bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of nitric oxide scavenging in vascular response to cell-free hemoglobin transfusion
Authors: Sampei Kenji , Ulatowski John A. , Asano Yoshio , Kwansa Herman , Bucci Enrico , Koehler Raymond C.
Published: May 2005

Modified Hb solutions have been developed as O2 carrier transfusion fluids, but of concern is the possibility that increased scavenging of nitric oxide (NO) within the plasma will alter vascular reactivity even if the Hb does not readily extravasate. The effect of decreasing hematocrit from ∼30% to 18% by an exchange transfusion of a 6% sebacyl cross-linked tetrameric Hb solution on the diameter of pial arterioles possessing tight endothelial junctions was examined through a cranial window in anesthetized cats with and without a NO synthase (NOS) inhibitor. Superfusion of a NOS inhibitor decreased diameter, and subsequent Hb transfusion produced additional constriction that was not different from Hb transfusion alone but was different from the dilation observed by exchange transfusion of an albumin solution after NOS inhibition. In contrast, abluminal application of the cross-linked Hb produced constriction that was attenuated by the NOS inhibitor. Neither abluminal nor intraluminal cross-linked Hb interfered with pial arteriolar dilation to cromakalim, an activator of ATP-sensitive potassium channels. Pial vascular reactivity to hypocapnia and hypercapnia was unaffected by Hb transfusion. Microsphere-determined regional blood flow indicated selective decreases in perfusion after Hb transfusion in the kidney, small intestine, and neurohypophysis, which does not have tight endothelial junctions. Administration of a NOS inhibitor to reduce the basal level of NO available for scavenging before Hb transfusion prevented further decreases in blood flow to these regions compared with NOS inhibition alone. In contrast, blood flow to skeletal and left ventricular muscle increased, and cerebral blood flow was unchanged after Hb transfusion. This cross-linked Hb tetramer is known to appear in renal lymph but not in urine. We conclude that cell-free tetrameric Hb does not scavenge sufficient NO in the plasma space to significantly affect baseline tone in vascular beds with tight endothelial junctions but does produce substantial constriction in beds with porous endothelium. The data support increasing the molecular size of Hb by polymerization or conjugation to limit extravasation in all vascular beds to preserve normal vascular reactivity.
Effects of hyperthyroidism on delayed rectifier K+ currents in left and right murine atria
Authors: Hu Ying , Jones S. V. Penelope , Dillmann Wolfgang H.
Published: May 2005

Hyperthyroidism has been associated with atrial fibrillation (AF); however, hyperthyroidism-induced ion channel changes that may predispose to AF have not been fully elucidated. To understand the electrophysiological changes that occur in left and right atria with hyperthyroidism, the patch-clamp technique was used to compare action potential duration (APD) and whole cell currents in myocytes from left and right atria from both control and hyperthyroid mice. Additionally, RNase protection assays and immunoblotting were performed to evaluate the mRNA and protein expression levels of K+ channel α-subunits in left and right atria. The results showed that 1) in control mice, the APD was shorter and the ultra-rapid delayed rectifier K+ conductance ( IKur) and the sustained delayed rectifier K+ conductance ( Iss) were larger in the left than in the right atrium; also, mRNA and protein expression levels of Kv1.5 and Kv2.1 were higher in the left atrium; 2) in hyperthyroid mice, the APD was shortened and IKur and Iss were increased in both left and right atrial myocytes, and the protein expression levels of Kv1.5 and Kv2.1 were increased significantly in both atria; and 3) the influence of hyperthyroidism on APD and delayed rectifier K+ currents was more prominent in right than in left atrium, which minimized the interatrial APD difference. In conclusion, hyperthyroidism resulted in more significant APD shortening and greater delayed rectifier K+ current increases in the right vs. the left atrium, which can contribute to the propensity for atrial arrhythmia in hyperthyroid heart.
PKC-ε-dependent survival signals in diabetic hearts
Authors: Malhotra Ashwani , Begley Rebecca , Kang Barinder P. S. , Rana Irmindra , Liu Jing , Yang Guiping , Mochly-Rosen Daria , Meggs Leonard G.
Published: May 2005

Diabetes mellitus is complicated by the development of a primary cardiomyopathy, which contributes to the excess morbidity and mortality of this disorder. The protein kinase C (PKC) family of isozymes plays a key role in the cardiac phenotype expressed during postnatal development and in response to pathological stimuli. Hyperglycemia is an activating signal for cardiac PKC isozymes that modulate a myriad of cell events including cell death and survival. The ε-isozyme of the PKC family transmits a powerful survival signal in cardiac muscle cells. Accordingly, to test the hypothesis that endogenous activation of cardiac PKC-ε will protect against hyperglycemic cell injury and left ventricular dysfunction, diabetes mellitus was induced using streptozotocin in genetically engineered mice with cardiac-specific expression of the PKC-ε translocation activator [ψε-receptors for activated C kinase (ψε-RACK)]. The results demonstrate a striking PKC-ε cardioprotective phenotype in diabetic ψε-RACK (ε-agonist) mice that is characterized by inhibition of the hyperglycemia apoptosis signal, attenuation of hyperglycemia-mediated oxidative stress, and preservation of parameters of left ventricular pump function. Hearts of diabetic ε-agonist mice exhibited selective trafficking of PKC-ε to membrane and mitochondrial compartments, phosphorylation/inactivation of the mitochondrial Bad protein, and inhibition of cytochrome c release. We conclude that activation of endogenous PKC-ε in hearts of diabetic ε-agonist mice promotes the survival phenotype, attenuates markers of oxidative stress, and inhibits the negative inotropic properties of chronic hyperglycemia.
Circadian periodicity of cerebral blood flow revealed by laser-Doppler flowmetry in awake rats: relation to blood pressure and activity
Authors: Wauschkuhn C. A. , Witte K. , Gorbey S. , Lemmer B. , Schilling L.
Published: May 2005

Cardiovascular parameters such as arterial blood pressure (ABP) and heart rate display pronounced circadian variation. The present study was performed to detect whether there is a circadian periodicity in the regulation of cerebral perfusion. Normotensive Sprague-Dawley rats (SDR, ∼15 wk old) and hypertensive (mREN2)27 transgenic rats (TGR, ∼12 wk old) were instrumented in the abdominal aorta with a blood pressure sensor coupled to a telemetry system for continuous recording of ABP, heart rate, and locomotor activity. After 5–12 days, a laser-Doppler flow (LDF) probe was attached to the skull by means of a guiding device to measure changes in brain cortical blood flow (CBF). After the animals recovered from anesthesia, measurements were taken for 3–4 days. The time series were analyzed with respect to the midline estimating statistic of rhythm (i.e., mean value of a periodic event after fit to a cosine function), amplitude, and acrophase (i.e., phase angle that corresponds to the peak of a given period) of the 24-h period. The LDF signal displayed a significant circadian rhythm, with the peak occurring at around midnight in SDR and TGR, despite inverse periodicity of ABP in TGR. This finding suggests independence of LDF periodicity from ABP regulation. Furthermore, the acrophase of the LDF was consistently found before the acrophase of the activity. From the present data, it is concluded that there is a circadian periodicity in the regulation of cerebral perfusion that is independent of circadian changes in ABP and probably is also independent of locomotor activity. The presence of a circadian periodicity in CBF may have implications for the occurrence of diurnal alterations in cerebrovascular events in humans.
Modeling the oscillation dynamics of activated airway smooth muscle strips
Authors: Bates Jason H. T. , Lauzon Anne-Marie
Published: May 2005

When strips of activated airway smooth muscle are stretched cyclically, they exhibit force-length loops that vary substantially in both position and shape with the amplitude and frequency of the stretch. This behavior has recently been ascribed to a dynamic interaction between the imposed stretch and the number of actin-myosin interactions in the muscle. However, it is well known that the passive rheological properties of smooth muscle have a major influence on its mechanical properties. We therefore hypothesized that these rheological properties play a significant role in the force-length dynamics of activated smooth muscle. To test the plausibility of this hypothesis, we developed a model of the smooth muscle strip consisting of a force generator in series with an elastic component. Realistic steady-state force-length loops are predicted by the model when the force generator obeys a hyperbolic force-velocity relationship, the series elastic component is highly nonlinear, and both elastic stiffness and force generation are adjusted so that peak loop force equals isometric force. We conclude that the dynamic behavior of airway smooth muscle can be ascribed in large part to an interaction between connective tissue rheology and the force-velocity behavior of contractile proteins.
Metabolism and thermoregulation during fasting in king penguins,Aptenodytes patagonicus,in air and water
Authors: Fahlman A. , Schmidt A. , Handrich Y. , Woakes A. J. , Butler P. J.
Published: May 2005

We measured oxygen consumption rate (V̇o2) and body temperatures in 10 king penguins in air and water. V̇o2was measured during rest and at submaximal and maximal exercise before (fed) and after (fasted) an average fasting duration of 14.4 ± 2.3 days (mean ± 1 SD, range 10–19 days) in air and water. Concurrently, we measured subcutaneous temperature and temperature of the upper (heart and liver), middle (stomach) and lower (intestine) abdomen. The mean body mass (Mb) was 13.8 ± 1.2 kg in fed and 11.0 ± 0.6 kg in fasted birds. After fasting, resting V̇o2was 93% higher in water than in air (air: 86.9 ± 8.8 ml/min; water: 167.3 ± 36.7 ml/min, P < 0.01), while there was no difference in resting V̇o2between air and water in fed animals (air: 117.1 ± 20.0 ml O2/min; water: 114.8 ± 32.7 ml O2/min, P > 0.6). In air, V̇o2decreased with Mb, while it increased with Mbin water. Body temperature did not change with fasting in air, whereas in water, there were complex changes in the peripheral body temperatures. These latter changes may, therefore, be indicative of a loss in body insulation and of variations in peripheral perfusion. Four animals were given a single meal after fasting and the temperature changes were partly reversed 24 h after refeeding in all body regions except the subcutaneous, indicating a rapid reversal to a prefasting state where body heat loss is minimal. The data emphasize the importance in considering nutritional status when studying king penguins and that the fasting-related physiological changes diverge in air and water.
Age-specific changes in the regulation of LH-dependent testosterone secretion: assessing responsiveness to varying endogenous gonadotropin output in normal men
Authors: Liu Peter Y. , Takahashi Paul Y. , Roebuck Pamela D. , Iranmanesh Ali , Veldhuis Johannes D.
Published: May 2005

Pulsatile and thus total testosterone (Te) secretion declines in older men, albeit for unknown reasons. Analytical models forecast that aging may reduce the capability of endogenous luteinizing hormone (LH) pulses to stimulate Leydig cell steroidogenesis. This notion has been difficult to test experimentally. The present study used graded doses of a selective gonadotropin releasing hormone (GnRH)-receptor antagonist to yield four distinct strata of pulsatile LH release in each of 18 healthy men ages 23–72 yr. Deconvolution analysis was applied to frequently sampled LH and Te concentration time series to quantitate pulsatile Te secretion over a 16-h interval. Log-linear regression was used to relate pulsatile LH secretion to attendant pulsatile Te secretion (LH-Te drive) across the four stepwise interventions in each subject. Linear regression of the 18 individual estimates of LH-Te feedforward dose-response slopes on age disclosed a strongly negative relationship ( r = −0.721, P < 0.001). Accordingly, the present data support the thesis that aging in healthy men attenuates amplitude-dependent LH drive of burst-like Te secretion. The experimental strategy of graded suppression of neuroglandular outflow may have utility in estimating dose-response adaptations in other endocrine systems.
Short-term stress experienced at time of immunization induces a long-lasting increase in immunologic memory
Authors: Dhabhar Firdaus S. , Viswanathan Kavitha
Published: May 2005

It would be extremely beneficial if one could harness natural, endogenous, health-promoting defense mechanisms to fight disease and restore health. The psychophysiological stress response is the most underappreciated of nature's survival mechanisms. We show that acute stress experienced before primary immunization induces a long-lasting increase in immunity. Compared with controls, mice restrained for 2.5 h before primary immunization with keyhole limpet hemocyanin (KLH) show a significantly enhanced immune response when reexposed to KLH 9 mo later. This immunoenhancement is mediated by an increase in numbers of memory and effector helper T cells in sentinel lymph nodes at the time of primary immunization. Further analyses show that the early stress-induced increase in T cell memory may stimulate the robust increase in infiltrating lymphocyte and macrophage numbers observed months later at a novel site of antigen reexposure. Enhanced leukocyte infiltration may be driven by increased levels of the type 1 cytokines, IL-2 and IFN-γ, and TNF-α, observed at the site of antigen reexposure in animals that had been stressed at the time of primary immunization. In contrast, no differences were observed in type 2 cytokines, IL-4 or IL-5. Given the importance of inducing long-lasting increases in immunologic memory during vaccination, we suggest that the neuroendocrine stress response is nature's adjuvant that could be psychologically and/or pharmacologically manipulated to safely increase vaccine efficacy. These studies introduce the novel concept that a psychophysiological stress response is nature's fundamental survival mechanism that could be therapeutically harnessed to augment immune function during vaccination, wound healing, or infection.
Temporal dynamics of late-night photic stimulation of the human circadian timing system
Authors: Zeitzer Jamie M. , Khalsa Sat Bir S. , Boivin Diane B. , Duffy Jeanne F. , Shanahan Theresa L. , Kronauer Richard E. , Czeisler Charles A.
Published: May 2005

The light-dark cycle is the primary synchronizing factor that keeps the internal circadian pacemaker appropriately aligned with the environmental 24-h day. Although it is known that ocular light exposure can effectively shift the human circadian pacemaker and do so in an intensity-dependent manner, the curve that describes the relationship between light intensity and pacemaker response has not been fully characterized for light exposure in the late biological night. We exposed subjects to 3 consecutive days of 5 h of experimental light, centered 1.5 h after the timing of the fitted minimum of core body temperature, and show that such light can phase advance shift the human circadian pacemaker in an intensity-dependent manner, with a logistic model best describing the relationship between light intensity and phase shift. A similar sigmoidal relationship is also observed between light intensity and the suppression of plasma melatonin concentrations that occurs during the experimental light exposure. As with a simpler, 1-day light exposure during the early biological night, our data indicate that the human circadian pacemaker is highly sensitive even to typical room light intensities during the late biological night, with ∼100 lux evoking half of the effects observed with light 10 times as bright.
Calcium/calmodulin-dependent kinase II mediates critical components of the hypoxic ventilatory response within the nucleus of the solitary tract in adult rats
Authors: Reeves Stephen R. , Carter Edwin S. , Guo Shang Z. , Gozal David
Published: May 2005

Calcium/calmodulin-dependent kinase II (CaMKII) is an ubiquitous second messenger that is highly expressed in neurons, where it has been implicated in some of the pathways regulating neuronal discharge as well as N-methyl-d-aspartate receptor-mediated synaptic plasticity. The full expression of the mammalian hypoxic ventilatory response (HVR) requires intact central relays within the nucleus of the solitary tract (NTS), and neural transmission of hypoxic afferent input is mediated by glutamatergic receptor activity, primarily through N-methyl-d-aspartate receptors. To examine the functional role of CaMKII in HVR, KN-93, a highly selective antagonist of CaMKII, was microinjected in the NTS via bilaterally placed osmotic pumps in freely behaving adult male Sprague-Dawley rats for 3 days. Vehicle-loaded osmotic pumps were surgically placed in control animals, and adequate placement of cannulas was ascertained for all animals. HVR was measured using whole body plethysmography during exposure to 10% O2-balance N2 for 20 min. Compared with control rats, KN-93 administration elicited marked attenuations of peak HVR (pHVR) but did not modify normoxic minute ventilation. Differences in pHVR were primarily attributable to diminished respiratory frequency recruitments during pHVR without significant differences in tidal volume. These findings indicate that CaMKII activation in the NTS mediates respiratory frequency components of the ventilatory response to acute hypoxia; however, CaMKII activity does not appear to underlie components of normoxic ventilation.
Genetic and physiological insights into the metabolic syndrome
Authors: Hegele Robert A. , Pollex Rebecca L.
Published: May 2005

The metabolic syndrome (MetS) is a common phenotype that is clinically defined by threshold values applied to measures of central obesity, dysglycemia, dyslipidemia, and/or elevated blood pressure, which must be present concurrently in any one of a variety of combinations. Insulin resistance, although not a defining component of the MetS, is nonetheless considered to be a core feature. MetS is important because it is rapidly growing in prevalence and is strongly related to the development of cardiovascular disease. To define etiology, pathogenesis and expression of MetS, we have studied patients, specifically Canadian families and communities. One example is familial partial lipodystrophy (FPLD), a rare monogenic form of insulin resistance caused by mutations in either LMNA, encoding nuclear lamin A/C (subtype FPLD2), or in PPARG, encoding peroxisomal proliferator-activated receptor-γ (subtype FPLD3). Because it evolves slowly and recapitulates key clinical and biochemical attributes, FPLD seems to be a useful monogenic model of MetS. A second example is the disparate MetS prevalence between two Canadian aboriginal groups that is mirrored by disparate prevalence of diabetes and cardiovascular disease. Careful phenotypic evaluation of such special cases of human MetS by using a wide range of diagnostic methods, an approach called “phenomics,” may help uncover early presymptomatic disease biomarkers, which in turn might reveal new pathways and targets for interventions for MetS, diabetes, and atherosclerosis.
Differentiation of C2C12myoblasts is critically regulated by FAK signaling
Authors: Clemente Carolina F. M. Z. , Corat Marcus A. F. , Saad Sara T. O. , Franchini Kleber G.
Published: May 2005

This study examined whether focal adhesion kinase (FAK) plays a role in the differentiation of C2C12myoblasts into myotubes. Differentiation of C2C12myoblasts induced by switch to differentiation culture medium was accompanied by a transient reduction of FAK phosphorylation at Tyr-397 (to ∼50%, at 1 and 2 h), followed by an increase thereafter (to 240% up to 5 days), although FAK protein expression remained unchanged. FAK and phosphorylated FAK were found at the edge of lamellipodia in proliferating cells, whereas the later increase in FAK phosphorylation in differentiating cells was accompanied by its preferential location at the tip of well-organized actin stress fibers. Hyperexpression of FAK autophosphorylation site (Tyr-397) mutant (MT-FAK) reduced FAK phosphorylation at Tyr-397 in proliferating cells and was accompanied by reduction of cyclin D1 and increase of myogenin expression. These cells failed to progress to myotubes in differentiation medium. In contrast, hyperexpression of a wild-type FAK construction (WT-FAK) increased baseline and abolished the transient reduction of FAK phosphorylation at Tyr-397 in serum-starved C2C12cells. Cells transfected with WT-FAK failed to reduce cyclin D1 and to increase myogenin expression, as well as to progress to terminal differentiation in differentiation medium. These data indicate that FAK signaling plays a critical role in the control of cell cycle as well as in the progression of C2C12cells to terminal differentiation. Transient inhibition of FAK phosphorylation at Tyr-397 contributes to trigger the myogenic genetic program, but its later activation is also central to terminal differentiation into myotubes.
Angiotensin II and nitric oxide in neural control of intrarenal blood flow
Authors: Rajapakse Niwanthi W. , Sampson Amanda K. , Eppel Gabriela A. , Evans Roger G.
Published: May 2005

We investigated the roles of the renin-angiotensin system and the significance of interactions between angiotensin II and nitric oxide, in responses of regional kidney perfusion to electrical renal nerve stimulation (RNS) in pentobarbital sodium-anesthetized rabbits. Under control conditions, RNS (0.5–8 Hz) reduced total renal blood flow (RBF; −89 ± 3% at 8 Hz) and cortical perfusion (CBF; −90 ± 2% at 8 Hz) more than medullary perfusion (MBF; −55 ± 5% at 8 Hz). Angiotensin II type 1 (AT1)-receptor antagonism (candesartan) blunted RNS-induced reductions in RBF ( P = 0.03), CBF ( P = 0.007), and MBF ( P = 0.04), particularly at 4 and 8 Hz. Nitric oxide synthase inhibition with NG-nitro-l-arginine (l-NNA) enhanced RBF ( P = 0.003), CBF ( P = 0.001), and MBF ( P = 0.03) responses to RNS, particularly at frequencies of 2 Hz and less. After candesartan pretreatment, l-NNA significantly enhanced RNS-induced reductions in RBF ( P = 0.04) and CBF ( P = 0.007) but not MBF ( P = 0.66). Renal arterial infusion of angiotensin II (5 ng·kg−1·min−1) selectively enhanced responses of MBF to RNS in l-NNA-pretreated but not in vehicle-pretreated rabbits. In contrast, greater doses of angiotensin II (5–15 ng·kg−1·min−1) blunted responses of MBF to RNS in rabbits with intact nitric oxide synthase. These results suggest that endogenous angiotensin II enhances, whereas nitric oxide blunts, neurally mediated vasoconstriction in the renal cortical and medullary circulations. In the renal medulla, but not the cortex, angiotensin II also appears to be able to blunt neurally mediated vasoconstriction.
Ionizing radiation alters myofilament calcium sensitivity in vascular smooth muscle: potential role of protein kinase C
Authors: Soloviev Anatoly I. , Tishkin Sergey M. , Zelensky Sergey N. , Ivanova Irina V. , Kizub Igor V. , Pavlova Alexandra A. , Moreland Robert S.
Published: May 2005

Radiation exposure increases vascular responsiveness, and this change involves endothelial damage, as well as direct effects on vascular smooth muscle. In this study, we tested the hypothesis that myofilament Ca2+sensitivity in vascular smooth muscle is increased from single whole body gamma irradiation (6 Gy). We measured contractile responses from intact and permeabilized rat thoracic aortic rings combined with cytosolic Ca2+([Ca2+]i) measurements. The sensitivity to KCl and phenylephrine increased significantly in tissues from animals on the 9th and 30th days postirradiation compared with control. Irradiation also significantly increased Ca2+sensitivity in β-escin permeabilized smooth muscle on the 9th and 30th days postirradiation. Inhibitors of protein kinase C, chelerythrine, and staurosporine, had no effect on the pCa-tension curves in control permeabilized tissues but significantly decreased Ca2+sensitivity in permeabilized tissues on the 9th and 30th days postirradiation. Phorbol dibutyrate (PDBu, 10−7M) increased Ca2+sensitivity in control skinned smooth muscle but was without effect in irradiated vascular rings. Simultaneous measurement of contractile force and [Ca2+]ishowed that myofilament Ca2+sensitivity defined as the ratio of force change to [Ca2+]isignificantly increased following γ-irradiation. PDBu (10−6M) stimulation of intact aorta produced a sustained contraction, while the increase in [Ca2+]iwas transient. In irradiated tissues, PDBu-induced contractions were greater than those seen in control tissues but there was no elevation in [Ca2+]i. Taken together, these data strongly support the hypothesis that irradiation increases the sensitivity of vascular smooth muscle myofilaments to Ca2+and this effect is dependent on activation of protein kinase C.
ACTH, α-MSH, and control of cortisol release: cloning, sequencing, and functional expression of the melanocortin-2 and melanocortin-5 receptor in Cyprinus carpio
Authors: Metz Juriaan R. , Geven Edwin J. W. , van den Burg Erwin H. , Flik Gert
Published: May 2005

Cortisol release from fish head kidney during the acute phase of the stress response is controlled by the adrenocorticotropic hormone (ACTH) from the pituitary pars distalis (PD). Alpha-melanocyte-stimulating hormone (α-MSH) and β-endorphin, from the pars intermedia (PI), have been implicated in cortisol release during the chronic phase. The present study addresses the regulation of cortisol release by ACTH and α-MSH in common carp ( Cyprinus carpio) and includes characterization of their receptors, namely, the melanocortin-2 and melanocortin-5 receptors (MC2R and MC5R). We could not demonstrate corticotropic activity of α-MSH, β-endorphin, and combinations of these. We do show a corticotrope in the PI, but its identity is as yet uncertain. Carp restrained for 1 and 7 days showed elevated plasma cortisol and α-MSH levels; cortisol is still elevated but lower at day 7 than day 1 of restraint. Interrenal response capacity is unaffected, as estimated by stimulation with a maximum dose ACTH in a superfusion setup. MC2R and MC5R appear phylogenetically well conserved. MC2R is predominantly expressed in head kidney; a low abundance was found in spleen and kidney. MC5R is expressed in brain, pituitary PD, kidney, and skin. Quantitative PCR analysis of MC2R and MC5R expression in the head kidney of restrained fish reveals MC2R mRNA downregulation after 7 days restraint, in line with lower plasma cortisol levels seen. We discuss regulation of corticosteroid production from a phylogenetic perspective. We propose that increased levels of α-MSH exert a positive feedback on hypothalamic corticotropin-releasing hormone release to sustain a mild stress axis activity.
Dose-response relationship of endurance training for autonomic circulatory control in healthy seniors
Authors: Okazaki Kazunobu , Iwasaki Ken-ichi , Prasad Anand , Palmer M. Dean , Martini Emily R. , Fu Qi , Arbab-Zadeh Armin , Zhang Rong , Levine Benjamin D.
Published: May 2005

Aging results in marked abnormalities of cardiovascular regulation. Regular exercise can improve many of these age-related abnormalities. However, it remains unclear how much exercise is optimal to achieve this improvement or whether the elderly can ever improve autonomic control by exercise training to a degree similar to that observed in healthy young individuals. Ten healthy sedentary seniors [71 ± 3 (SD) yr] trained for 12 mo; training involved progressive increases in volume and intensity. Static hemodynamics were measured, and R-wave-R-wave interval (RRI), beat-to-beat blood pressure (BP) variability, and transfer function gain between systolic BP and RRI were calculated at baseline and every 3 mo during training. Data were compared with those obtained in 12 Masters athletes (68 ± 3 yr) and 11 healthy sedentary young individuals (29 ± 6 yr) at baseline. Additionally, the adaptation of these variables after completion of identical training loads was compared between the seniors and the young. Indexes of RRI variability and baroreflex gain were decreased in the sedentary seniors but preserved in the Masters athletes compared with the young at baseline. With training in the seniors, baroreflex gain and resting BP showed a peak adaptation after moderate doses of training following 3–6 mo. Indexes of RRI variability continued to improve with increasing doses of training and increased to the same magnitude as the young at baseline after heavy doses of training for 12 mo; however, baroreflex gain never achieved values equivalent to the young at baseline, even after a year of training. The magnitude of the adaptation of these variables to identical training loads was similar (no interaction effects of age × training) between the seniors and the young. Thus RRI variability in seniors improves with increasing “dose” of exercise over 1 yr of training. In contrast, more moderate doses of training for 3–6 mo may optimally improve baroreflex sensitivity, associated with a modest hypotensive effect; however, higher doses of training do not lead to greater enhancement of these changes. Seniors retain a similar degree of “trainability” as young subjects for cardiac autonomic function to dynamic exercise.
Marching to the beat of the same drummer: the spontaneous tempo of human locomotion
Authors: MacDougall Hamish G. , Moore Steven T.
Published: May 2005

Laboratory studies have suggested that the preferred cadence of walking is ∼120 steps/min, and the vertical acceleration of the head exhibits a dominant peak at this step frequency (2 Hz). These studies have been limited to short periods of walking along a predetermined path or on a treadmill, and whether such a highly tuned frequency of movement can be generalized to all forms of locomotion in a natural setting is unknown. The aim of this study was to determine whether humans exhibit a preferred cadence during extended periods of uninhibited locomotor activity and whether this step frequency is consistent with that observed in laboratory studies. Head linear acceleration was measured over a 10-h period in 20 subjects during the course of a day, which encompassed a broad range of locomotor (walking, running, cycling) and nonlocomotor (working at a desk, driving a car, riding a bus or subway) activities. Here we show a highly tuned resonant frequency of human locomotion at 2 Hz (SD 0.13) with no evidence of correlation with gender, age, height, weight, or body mass index. This frequency did not differ significantly from the preferred step frequency observed in the seminal laboratory study of Murray et al. (Murray MP, Drought AB, and Kory RC. J Bone Joint Surg 46A: 335–360, 1964). [1.95 Hz (SD 0.19)]. On the basis of the frequency characteristics of otolith-spinal reflexes, which drive lower body movement via the lateral vestibulospinal tract, and otolith-mediated collic and ocular reflexes that maintain gaze when walking, we speculate that this spontaneous tempo of locomotion represents some form of central “resonant frequency” of human movement.
Effects of prior heavy-intensity exercise during single-leg knee extension on v̇o2 kinetics and limb blood flow
Authors: Paterson Nicole D. , Kowalchuk John M. , Paterson Donald H.
Published: May 2005

The effects of prior heavy-intensity exercise on O2 uptake (V̇o2) kinetics of a second heavy exercise may be due to vasodilation (associated with metabolic acidosis) and improved muscle blood flow. This study examined the effect of prior heavy-intensity exercise on femoral artery blood flow (Qleg) and its relationship with V̇o2 kinetics. Five young subjects completed five to eight repeats of two 6-min bouts of heavy-intensity one-legged, knee-extension exercise separated by 6 min of loadless exercise. V̇o2 was measured breath by breath. Pulsed-wave Doppler ultrasound was used to measure Qleg. V̇o2 and blood flow velocity data were fit using a monoexponential model to identify phase II and phase III time periods and estimate the response amplitudes and time constants (τ). Phase II V̇o2 kinetics was speeded on the second heavy-intensity exercise [mean τ (SD), 29 ( 10 ) s to 24 ( 10 ) s, P < 0.05] with no change in the phase II (or phase III) amplitude. Qleg was elevated before the second exercise [1.55 (0.34) l/min to 1.90 (0.25) l/min, P < 0.05], but the amplitude and time course [τ, 25 ( 13 ) s to 35 ( 13 ) s] were not changed, such that throughout the transient the Qleg (and ΔQleg/ΔV̇o2) did not differ from the prior heavy exercise. Thus V̇o2 kinetics were accelerated on the second exercise, but the faster kinetics were not associated with changes in Qleg. Thus limb blood flow appears not to limit V̇o2 kinetics during single-leg heavy-intensity exercise nor to be the mechanism of the altered V̇o2 response after heavy-intensity prior exercise.
Induction of long-lasting depolarization in medioventral medulla neurons by cholinergic input from the pedunculopontine nucleus
Authors: Mamiya Keiko , Bay Kevin , Skinner R. D. , Garcia-Rill E.
Published: May 2005

Stimulation of the pedunculopontine nucleus (PPN) is known to induce changes in arousal and postural/locomotor states by activation of such descending targets as the caudal pons and the medioventral medulla (MED). Previously, PPN stimulation was reported to induce prolonged responses (PRs) in intracellularly recorded caudal pontine neurons in vitro. The present study used intracellular recordings in semihorizontal slices from rat brain stem (postnatal days 12–21) to determine responses in MED neurons following PPN stimulation. One-half (40/81) of MED neurons showed PRs after PPN stimulation. MED neurons with PRs had shorter duration action potential, longer duration afterhyperpolarization, and higher amplitude afterhyperpolarization than non-PR MED neurons. PR MED neurons were significantly larger (568 ± 44 μm2) than non-PR MED neurons (387 ± 32 μm2). The longest mean duration PRs and maximal firing rates during PRs were induced by PPN stimulation at 60 Hz compared with 10, 30, or 90 Hz. The muscarinic cholinergic agonist carbachol induced depolarization in all PR neurons tested, and the muscarinic cholinergic antagonist scopolamine reduced or blocked carbachol- and PPN stimulation-induced PRs in all MED neurons tested. These findings suggest that PPN stimulation-induced PRs may be due to activation of muscarinic receptor-sensitive channels, allowing MED neurons to respond to a transient, frequency-dependent depolarization with long-lasting stable states. PPN stimulation appears to induce PRs in large MED neurons using parameters known best to induce locomotion.
Metabolic energy and muscular activity required for leg swing in running
Authors: Modica Jesse R. , Kram Rodger
Published: May 2005

The metabolic cost of leg swing in running is highly controversial. We investigated the cost of initiating and propagating leg swing at a moderate running speed and some of the muscular actions involved. We constructed an external swing assist (ESA) device that applied small anterior pulling forces to each foot during the first part of the swing phase. Subjects ran on a treadmill at 3.0 m/s normally and with ESA forces up to 4% body weight. With the greatest ESA force, net metabolic rate was 20.5% less than during normal running. Thus we infer that the metabolic cost of initiating and propagating leg swing comprises ∼20% of the net cost of normal running. Even with the greatest ESA, mean electromyograph (mEMG) of the medial gastrocnemius and soleus muscles during later portions of stance phase did not change significantly compared with normal running, indicating that these muscles are not responsible for the initiation of leg swing. However, with ESA, rectus femoris mEMG during the early portions of swing phase was as much as 74% less than during normal running, confirming that it is responsible for the propagation of leg swing.
Muscle strength response to strength training is influenced by insulin-like growth factor 1 genotype in older adults
Authors: Kostek Matthew C. , Delmonico Matthew J. , Reichel Jonathan B. , Roth Stephen M. , Douglass Larry , Ferrell Robert E. , Hurley Ben F.
Published: May 2005

Strength training (ST) is considered an intervention of choice for the prevention and treatment of sarcopenia. Reports in the literature have suggested that the insulin-like growth factor I protein (IGF-I) plays a major role in ST-induced skeletal muscle hypertrophy and strength improvements. A microsatellite repeat in the promoter region of the IGF1 gene has been associated with IGF-I blood levels and phenotypes related to IGF-I in adult men and women. To examine the influence of this polymorphism on muscle hypertrophic and strength responses to ST, we studied 67 Caucasian men and women before and after a 10-wk single-leg knee-extension ST program. One repetition maximum strength, muscle volume via computed tomography, and muscle quality were assessed at baseline and after 10 wk of training. The IGF1 repeat promoter polymorphism and three single-nucleotide polymorphisms were genotyped. For the promoter polymorphism, subjects were grouped as homozygous for the 192 allele, heterozygous, or noncarriers of the 192 allele. After 10 wk of training, 1-repetition maximum, muscle volume, and muscle quality increased significantly for all groups combined ( P < 0.001). However, carriers of the 192 allele gained significantly more strength with ST than noncarriers of the 192 allele ( P = 0.02). There was also a nonsignificant trend for a greater increase in muscle volume in 192 carriers than noncarriers ( P = 0.08). No significant associations were observed for the other polymorphisms studied. Thus these data suggest that the IGF1 promoter polymorphism may influence the strength response to ST. Larger sample sizes should be used in future studies to verify these results.
Mechanical, biochemical, and extracellular matrix effects on vascular smooth muscle cell phenotype
Authors: Stegemann Jan P. , Hong Helen , Nerem Robert M.
Published: May 2005

The vascular smooth muscle cell (VSMC) is surrounded by a complex extracellular matrix that provides and modulates a variety of biochemical and mechanical cues that guide cell function. Conventional two-dimensional monolayer culture systems recreate only a portion of the cellular environment, and therefore there is increasing interest in developing more physiologically relevant three-dimensional culture systems. This review brings together recent studies on how mechanical, biochemical, and extracellular matrix stimulation can be applied to study VSMC function and how the combination of these factors leads to changes in phenotype. Particular emphasis is placed on in vitro experimental studies in which multiple stimuli are combined, especially in three-dimensional culture systems and in vascular tissue engineering applications. These studies have provided new insight into how VSMC phenotype is controlled, and they have underscored the interdependence of biochemical and mechanical signaling. Future improvements in creating more complex in vitro culture environments will lead to a better understanding of VSMC biology, new treatments for vascular disease, as well as improved blood vessel substitutes.
Muscle activation and its distribution within human triceps surae muscles
Authors: Kinugasa Ryuta , Kawakami Yasuo , Fukunaga Tetsuo
Published: May 2005

The purposes of this study were 1) to quantify the volume of activated parts within a whole muscle and 2) to examine activated area distributions along the length of muscle. Seven male subjects performed five sets of 10 repetitions of a single-leg calf-raise exercise with the knee fully extended. Transverse relaxation time (T2)-weighted spin echo images were acquired before and immediately after the exercise. A range of pixels with a T2 greater than the mean +1 SD of the region of interest (ROI) from the preexercise image and pixels with a T2 lower than the mean + SD of the ROI from the postexercise image were defined as “active” muscle. The active muscle images were three dimensionally reconstructed, from which the volume of the activated muscle was determined for individual triceps surae (TS) muscles. Our data indicate that ∼46% of the medial gastrocnemius (MG) muscle was activated during the exercise, with activation of the lateral gastrocnemius (LG) and soleus (Sol) muscles being ∼35%. In the MG, distal portions had a greater percentage area of activated muscle than the proximal portions ( P < 0.05), which was consistent with the results regarding electromyogram activity. In contrast, regional activation differences were not observed in the LG and Sol. These findings suggest that the amounts of activated muscle and its distribution would be different among TS muscles.
Motor skill training and strength training are associated with different plastic changes in the central nervous system
Authors: Jensen Jesper Lundbye , Marstrand Peter C. D. , Nielsen Jens B.
Published: May 2005

Changes in corticospinal excitability induced by 4 wk of heavy strength training or visuomotor skill learning were investigated in 24 healthy human subjects. Measurements of the input-output relation for biceps brachii motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation were obtained at rest and during voluntary contraction in the course of the training. The training paradigms induced specific changes in the motor performance capacity of the subjects. The strength training group increased maximal dynamic and isometric muscle strength by 31% ( P < 0.001) and 12.5% ( P = 0.045), respectively. The skill learning group improved skill performance significantly ( P < 0.001). With one training bout, the only significant change in transcranial magnetic stimulation parameters was an increase in skill learning group maximal MEP level (MEPmax) at rest ( P = 0.02) for subjects performing skill training. With repeated skill training three times per week for 4 wk, MEPmax increased and the minimal stimulation intensity required to elicit MEPs decreased significantly at rest and during contraction ( P < 0.05). In contrast, MEPmax and the slope of the input-output relation both decreased significantly at rest but not during contraction in the strength-trained subjects ( P ≤ 0.01). No significant changes were observed in a control group. A significant correlation between changes in neurophysiological parameters and motor performance was observed for skill learning but not strength training. The data show that increased corticospinal excitability may develop over several weeks of skill training and indicate that these changes may be of importance for task acquisition. Because strength training was not accompanied by similar changes, the data suggest that different adaptive changes are involved in neural adaptation to strength training.
Can We Prevent Prostate Cancer? Rationale and Current Status of Prostate Cancer Chemoprevention
Authors: Fujimoto Noahiro , Chang Chawnshang , Nomura Masayoshi , Matsumoto Tetsuro
Published: May 2005

Prostate cancer has been one of the most frequent cancers among men in Western countries for the past decade. Investigation of prostate cancer prevention is very attractive, because prostate cancer has a high incidence, long-term natural history, regional difference in incidence, and is effected by sex steroids. Chemoprevention is defined as the use of specific agents to suppress or reverse carcinogenesis and to prevent the development of cancer. The development of chemoprevention strategies against prostate cancer would be of medical and economic importance. Basic and clinical research of chemoprevention of prostate cancer are under active investigation. This article aims to summarize and review the basic evidence and clinical trials on prostate cancer chemoprevention. Recent research has demonstrated that many agents, such as agents altering sex steroid signaling, drugs inducing antiproliferation/differentiation, retinoids, anti-inflammatory drugs, and antioxidants, could be potential preventatives for prostate cancer. Large-scale clinical trials have suggested that 5α-reductase inhibitor finasteride, selenium, and vitamin E can function as a chemopreventive agent. Although no definitely effective strategies of prostate cancer prevention have been identified yet, increasing evidence will provide effective and safe strategies that bring clinical benefits.
Comparative Effects of Bicalutamide (Casodex) versus Orchidectomy on Bone Mineral Density, Bone Remodelling, and Bone Biomechanics in Healthy Rats
Authors: Lefort Mar , Díaz Curiel Manuel , Carrascal María-Teresa , Méndez-Dávila Cioly , de la Piedra Concepción
Published: May 2005

Introduction: The aim of this work was to analyze the effects produced on bone mineral density (BMD) by the administration of bicalutamide and to compare them with those produced by orchidectomy. Bone formation rate (serum osteocalcin), bone resorption (serum carboxyterminal telopeptide of collagen I; CTX), and biomechanical properties of bone were also studied. Methods: Thirty-eight male Wistar rats were used: (1) Sham group, rats sham operated at 16 weeks of age; (2) OQX group, rats orchidectomized at 16 weeks of age, and (3) Bic group, rats sham operated at 16 weeks of age and treated during 6 weeks with bicalutamide. The rats were sacrificed at 22 weeks of age, and the BMD in femur and lumbar spine was determined. Serum osteocalcin and serum CTX were also analyzed. Biomechanical parameters related to torsion assay were also studied. Results: The OQX group showed a significant decrease in femoral BMD with respect to Sham rats, whereas bicalutamide treatment did not produce any significant change in BMD. Both Sham and Bic groups showed similar serum osteocalcin and CTX values, whereas OQX rats presented higher osteocalcin and CTX levels than the Sham group. The OQX group showed a significant decrease in femoral thickness. No significant differences were observed in the rest of the biomechanical parameters between groups. Conclusion:These results indicate that bicalutamide treatment, in spite of its anti-androgenic properties, does not affect bone remodelling nor BMD in male healthy rats, suggesting that this compound may function as a selective androgen receptor modulator for effects on bone remodelling in the osteoblasts.
Ureteroscopic Management of Sepsis Associated with Ureteral Stone Impaction: Is It Still Contraindicated?
Authors: Hsu Jong-Ming , Chen Marcelo , Lin Wen-Chou , Chang Huang-Kuang , Yang Stone
Published: May 2005

Introduction: Retrograde decompression is generally not advocated for patients with sepsis owing to ureteral obstruction by stone impaction, and the initial treatment of choice is percutaneous nephrostomy (PCN). We report our experience with the treatment of urosepsis with retrograde ureteroscopy (URS) instead of PCN drainage. Patients and Methods: Fifty-six consecutive patients diagnosed with ureteral stone-related sepsis received URS as primary treatment at our institution. Patients with uncontrollable sepsis underwent emergent URS and hemodynamically stable patients underwent elective URS within two days of diagnosis. Results: URS was successful in 53 (94.6%) of the 56 patients. PCN was performed in the 3 cases of URS failure. Internal ureteral stenting was performed in 48 patients. Secondary procedures were performed in 10 (18.9%) patients. Twenty-six patients suffered from postoperative fever for an average of 1.6 days (range 1–4 days). There were no anesthesia-related morbidities, postoperative exacerbations of the clinical condition, or postoperative deaths. The median length of hospital stay was 7 days (range 3–94 days). Conclusion: PCN drainage is the standard treatment of sepsis associated with ureteral stone obstruction. However, our results show that URS can be safely and successfully performed by skilled endourologists in select clinical situations.