The Foot, Our Base of Support

The purpose of this independent study was to consolidate information on biomechanics of the foot and ankle and the possible effects on the rest of the body of faulty mechanics. A literature search and specialized continuing education contributed to improved working knowledge of the significance of variations of the normal biomechanics. The physical therapist relates to the patient through complaints of foot pain, or through foot evaluation to get to other sites of pain. A thorough evaluation process, shoe recommendations, stretching, and/or strengthening exercises, and orthotic evaluation are the results of study

Pentosan Polysulfate Decreases Myocardial Expression of the Extracellular Matrix Enzyme ADAMTS4 and Improves Cardiac Function In Vivo in Rats Subjected to Pressure Overload by Aortic Banding

Background: We hypothesized that cleavage of the extracellular matrix (ECM) proteoglycans versican and aggrecan by ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteases, which contributes to stress-induced ECM-reorganization in atherogenesis and osteoarthritis, also play a role in heart failure development. Objectives: The primary objective was to identify alterations in expression of ADAMTS versicanases and aggrecanases during development of heart failure, while evaluation of the effects of in vivo modulation of relevant changes in ADAMTS activity constituted the secondary objective. Methods: Myocardial levels of versican, aggrecan, and their ADAMTS cleaving proteases were examined in Wistar rats six weeks after aortic banding (AB), and versican and selected ADAMTS versicanases were further analyzed in neonatal cardiomyocytes (NCM) and cardiac fibroblasts (NFB) after stimulation by inflammatory mediators. Based on the initial findings, ADAMTS4 was selected the most promising therapeutic target. Thus, rats with AB were treated with pentosan polysulfate (PPS), a polysaccharide with known ADAMTS4-inhibitory properties, and effects on versican fragmentation, left ventricular function and geometry were evaluated. Results: We discovered that myocardial mRNA and protein levels of ADAMTS1 and -4, and mRNA levels of versican, aggrecan, and ADAMTS8 increased after AB, and TNF-α and IL-1β synergistically increased mRNA of versican and ADAMTS4 in NCM and NFB and secretion of ADAMTS4 from NCM. Furthermore, PPS-treatment improved systolic function, demonstrated by an improved fractional shortening (vehicle 48±3% versus PPS 60±1%, p<0.01) after AB. Following PPS-treatment, we observed an ∼80% reduction in myocardial ADAMTS4 mRNA (p = 0.03), and ∼50% reduction in the extracellular amount of the p150 versican fragments (p = 0.05), suggesting reduced versicanase activity. Conclusions: Our findings suggest that AB induces an increase in myocardial ADAMTS4 versicanase activity, and that PPS-treatment improved systolic function in the pressure-overloaded heart, holding promise as a novel therapeutic agent in heart failure

New Guinea Coccymys and "Melomys" albidens.

139 p. : ill. (some col.), maps ; 26 cm. "Issued December 9, 2009." Some specimens of Coccymys collected during the fourth Archbold Expedition to New Guinea (1953). Includes bibliographical references (p. 135-139).A new species of the New Guinea endemic murine genus Coccymys is described, based on a small sample from Mt. Dayman and Mt. Simpson in the Maneau Range at the far eastern end of the Owen Stanley Ranges of eastern Papua New Guinea, and two specimens from the western portion of the Owen Stanleys, one from Smith’s Gap near Mt. St. Mary, the other from Bulldog Road in the Wau area. Coccymys kirrhos, n. sp., is a vicariant relative of C. shawmayeri, which occurs in the Central Cordillera of Papua New Guinea extending from Mt. St. Mary in the east to the Telefomin region in the west. Coccymys shawmayeri in turn is the eastern montane vicariant of the western New Guinea C. ruemmleri, so far recorded only from the Snow Mountains in western New Guinea ‪(‬Papua Province of Indonesia‪)‬ and the eastern end of the Star Mountains over the border in the western section of Papua New Guinea. Coccymys ruemmleri and C. shawmayeri are regionally sympatric in western Papua New Guinea where the former is apparently restricted to high altitudes on the Star Mountains and the latter occurs at lower altitudes in the highlands bounding the Telefomin Valley. The ranges of C. shawmayeri and C. kirrhos, n. sp., overlap at the western section of the Owen Stanley Ranges, and both species have been caught at Bulldog Road, but in different years. This linearly distributed trio of species has been found only in the montane forests and alpine grasslands of the Central Cordillera--there are no records from mountains on Vogelkop Peninsula and the Huon Peninsula, nor from any of the north coast ranges. The new species is described within the context of rediagnosing the genus Coccymys, and documenting morphometric and geographic limits of C. ruemmleri and C. shawmayeri based on most specimens stored in collections of museums. This material consists primarily of museum study skins and accompanying skulls, some fluid-preserved specimens, skeletal fragments from modern samples of owl pellets, and Holocene and late Pleistocene fossils ‪(‬for C. ruemmleri only‪)‬. All species of Coccymys are nocturnal and scansorial; stomach contents from samples of C. shawmayeri indicate the diet consists of seeds, fruit, and arthropods. The taxon albidens is represented by six modern examples collected at 2800 m and 3225 m in 1938 from the northern slopes of the Snow Mountains of western New Guinea, and three late Pleistocene fossils obtained from the same region. The species was initially described as a Melomys ‪(‬Tate, 1951‪)‬; later an alliance with Coccymys was suggested ‪(‬Flannery, 1990; Menzies, 1990; Musser and Carleton, 1993‪)‬, but restudy of anatomical traits ‪(‬derived solely from stuffed skins with accompany‪[‬y‪]‬ing skulls‪)‬ reveals a degree of morphological divergence not only from species in Coccymys but from any other ‪"‬Old Endemic‪"‬ New Guinea murine. A new genus, Brassomys, sampled by only six modern specimens and three late Pleistocene fossils, is proposed to embrace albidens. Morphological attributes of that species are contrasted primarily with those characterizing Coccymys, and secondarily with the genera Melomys, Paramelomys, Mammelomys, Protochromys, Abeomelomys, and Pogonomelomys. Biological aspects of albidens are unknown; however, particular external, cranial, and dental traits in combination strongly suggest the species is a nocturnal, arboreal/scansorial invertebrate predator

Secretoneurin Is an Endogenous Calcium/Calmodulin-Dependent Protein Kinase II Inhibitor That Attenuates Ca2+-Dependent Arrhythmia

BACKGROUND: Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKII delta (Ca2+/calmodulin-dependent protein kinase II delta) activity, we hypothesized that upregulation of SN in patients protects against cardiomyocyte mechanisms of arrhythmia. METHODS: Circulating levels of SN and other biomarkers were assessed in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; n=8) and in resuscitated patients after ventricular arrhythmia-induced cardiac arrest (n=155). In vivo effects of SN were investigated in CPVT mice (RyR2 [ryanodine receptor 2]-R2474S) using adeno-associated virus-9-induced overexpression. Interactions between SN and CaMKII delta were mapped using pull-down experiments, mutagenesis, ELISA, and structural homology modeling. Ex vivo actions were tested in Langendorff hearts and effects on Ca2+ homeostasis examined by fluorescence (fluo-4) and patchclamp recordings in isolated cardiomyocytes. RESULTS: SN levels were elevated in patients with CPVT and following ventricular arrhythmia-induced cardiac arrest. In contrast to NT-proBNP (N-terminal proB- type natriuretic peptide) and hs-TnT (high-sensitivity troponin T), circulating SN levels declined after resuscitation, as the risk of a new arrhythmia waned. Myocardial pro-SN expression was also increased in CPVT mice, and further adeno-associated virus-9-induced overexpression of SN attenuated arrhythmic induction during stress testing with isoproterenol. Mechanistic studies mapped SN binding to the substrate binding site in the catalytic region of CaMKII delta. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKII delta in Langendorff hearts and inhibited CaMKII delta-dependent RyR phosphorylation. In line with CaMKII delta and RyR inhibition, SN treatment decreased Ca2+ spark frequency and dimensions in cardiomyocytes during isoproterenol challenge, and reduced the incidence of Ca2+ waves, delayed afterdepolarizations, and spontaneous action potentials. SN treatment also lowered the incidence of early afterdepolarizations during isoproterenol; an effect paralleled by reduced magnitude of L-type Ca2+ current. CONCLUSIONS: SN production is upregulated in conditions with cardiomyocyte Ca2+ dysregulation and offers compensatory protection against cardiomyocyte mechanisms of arrhythmia, which may underlie its putative use as a biomarker in at-risk patients.Peer reviewe

Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress

Pressure overload activates cardiac fibroblasts leading to excessive production of extracellular matrix which may contribute to compromised heart function. The activated fibroblast acquires smooth muscle-like features such as expression of smooth muscle alpha-actin (SMA) and SM22 and is therefore referred to as myofibroblast. The molecular mechanisms underlying mechanical stress-induced myofibroblast differentiation are poorly defined. The objective of this study was to examine the potential roles of the transmembrane proteoglycan syndecan-4 and the calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) in myofibroblast differentiation. Aortic banding resulted in elevated collagen land III, fibronectin, SMA and SM22 mRNA in the left ventricles of wild-type mice, whereas this response was markedly reduced in syndecan-4(-/-) mice. Myofibroblast differentiation in vitro was associated with increased SMA, collagen I and III expression and NFAT-luciferase activity, all of which were reduced in fibroblasts from syndecan-4(-/-) mice or after treatment with calcineurin/NFAT blockers. Following cyclic stretch, NFATc4 was activated in cardiac fibroblasts in a syndecan-4- and calcineurin-dependent manner. Syndecan-4 and calcineurin co-localized and mechanical stress resulted in dephosphorylation of serine179 of syndecan-4, an intracellular residue critical for calcineurin interaction. Over-expression of NFATc4 up-regulated collagen III, MRTF-A (a transcriptional regulator of SMA) and the NFAT-target regulator of calcineurin 1.4 (RCAN1.4). Our data demonstrate that syndecan-4 is important for the differentiation of cardiac fibroblasts into myofibroblasts in the pressure-overloaded heart and that the calcineurin/NFAT pathway is engaged upon mechanical stress in a syndecan-4-dependent manner, playing an active role in myofibroblast differentiation and extracellular matrix production. This article is part of a Special Issue entitled 'Possible Editorial'. (c) 2012 Elsevier Ltd. All rights reserved

Review of Leptomys

60 p. : ill. (some col.), maps ; 26 cm.Includes bibliographical references (p. 56-60).Two new species of the endemic New Guinea rodent genus Leptomys Thomas, 1897, are described: L. paulus, indigenous to the montane forests in the Owen Stanley Range in eastern New Guinea, and L. arfakensis, known only from the Arfak Mountains on the Vogelkop Peninsula in western New Guinea. These descriptions are presented within a taxonomic review of Leptomys based on all known specimens in collections of the world's museums. In addition to the new species, the morphological attributes and geographic distributions of three others are documented. Leptomys elegans occurs in southcentral and southeastern New Guinea both north and south of the Central Cordillera, ranging from the Kikori River Basin in the west to the southern slopes of the Owen Stanley Range, then extending round to the north side of the Cordillera in the Maneau Range, and in the outlying highland block of Mount Victory. Leptomys signatus is recorded only from the Fly and Kikori River drainages south of the Central Cordillera. Leptomys ernstmayri is found in montane forests of the eastern Central Cordillera (Aroa River to Mt. Karimui), reaches to the outlying mountains on the Huon Peninsula and the Adelbert Range, and also occurs in the isolated Foja Mountains of far western New Guinea. Judged by variation in qualitative and morphometric external, cranial, and dental traits associated with available samples, L. arfakensis, n. sp., is likely more closely related to L. elegans and L. signatus, all with large bodies and relatively short tails, than to L. ernstmayri and L. paulus, n. sp., that are characterized, among other features, by smaller body size and relatively longer tails. There is significant phenetic divergence among the geographic samples identified here as L. ernstmayri, and additional inquiry, especially utilizing data from molecular sources, is required to determine whether this intersample variation reflects the presence of separate species, each endemic to the Huon Peninsula, Adelbert Range, Central Cordillera, and possibly the Foja Mountains, or instead represents montane variation within a single morphologically variable species