 11β-HSDs. However, using combined dexamethasone and hypoxia treatments, we demonstrated that these two systems operate practically without mutual interactions. A seemingly surprising separation of the two systems that both organize response to hypoxic stress can be explained on the evolutionary basis: the phylogenetically older HIF-1α response is a protection at the cellular level, whereas the GC stress response protects the organism as a whole. This necessitates actions, like downregulation of IL-6 secretion and vascular endothelial growth factor, that might not be of direct benefit for the affected myoblasts.
Downstream mechanisms of nitric oxide-mediated skeletal muscle glucose uptake during contraction
Authors: Merry Troy L. , Lynch Gordon S. , McConell Glenn K.
Published: October 2010

There is evidence that nitric oxide (NO) is required for the normal increases in skeletal muscle glucose uptake during contraction, but the mechanisms involved have not been elucidated. We examined whether NO regulates glucose uptake during skeletal muscle contractions via cGMP-dependent or cGMP-independent pathways. Isolated extensor digitorum longus (EDL) muscles from mice were stimulated to contract ex vivo, and potential NO signaling pathways were blocked by the addition of inhibitors to the incubation medium. Contraction increased ( P < 0.05) NO synthase (NOS) activity (∼40%) and dichlorofluorescein (DCF) fluorescence (a marker of oxidant levels; ∼95%), which was prevented with a NOS inhibitor NG-monomethyl-l-arginine (l-NMMA), and antioxidants [nonspecific antioxidant, N-acetylcysteine (NAC); thiol-reducing agent, DTT], respectively. l-NMMA and NAC both attenuated glucose uptake during contraction by ∼50% ( P < 0.05), and their effects were not additive. Neither the guanylate cyclase inhibitor 1 H-[1,2,4]oxadiazolo-[4,3- a]quinoxalin-1-one, which prevents the formation of cGMP, the cGMP-dependent protein (PKG) inhibitor Rp-8-bromo-β-phenyl-1,N2-ethenoguanosine 3′,5′-cyclic monophosphorothioate sodium salt nor white light, which breaks S-nitrosylated bonds, affects glucose uptake during contraction; however, DTT attenuated ( P < 0.05) contraction-stimulated glucose uptake (by 70%). NOS inhibition and antioxidant treatment reduced contraction-stimulated increases in protein S-glutathionylation and tyrosine nitration ( P < 0.05), without affecting AMPK or p38 MAPK phosphorylation. In conclusion, we provide evidence to suggest that NOS-derived oxidants regulate skeletal muscle glucose uptake during ex vivo contractions via a cGMP/PKG-, AMPK-, and p38 MAPK-independent pathway. In addition, it appears that NO and ROS may regulate skeletal muscle glucose uptake during contraction through a similar pathway.
Prolactin promotes oxytocin and vasopressin release by activating neuronal nitric oxide synthase in the supraoptic and paraventricular nuclei
Authors: Vega Claudia , Moreno-Carranza Bibiana , Zamorano Miriam , Quintanar-Stéphano Andrés , Méndez Isabel , Thebault Stéphanie , Martínez de la Escalera Gonzalo , Clapp Carmen
Published: October 2010

Prolactin (PRL) stimulates the secretion of oxytocin (OXT) and arginine AVP as part of the maternal adaptations facilitating parturition and lactation. Both neurohormones are under the regulation of nitric oxide. Here, we investigate whether the activation of neuronal nitric oxide synthase (nNOS) in the hypothalamo-neurohypophyseal system mediates the effect of PRL on OXT and AVP release and whether these effects operate in males. Plasma levels of OXT and AVP were measured in male rats after the intracerebroventricular injection of PRL or after inducing hyperprolactinemia by placing two anterior pituitary glands under the kidney capsule. NOS activity was evaluated in the paraventricular (PVN) and supraoptic (SON) hypothalamic nuclei by NADPH-diaphorase histochemistry and in hypothalamic extracts by the phosphorylation/inactivation of nNOS at Ser847. Elevated central and systemic PRL correlated with increased NOS activity in the PVN and SON and with higher OXT and AVP circulating levels. Notably, treatment with 7-nitroindazole, a selective inhibitor of nNOS, prevented PRL-induced stimulation of the release of both neurohormones. Also, phosphorylation of nNOS was reduced in hyperprolactinemic rats, and treatment with bromocriptine, an inhibitor of anterior pituitary PRL secretion, suppressed this effect. These findings suggest that PRL enhances nNOS activity in the PVN and SON, thereby contributing to the regulation of OXT and AVP release. This mechanism likely contributes to the regulation of processes beyond those of female reproduction.
Transient and sustained increases in glomerular permeability following ANP infusion in rats
Authors: Axelsson Josefin , Rippe Anna , Rippe Bengt
Published: October 2010

The present study was performed to investigate the effects of systemic atrial natriuretic peptide (ANP) infusion on the glomerular permeability to macromolecules in rats. In anesthetized Wistar rats (250–280 g), the left urether was cannulated for urine collection while simultaneously blood access was achieved. Rats were continuously infused intravenously with ANP [30 ng·kg−1·min−1(Lo-ANP; n = 8) or 800 ng·kg−1·min−1(Hi-ANP; n = 10)] or 0.9% NaCl (SHAM; n = 16), respectively, and with polydisperse FITC-Ficoll-70/400 (molecular radius 13–90 Å) and51Cr-EDTA for 2 h. Plasma and urine samples were taken at 5, 15, 30, 60, and 120 min of ANP infusion and analyzed by high-performance size-exclusion chromatography (HPLC) for determination of glomerular sieving coefficients (θ) for Ficoll. GFR was also assessed (51Cr-EDTA). In Hi-ANP, there was a rapid (within 5 min), but bimodal, increase in glomerular permeability. θ to high-molecular-weight Ficoll thus reached a maximum at 15 min, after which θ returned to near control at 30 min, to again increase moderately at 60 and 120 min. In Lo-ANP, there was also a rapid, reversible increase in glomerular θ, returning to near control at 30 min, followed by just a tendency of a sustained increase in permeability, but with a significant increase in “large-pore” radius. In conclusion, in Hi-ANP there was a rapid increase in glomerular permeability, with an early, partly reversible permeability peak, followed by a (moderate) sustained increase in permeability. In Lo-ANP animals, only the initial permeability peak was evident. In both Lo-ANP and Hi-ANP, the glomerular sieving pattern observed was found to mainly reflect an increase in the number and radius of large pores in the glomerular filter.
Early glomerular alterations in genetically determined low nephron number
Authors: Benz Kerstin , Campean Valentina , Cordasic Nada , Karpe Britta , Neuhuber Winfried , Mall Gerhard , Hartner Andrea , Hilgers Karl F. , Amann Kerstin
Published: October 2010

An association between low nephron number and subsequent development of hypertension in later life has been demonstrated. The underlying pathomechanisms are unknown, but glomerular and postglomerular changes have been discussed. We investigated whether such changes are already present in prehypertensive “glial cell line-derived neurotrophic growth factor” heterozygous mice (GDNF+/−) with lower nephron number. Twenty-six-week-old mice [22 GDNF+/−, 29 C57B6 wild-type control (wt)] were used for in vivo experiments with intra-arterial and tail cuff blood pressure measurements. After perfusion fixation, kidneys were investigated with morphological, morphometric, stereological, and immunohistochemical techniques and TaqMan PCR analysis. As expected at this age, blood pressure was comparable between GDNF+/− and wt. Nephron number per kidney was significantly lower in GDNF+/− than in wt (−32.8%, P < 0.005), and mean glomerular volume was significantly higher (+49.5%, P < 0.001). Renal damage scores, glomerular and tubular proliferation, analysis of intrarenal arteries and peritubular capillaries, expression of relevant tubular transporter proteins, as well as gene expression of profibrotic, proinflammatory, or prohypertensive markers were not significantly different between GDNF+/− and wt. Compensatory glomerular hypertrophy in GDNF+/− was accompanied by higher numbers of endothelial and mesangial cells as well as PCNA-positive glomerular cells, whereas podocyte density was significantly reduced. Further electron microscopic analysis showed marked thickening of glomerular basement membrane. In conclusion, lower nephron number is associated with marked early glomerular structural changes, in particular lower capillary supply, reduced podocyte density, and thickened glomerular basement membrane, that may predispose to glomerular sclerosis.
CCL2 and CCR2 variants are associated with skeletal muscle strength and change in strength with resistance training
Authors: Harmon Brennan T. , Orkunoglu-Suer E. Funda , Adham Kasra , Larkin Justin S. , Gordish-Dressman Heather , Clarkson Priscilla M. , Thompson Paul D. , Angelopoulos Theodore J. , Gordon Paul M. , Moyna Niall M. , Pescatello Linda S. , Visich Paul S. , Zoeller Robert F. , Hubal Monica J. , Tosi Laura L. , Hoffman Eric P. , Devaney Joseph M.
Published: October 2010

Baseline muscle size and muscle adaptation to exercise are traits with high variability across individuals. Recent research has implicated several chemokines and their receptors in the pathogenesis of many conditions that are influenced by inflammatory processes, including muscle damage and repair. One specific chemokine, chemokine (C-C motif) ligand 2 (CCL2), is expressed by macrophages and muscle satellite cells, increases expression dramatically following muscle damage, and increases expression further with repeated bouts of exercise, suggesting that CCL2 plays a key role in muscle adaptation. The present study hypothesizes that genetic variations in CCL2 and its receptor ( CCR2) may help explain muscle trait variability. College-aged subjects [ n = 874, Functional Single-Nucleotide Polymorphisms Associated With Muscle Size and Strength (FAMUSS) cohort] underwent a 12-wk supervised strength-training program for the upper arm muscles. Muscle size (via MR imaging) and elbow flexion strength (1 repetition maximum and isometric) measurements were taken before and after training. The study participants were then genotyped for 11 genetic variants in CCL2 and five variants in CCR2. Variants in the CCL2 and CCR2 genes show strong associations with several pretraining muscle strength traits, indicating that inflammatory genes in skeletal muscle contribute to the polygenic system that determines muscle phenotypes. These associations extend across both sexes, and several of these genetic variants have been shown to influence gene regulation.
Time Course of Information Representation of Macaque AIP Neurons in Hand Manipulation Task Revealed by Information Analysis
Authors: Sakaguchi Yutaka , Ishida Fumihiko , Shimizu Takashi , Murata Akira
Published: October 2010

We used mutual information analysis of neuronal activity in the macaque anterior intraparietal area (AIP) to examine information processing during a hand manipulation task. The task was to reach-to-grasp a three-dimensional (3D) object after presentation of a go signal. Mutual information was calculated between the spike counts of individual neurons in 50-ms-wide time bins and six unique shape classifications or 15 one-versus-one classifications of these shapes. The spatiotemporal distribution of mutual information was visualized as a two-dimensional image (“information map”) to better observe global profiles of information representation. In addition, a nonnegative matrix factorization technique was applied for extracting its structure. Our major finding was that the time course of mutual information differed significantly according to different classes of task-related neurons. This strongly suggests that different classes of neurons were engaged in different information processing stages in executing the hand manipulation task. On the other hand, our analysis revealed the heterogeneous nature of information representation of AIP neurons. For example, “information latency” (or information onset) varied among individual neurons even in the same neuron class and the same shape classification. Further, some neurons changed “information preference” (i.e., shape classification with the largest amount of information) across different task periods. These suggest that neurons encode different information in the different task periods. Taking the present result together with previous findings, we used a Gantt chart to propose a hypothetical scheme of the dynamic interactions between different types of AIP neurons.
A closed-loop human simulator for investigating the role of feedback control in brain-machine interfaces
Authors: Cunningham John P. , Nuyujukian Paul , Gilja Vikash , Chestek Cindy A. , Ryu Stephen I. , Shenoy Krishna V.
Published: October 2010

Neural prosthetic systems seek to improve the lives of severely disabled people by decoding neural activity into useful behavioral commands. These systems and their decoding algorithms are typically developed “offline,” using neural activity previously gathered from a healthy animal, and the decoded movement is then compared with the true movement that accompanied the recorded neural activity. However, this offline design and testing may neglect important features of a real prosthesis, most notably the critical role of feedback control, which enables the user to adjust neural activity while using the prosthesis. We hypothesize that understanding and optimally designing high-performance decoders require an experimental platform where humans are in closed-loop with the various candidate decode systems and algorithms. It remains unexplored the extent to which the subject can, for a particular decode system, algorithm, or parameter, engage feedback and other strategies to improve decode performance. Closed-loop testing may suggest different choices than offline analyses. Here we ask if a healthy human subject, using a closed-loop neural prosthesis driven by synthetic neural activity, can inform system design. We use this online prosthesis simulator (OPS) to optimize “online” decode performance based on a key parameter of a current state-of-the-art decode algorithm, the bin width of a Kalman filter. First, we show that offline and online analyses indeed suggest different parameter choices. Previous literature and our offline analyses agree that neural activity should be analyzed in bins of 100- to 300-ms width. OPS analysis, which incorporates feedback control, suggests that much shorter bin widths (25–50 ms) yield higher decode performance. Second, we confirm this surprising finding using a closed-loop rhesus monkey prosthetic system. These findings illustrate the type of discovery made possible by the OPS, and so we hypothesize that this novel testing approach will help in the design of prosthetic systems that will translate well to human patients.
Polymers for Fabricating Nerve Conduits
Authors: Wang Shanfeng , Cai Lei
Published: October 2010

Peripheral nerve regeneration is a complicated and long-term medical challenge that requires suitable guides for bridging nerve injury gaps and restoring nerve functions. Many natural and synthetic polymers have been used to fabricate nerve conduits as well as luminal fillers for achieving desired nerve regenerative functions. It is important to understand the intrinsic properties of these polymers and techniques that have been used for fabricating nerve conduits. Previously extensive reviews have been focused on the biological functions and in vivo performance of polymeric nerve conduits. In this paper, we emphasize on the structures, thermal and mechanical properties of these naturally derived synthetic polymers, and their fabrication methods. These aspects are critical for the performance of fabricated nerve conduits. By learning from the existing candidates, we can advance the strategies for designing novel polymeric systems with better properties for nerve regeneration.
Acne Scars: Pathogenesis, Classification and Treatment
Authors: Fabbrocini Gabriella , Annunziata M. C. , D′Arco V. , De Vita V. , Lodi G. , Mauriello M. C. , Pastore F. , Monfrecola G.
Published: October 2010

Acne has a prevalence of over 90% among adolescents and persists into adulthood in approximately 12%–14% of cases with psychological and social implications. Possible outcomes of the inflammatory acne lesions are acne scars which, although they can be treated in a number of ways, may have a negative psychological impact on social life and relationships. The main types of acne scars are atrophic and hypertrophic scars. The pathogenesis of acne scarring is still not fully understood, but several hypotheses have been proposed. There are numerous treatments: chemical peels, dermabrasion/microdermabrasion, laser treatment, punch techniques, dermal grafting, needling and combined therapies for atrophic scars: silicone gels, intralesional steroid therapy, cryotherapy, and surgery for hypertrophic and keloidal lesions. This paper summarizes acne scar pathogenesis, classification and treatment options.
Clonal Identification Based on Quantitative, Codominant, and Dominant Marker Data: A Comparative Analysis of Selected Willow (SalixL.) Clones
Authors: Aravanopoulos F. A.
Published: October 2010

Clonal identification in forestry may employ different means, each with unique advantages. A comparative evaluation of different approaches is reported. Nine quantitative leaf morphometric parameters, 15 variable codominant (isoenzyme) and 15 variable dominant (RAPD) loci, were used. All clones presented unique multilocus isoenzyme genotypes and 86% presented unique multilocus RAPD genotypes. Quantitative, isoenzyme and molecular data were subjected to principal component analysis, the latter two data sets after vector transformation. Most of the variability (quantitative 99%, isoenzyme 72.5%, RAPD 89%) was accounted for in the first three axes. This study has shown: (1) individual quantitative parameters were inefficient for clonal identification, (2) multilocus clonal identification was successful, (3) dominant markers were more polymorphic than codominant ones: 1.5 variable loci per enzyme system, 7.5 variable RAPD loci per primer, (4) 15 codominant marker loci could identify about 2.8 times more individuals than 15 dominant ones, but this advantage is surpassed when 42 dominant loci are employed, (5) multivariate analysis of morphological, codominant and dominant genetic data could not discriminate at the clonal level. It was concluded that due to their higher number of loci available dominant markers perform better than codominant ones, despite the higher informativeness of the latter.
Hypoglycemic and Hepatoprotective Activity of Fermented Fruit Juice ofMorinda citrifolia(Noni) in Diabetic Rats
Authors: Nayak B. Shivananda , Marshall Julien R. , Isitor Godwin , Adogwa Andrew
Published: October 2010

Morinda citrifoliais a medicinal plant used to treat diabetes and liver diseases. The fermented fruit juice of theM. Citrifolia(optical density = 1.25) was used to study the hypoglycemic and hepatoprotective properties in diabetes‐induced rats. The rats were randomly distributed into 4 groups (control, diabetic experimental, diabetic standard, and diabetic untreated) of 6 each. Diabetes was induced by administering Streptozotocin (50 mg/kg body weight). Fasting blood glucose, body mass, liver tissue glycogen content, and the extent of liver degeneration were assessed. Diabetic experimental animals were treated withM. citrifoliajuice (2 ml/kg, twice a day) and diabetic standard with reference hypoglycemic drug, glibenclamide orally for 20 days. Both the groups exhibited a significant reduction in blood glucose level of 150 mg/dl ±15.88 and 125 mg/dl ±3.89, respectively, as compared to diabetic untreated with FBS = 360.0 mg/dl ±15.81, (P< .003). On 10th day of experiment, diabetic experimental animals exhibited a decrease in body mass (10.2 g, 5.11%) which increased significantly by the 20th day (6 g, 3.0%,P< .022). Histological study of liver tissue obtained from untreated diabetic animals revealed significant fatty degeneration as compared to other three groups. The data of this study proved the hypoglycemic and hepatoprotective activity ofM. citrifolia.
Blockade of the Ubiquitin Protease UBP43 Destabilizes Transcription Factor PML/RARα and Inhibits the Growth of Acute Promyelocytic Leukemia
Authors: Guo Yongli , Dolinko Andrey V. , Chinyengetere Fadzai , Stanton Bruce , Bomberger Jennifer M. , Demidenko Eugene , Zhou Da-Cheng , Gallagher Robert , Ma Tian , Galimberti Fabrizio , Liu Xi , Sekula David , Freemantle Sarah , Dmitrovsky Ethan
Published: October 2010

More effective treatments for acute promyelocytic leukemia (APL) are needed. APL cell treatment with all-trans-retinoic acid (RA) degrades the chimeric, dominant-negative–acting transcription factor promyelocytic leukemia gene (PML)/RARα, which is generated in APL by chromosomal translocation. The E1-like ubiquitin-activating enzyme (UBE1L) associates with interferon-stimulated gene ISG15 that binds and represses PML/RARα protein. Ubiquitin protease UBP43/USP18 removes ISG15 from conjugated proteins. In this study, we explored how RA regulates UBP43 expression and the effects of UBP43 on PML/RARα stability and APL growth, apoptosis, or differentiation. RA treatment induced UBE1L, ISG15, and UBP43 expression in RA-sensitive but not RA-resistant APL cells. Similar in vivo findings were obtained in a transgenic mouse model of transplantable APL, and in the RA response of leukemic cells harvested directly from APL patients. UBP43 knockdown repressed PML/RARα protein levels and inhibited RA-sensitive or RA-resistant cell growth by destabilizing the PML domain of PML/RARα. This inhibitory effect promoted apoptosis but did not affect the RA differentiation response in these APL cells. In contrast, elevation of UBP43 expression stabilized PML/RARα protein and inhibited apoptosis. Taken together, our findings define the ubiquitin protease UBP43 as a novel candidate drug target for APL treatment. Cancer Res; 70(23); 9875–85. ©2010 AACR.
Plasma Micronutrients and the Acquisition and Clearance of Anal Human Papillomavirus Infection: The Hawaii HPV Cohort Study
Authors: Shvetsov Yurii B. , Hernandez Brenda Y. , Wilkens Lynne R. , Thompson Pamela J. , Franke Adrian A. , Zhu Xuemei , Goodman Marc T.
Published: October 2010

Anal human papillomavirus (HPV) infection is common among women and the cause of most anal malignancies. The incidence of anal cancer has been increasing among U.S. women, yet few cofactors for the natural history of anal HPV infection have been identified. We examined the hypothesis that plasma carotenoid, retinol, and tocopherol concentrations are associated with the acquisition and clearance of anal HPV infection in a cohort of 279 Hawaiian residents followed at 4-month intervals for a mean duration of 16 months. At each visit, interviews were conducted and biological specimens were obtained, including anal cell specimens for HPV DNA detection and genotyping, and a fasting blood sample to measure 27 micronutrients. Cohort participants acquired 189 anal HPV infections, 113 of which cleared during the study period. The most frequently acquired HPV genotypes were HPV-52, -53, -84, and -16. Women in the highest quartile of trans-zeaxanthin, trans -anhydro-lutein, and trans-, cis-, and total β-carotene had significant 43% to 50% reduction in the risk of acquisition of any HPV infection compared with women in the lowest quartile. Few associations were observed between micronutrient levels and clearance of transient (≤150 days) anal HPV infections. However, clearance of persistent (>150 days) infections was associated with higher levels of β-tocopherol + γ-tocopherol and lower levels of carotenoids and retinol. Our findings suggest that several carotenoids can reduce the risk and clearance of anal HPV infections that contribute to anal cancer. Cancer Res; 70(23); 9787–97. ©2010 AACR.
Definition of an Enhanced Immune Cell Therapy in Mice That Can Target Stem-Like Lymphoma Cells
Authors: Contag Christopher H. , Sikorski Rachel , Negrin Robert S. , Schmidt Tobi , Fan Alice C. , Bachireddy Pavan , Felsher Dean W. , Thorne Steve H.
Published: October 2010

Current treatments of high-grade lymphoma often have curative potential, but unfortunately many patients relapse and develop therapeutic resistance. Thus, there remains a need for novel therapeutics that can target the residual cancer cells whose phenotypes are distinct from the bulk tumor and that are capable of reforming tumors from very few cells. Oncolytic viruses offer an approach to destroy tumors by multiple mechanisms, but they cannot effectively reach residual disease or micrometastases, especially within the lymphatic system. To address these limitations, we have generated immune cells infected with oncolytic viruses as a therapeutic strategy that can combine effective cellular delivery with synergistic tumor killing. In this study, we tested this approach against minimal disease states of lymphomas characterized by the persistence of cancer cells that display stem cell–like properties and resistance to conventional therapies. We found that the immune cells were capable of trafficking to and targeting residual cancer cells. The combination biotherapy used prevented relapse by creating a long-term, disease-free state, with acquired immunity to the tumor functioning as an essential mediator of this effect. Immune components necessary for this acquired immunity were identified. We further demonstrated that the dual biotherapy could be applied before or after conventional therapy. Our approach offers a potentially powerful new way to clear residual cancer cells, showing how restoring immune surveillance is critical for maintenance of a disease-free state. Cancer Res; 70(23); 9837–45. ©2010 AACR.
Roles of Fibroblast Growth Factor Receptors in Carcinogenesis
Authors: Haugsten Ellen Margrethe , Wiedlocha Antoni , Olsnes Sjur , Wesche Jørgen
Published: October 2010

The fibroblast growth factor receptors (FGFR) play essential roles both during development and in the adult. Upon ligand binding, FGFRs induce intracellular signaling networks that tightly regulate key biological processes, such as cell proliferation, survival, migration, and differentiation. Deregulation of FGFR signaling can thus alter tissue homeostasis and has been associated with several developmental syndromes as well as with many types of cancer. In human cancer, FGFRs have been found to be deregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. In this review, we will give an overview of the main FGFR alterations described in human cancer to date and discuss their contribution to cancer progression. Mol Cancer Res; 8(11); 1439–52. ©2010 AACR.
Mutational and Functional Analysis Reveals ADAMTS18 Metalloproteinase as a Novel Driver in Melanoma
Authors: Wei Xiaomu , Prickett Todd D. , Viloria Cristina G. , Molinolo Alfredo , Lin Jimmy C. , Cardenas-Navia Isabel , Cruz Pedro , Rosenberg Steven A. , Davies Michael A. , Gershenwald Jeffrey E. , López-Otín Carlos , Samuels Yardena
Published: October 2010

The disintegrin-metalloproteinases with thrombospondin domains (ADAMTS) genes have been suggested to function as tumor suppressors as several have been found to be epigenetically silenced in various cancers. We performed a mutational analysis of the ADAMTS gene family in human melanoma and identified a large fraction of melanomas to harbor somatic mutations. To evaluate the functional consequences of the most commonly mutated gene, ADAMTS18, six of its mutations were biologically examined. ADAMTS18 mutations had little effect on melanoma cell growth under standard conditions, but reduced cell dependence on growth factors. ADAMTS18 mutations also reduced adhesion to laminin and increased migration in vitro and metastasis in vivo. Melanoma cells expressing mutant ADAMTS18 had reduced cell migration after short hairpin RNA–mediated knockdown of ADAMTS18, suggesting that ADAMTS18 mutations promote growth, migration, and metastasis in melanoma. Mol Cancer Res; 8(11); 1513–25. ©2010 AACR.
Long-Range Comparison between Genes and Languages Based on Syntactic Distances
Authors: Colonna Vincenza , Boattini Alessio , Guardiano Cristina , Dall’Ara Irene , Pettener Davide , Longobardi Giuseppe , Barbujani Guido
Published: October 2010

Objective: To propose a new approach for comparing genetic and linguistic diversity in populations belonging to distantly related groups. Background: Comparisons of linguistic and genetic differences have proved powerful tools to reconstruct human demographic history. Current models assume on both sides that similarities reflect either descent from common ancestry or the balance between isolation and contact. Most linguistic phylogenies are ultimately based on lexical evidence (roughly, words and morphemes with their sounds and meanings). However, measures of lexical divergence are reliable only for closely related languages, thus large-scale comparisons of genetic and linguistic diversity have appeared problematic so far. Methods: Syntax (abstract rules to combine words into sentences) appears more measurable, universally comparable, and stable than the lexicon, and hence certain syntactic similarities might reflect deeper linguistic relationships, such as those between distant language families. In this study, we for the first time compared genetic data to a matrix of syntactic differences among selected populations of three continents. Results: Comparing two databases of microsatellite (Short Tandem Repeat) markers and Single Nucleotides Polymorphisms (SNPs), with a linguistic matrix based on the values of 62 grammatical parameters, we show that there is indeed a correlation of syntactic and genetic distances. We also identified a few outliers and suggest a possible interpretation of the overall pattern. Conclusions: These results strongly support the possibility of better investigating population history by combining genetic data with linguistic information of a new type, provided by a theoretically more sophisticated method to assess the relationships between distantly related languages and language families.
Medical Prophylaxis following Hospitalization for Ischemic Stroke: Age- and Sex-Related Differences and Relation to Mortality
Authors: Palnum Kaare Haurvig , Mehnert Frank , Andersen Grethe , Ingeman Annette , Krog Birgitte Randrup , Bartels Paul Daniel , Johnsen Søren Paaske
Published: October 2010

Background: The extent and implications of age- and sex-related differences in prophylaxis following ischemic stroke are unknown. We examined differences in the use of medical prophylaxis across age and sex groups in stroke patients after hospital discharge in Denmark and estimated the possible impact on age- and sex-related differences in mortality. Methods: A nationwide population-based follow-up study was conducted involving 28,634 patients hospitalized for ischemic stroke in 2003–2006 who survived 30 days after discharge. The proportion of patients who filled prescriptions for cardiovascular drugs within 0–6 and 12–18 months after discharge was determined. Mortality rates were compared across age and sex groups with and without controlling for use of medical prophylaxis. Results: Increasing age was associated with lower prophylaxis. Adjusted odds ratios for the use of a combination of a platelet inhibitor, an antihypertensive and a statin were 0.45 [95% confidence interval (CI): 0.38–0.54] and 0.52 (95% CI: 0.43–0.62) for men and women >80 years, respectively, compared with men ≤65 years. No systematic sex-related differences were identified. Continued drug use ranged from 66.1 to 91.9% for different drugs 12–18 months after discharge, with the lowest rate of continued use found among patients >80 years. Controlling for use of medical prophylaxis was associated with lower mortality rate ratios for elderly compared with younger patients. Conclusions: Continuous efforts are warranted to ensure implementation of evidence-based secondary prophylaxis among elderly patients with ischemic stroke.
Older Age and Greater Carotid Intima-Media Thickness Predict Ischemic Events Associated with Carotid-Artery Stenting
Authors: Rosenkranz Michael , Thomalla Götz , Havemeister Stefanie , Wittkugel Oliver , Cheng Bastian , Krützelmann Anna , Fiehler Jens , Gerloff Christian
Published: October 2010

Background: Carotid-artery stenting (CAS) may be complicated by stroke. We aimed to determine predictors of procedure-related ischemic events. Methods: We analyzed new ischemic lesions in diffusion-weighted MRI (DWI) after CAS in 147 patients with symptomatic high-grade carotid stenosis. Nine covariates were assessed as potential risk factors for new lesions in DWI: age, gender, hypertension, diabetes, dyslipidemia, smoking status, severity of stenosis, side of intervention and carotid intima-media thickness (IMT). Results: From the nine covariates assessed, only age and IMT were independently associated with new DWI lesions. An age of 68 years and an IMT of 1.5 mm gave the best separation between high- and low-risk populations. The subgroup of patients <68 years who had an IMT ≤1.5 mm had the lowest rate of new DWI lesions (11.3%). This rate was greater in patients ≧68 years (30.0%; odds ratio, OR, 3.4; 95% confidence interval, CI, 1.1–10.8) and in patients with an IMT >1.5 mm (36.4%; OR 4.5; 95% CI 1.2–17.0) and was particularly high in patients aged ≧68 years with IMT >1.5 mm (69.6%; OR 18.0; 95% CI 4.8–71.9). Conclusions: Older age and greater IMT are independently associated with the risk of CAS-related ischemic events. This risk is particularly high in those patients in whom older age and greater IMT coincide.
International Survey on the Management of Acute Kidney Injury in Critically Ill Patients: Year 2007
Authors: Basso Flavio , Ricci Zaccaria , Cruz Dinna , Ronco Claudio
Published: October 2010

Introduction: Several aspects of acute kidney injury (AKI) management, including medical approaches to AKI patients and the optimal form of renal replacement therapy (RRT), remain a matter of debate. Subjects and Methods: The responses of 440 participants to a questionnaire on several points of AKI management, submitted during the 4th International Course on Critical Care Nephrology in June 2007, were analyzed. Results: The most common answer to the definition of AKI was the use of the RIFLE criteria (55%), followed by the presence of oligoanuria (24%). Responders seemed to preferentially start dialysis within a creatinine range from 2.3–3.4 mg/dl (28%) to 3.4–4.5 mg/dl (26%) and with a urine output level of 150–200 ml/12 h (43%). About 30% of responders showed that they would prescribe dialysis only in case of severe fluid overload (requiring mechanical ventilation and/or causing impaired skin integrity). Continuous RRT is used by most specialists (86%), followed by intermittent hemodialysis (65%), sustained low-efficiency dialysis (28%) and peritoneal dialysis (30%). The preferred RRT dosage was ‘35 ml/kg/h’ (46%) but 37% of responders did not explicitly answer this critical question. Bleeding, hypotension, filter clotting, vascular access and sepsis treatment were the most frequent complications and concerns of RRT. Conclusions: New classifications such as the RIFLE criteria did improve the well-known uncertainty about the definition of AKI. Awareness of the prescription and standardization of an adequate treatment dose seemed to have increased in recent years, even if there is still a significant level of uncertainty on this specific issue. Several concerns and RRT complications, such as bleeding and anticoagulation strategies, still need further exploration and development.