bluuebunny/crossref_metadata_2025 huggingface dataset:
Rho‐mediated cytoskeletal rearrangement in response to LPA is functionally antagonized by Rac1 and PIP2
Authors: Seasholtz Tammy M. , Radeff‐Huang Julie , Sagi Sarah A. , Matteo Rosalia , Weems Jessica M. , Cohen Annemarie Stoudt , Feramisco James R. , Brown Joan Heller
Published: September 2004

G‐protein‐coupled receptors signal through Rho to induce actin cytoskeletal rearrangement. We previously demonstrated that thrombin stimulates Rho‐dependent process retraction and rounding of 1321N1 astrocytoma cells. Surprisingly, while lysophosphatidic acid (LPA) activated RhoA in 1321N1 cells, it failed to produce cell rounding. Thrombin, unlike LPA, decreased Rac1 activity, and activated (GTPase‐deficient) Rac1 inhibited thrombin‐stimulated cell rounding, while expression of dominant‐negative Rac1 promoted LPA‐induced rounding. LPA and thrombin receptors appear to differ in coupling to Gi, as LPA but not thrombin‐stimulated 1321N1 cell proliferation was pertussis toxin‐sensitive. Blocking Gi with pertussis toxin enabled LPA to induce cell rounding and to decrease activated Rac1. These data support the hypothesis that Rac1 and Gi activation antagonize cell rounding. Thrombin and LPA receptors also differentially activated Gq pathways as thrombin but not LPA increased InsP3 formation and reduced phosphatidylinositol 4,5‐bisphosphate (PIP2) levels. Microinjection of the plekstrin homology domain of phospholipase C (PLC)δ1, which binds PIP2, enabled LPA to elicit cell rounding, consistent with a requirement for PIP2 reduction. We suggest that Rho‐mediated cytoskeletal responses are enhanced by concomitant reductions in cellular levels of PIP2 and Rac1 activation and thus effected only by G‐protein‐coupled receptors with appropriate subsets of G protein activation.
Sex‐specific patterns in body condition and testosterone level changes in a territorial migratory bird: the Bluethroat Luscinia svecica
Authors: Geslin Thomas , Chastel Olivier , Eybert Marie‐Christine
Published: September 2004

The Bluethroat Luscinia svecica is a migratory passerine that exhibits a socially monogamous pair bond and a high level of parental care. Males are territorial both when wintering and breeding whereas females are territorial only in winter. We investigated changes in body condition and testosterone levels during successive life‐history stages and determined their relationships. Sex‐specific patterns were observed in the variation in body condition and testosterone level. Male body condition varied mainly during the winter. It peaked at the onset of the prenuptial moult and then decreased, whereas it remained stable throughout breeding. In contrast, female body condition varied mainly during the breeding season. It increased during the prelaying stage and then abruptly decreased until fledgling provisioning. As in other monogamous and territorial passerines, testosterone levels in Bluethroat males were low during winter, increased in late winter, peaked during the prelaying stage and then decreased when provisioning young. In wintering females, territorial competition caused testosterone levels to rise. These females were able to produce territorial vocalizations and exhibit aggressive postures. Females showed higher mean testosterone levels than males when wintering whereas the opposite was observed when breeding. Our data from wintering female Bluethroats support the ‘challenge hypothesis’ under which high testosterone levels are associated with periods of social instability, and testosterone can regulate female territorial behaviour during this period.
Geographical variation in macrohabitat use and preferences of the Lesser Spotted EagleAquila pomarina
Authors: VÄLI ÜLO , Treinys Rimgaudas , Lõhmus Asko
Published: September 2004

Geographical variation in wildlife–habitat relationships has seldom been studied. We explored macrohabitat use and geographically distinct responses to habitat availability in the Lesser Spotted EagleAquila pomarinanear the centre (Lithuania) and on the edge (Estonia) of its European distribution range, and in different zones within Estonia. Land cover types and distances to landscape elements, as well as landscape diversity, were measured around 198 Eagle nests and random forest points. Out of six macrohabitat characteristics, two (landscape diversity, area of optimal foraging habitat) showed no geographical variation in use, or preferences by the Eagle. Whereas variation in the use of suboptimal foraging habitats and forests could be attributed to regional differences in their availability, there were geographically distinct preferences for distances between nests and landscape elements. The species avoided anthropogenic edges in Lithuania but tended even to prefer their proximity in Estonia; Eagles selected nest‐sites near remote waterbodies throughout Estonia but there was no such preference in Lithuania. The results did not support the hypothesis that latitudinal or range centre‐to‐periphery gradients existed in habitat relationships of the species; the main factor behind the geographical variation was probably land‐use history. In general, the diversity of geographical effects indicated that extrapolating local habitat relationships to other areas may give erroneous results, and large‐scale conservation planning regarding species’ habitat may be ineffective.
Does Entrepreneurship Capital Matter?
Authors: Audretsch David B. , Keilbach Max
Published: September 2004

Economics has identified three types of capital as the drivers of economic growth—physical capital, human capital, and knowledge capital. This article introduces the concept of entrepreneurship capital and suggests that it is also an important factor shaping the economic performance of an economy. We define entrepreneurship capital as those factors influencing and shaping an economy's milieu of agents in such a way as to be conducive to the creation of new firms. The hypothesis that entrepreneurship capital is positively linked to economic growth is then tested by examining the relationship between several different measures of entrepreneurship capital and regional economic performance, measured as per–capita income for Germany. The empirical evidence suggests that there is indeed a positive link between entrepreneurship capital and regional economic performance. These results suggest a new direction for public policy that focuses on instruments to enhance entrepreneurship capital.
Differences in Regional Firm Formation Rates: A Decomposition Analysis
Authors: Johnson Peter
Published: September 2004

This article examines regional differences in recent business formation activity in the United Kingdom over the period 1994–2001. It considers the extent to which regional differences can be accounted for by (i) variations in industrial structure, with some regions having a greater or lesser share of sectors where the formation rate tends to be high; and (ii) variations across regions in the formation rate in the same sector. The article shows wide variations across regions and over time in the relative importance of these two factors. The article explores some policy implications of this decomposition.
Clinical Significance of Preserving Spontaneous QRS Wave in the Therapy of DDD Pacing for Sick Sinus Syndrome
Authors: MANI HIROKI , SHIRAYAMA TAKESHI , SUZAKI YOKO , SAKATANI TOMOHIKO , SAKAMOTO TAKASHI , YAMAMURA MIDORI , MATSUBARA HIROAKI , TANIWAKI MASAFUMI
Published: September 2004

The aim of this clinical crossover study was to elucidate the effects of atrioventricular (AV) synchronous pacing on cardiac function in patients with sick sinus syndrome (SSS). Thirty SSS patients, each with dual chamber pacemaker (DDD), were enrolled and divided into two groups based on echocardiographic findings. Group A (n = 16) had hypertensive heart disease (wall thickness 11 ∼ 12 mm) or mitral or aortic regurgitation (Grade I or II). Group B (n = 14) had no organic heart disease. Three successive 3‐month pacing periods were tested. For the first 3 months, long AV delay that achieved > 80% ventricular sensing was chosen. For the next 3 months, AV delay was abbreviated to achieve > 80% ventricular pacing at an optimal AV interval. For the final 3 months, the first setting was resumed. At the end of each period, M mode echocardiography, pulsed‐Doppler study, and measurement of plasma brain natriuretic peptide (BNP) level were conducted. In both groups, echocardiographic parameters were not significantly changed during the evaluation. In group A, plasma BNP level was significantly higher at the end of the short AV delay period than at the long AV delay period (P = 0.009), while in group B it did not differ during each period. AV synchronous pacing (>80% ventricular pacing) in the SSS patients with a DDD pacemaker implanted could increase the ventricular load, and it is better to preserve the spontaneous QRS with the DDD mode with prolonged AV delay in patients with mild hypertensive or valvular disease.
Assessment of Ventricular Repolarization in a Large Group of Children with Early Onset Deafness
Authors: TUTAR ERCAN , TEKIN MUSTAFA , UÇAR TAYFUN , ÇOMAK ELIF , ÖCAL BURHAN , ATALAY SEMRA
Published: September 2004

This study examined the ECG traces of 397 deaf children (age 12.5 ± 2.9 years, range 6–19 years), after exclusion of cases with Jervell and Lange‐Nielsen syndrome (JLNS), and compared them to those of 361 normal hearing counterparts (age 12.5 ± 2.7 years; range 7–18 years). An observer, who was unaware of the hearing status of the subjects, measured QT and QTc intervals and calculated dispersions of QT and QTc from standard 12‐lead ECGs recorded at a speed of 25 mm/s at rest. Although the mean QT was found to be longer in deaf children than that observed in the control group (P < 0.0001), the mean QTc was significantly shorter (P < 0.0001). The mean heart rate was significantly lower in deaf children. When QT and QTc data were recompared after the children were grouped according to the heart rate, the observed difference became less significant or disappeared. In conclusion, there are no major abnormalities for repolarization parameters in children with congenital sensorineural deafness, when compared to hearing counterparts, if heart rates are similar. Based on these results, routine ECG screening of deaf children for repolarization abnormalities may be unnecessary unless they have a history of syncope or positive family history of syncope and/or early sudden death.
Far‐Field R Wave Oversensing in Dual Chamber Pacemakers Designed for Atrial Arrhythmia Management:
Authors: INAMA GIUSEPPE , SANTINI MASSIMO , PADELETTI LUIGI , BORIANI GIUSEPPE , BOTTO GIANLUCA , CAPUCCI ALESSANDRO , GULIZIA MICHELE , RICCI RENATO , RIZZON PAOLO , FERRI FABIO , MIRAGLIA FRANCESCO , RANERI ROSSANA , GRAMMATICO ANDREA
Published: September 2004

The aim of the study was to determine the incidence and practical implications of far‐field R wave oversensing (FFRWO) and its association with pacing site and lead tip to ring spacing (TTRS) in implantable devices designed to diagnose and treat atrial tachyarrhythmias and programmed with a fixed and short postventricular blanking period. The study included 395 patients who were implanted with a DDDRP pacemaker and prospectively followed. At implant and follow‐up visits FFRWO was assessed by analyzing lead electrical measures and atrial tachyarrhythmic episodes collected in the device diagnostics. During a median follow‐up of 12 months 11 (2.8%) of 395 patients showed a clinically significant FFRWO that induced inappropriate detection or pacemaker malfunctioning. The atrial pacing site of these 11 patients was right atrium appendage (RAA) for 3 patients, representing 1.1% of 254 RAA patients, coronary sinus ostium (CSO) for 7 patients, representing 7.4% of 94 CSO patients (P < 0.005 vs RAA), and lateral wall (LW) for 1 (2.9%) of 34 LW patients. The minimal value of the FFRWO to P wave ratio, measured at implant, associated with a clinically significant FFRWO was 0.6; therefore, a value of 0.5 was used as a cutoff to identify patients at risk of undesirable device behavior induced by FFRWO: there were 11 (9.6%) of 114 of RAA patients with short (≤ 10 mm) TTRS, 22 (18.8%) of 117 of RAA patients with long (≥ 17 mm) TTRS (P < 0.05 vs short TTRS), 21 (30.6%) of 64 of CSO patients short TTRS (P < 0.001 vs RAA patients with short TTRS) and 3 (30%) of 10 of CSO patients with long TTRS. The analysis showed that, despite the short postventricular blanking time, FFRWO inducing undesired functioning in AT500 pacemakers is infrequent (2.8% of patients). Compared to RAA, the CSO lead position was more frequently associated with FFRWO.TTRS < 10 mm was associated with lower risk of clinically significant FFRWO in RAA.
Electrophysiological Mechanisms and Catheter Ablation of Complex Atrial Arrhythmias from Crista Terminalis:
Authors: LIN YENN‐JIANG , TAI CHING‐TAI , LIU TU‐YING , HIGA SATOSHI , LEE PI‐CHANG , HUANG JIN‐LONG , YUNIADI YOGA , HUANG BIEN‐HSIEN , LEE KUN‐TAI , LEE SHIH‐HUANG , UENG KUANG‐CHANG , HSIEH MING‐HSUNG , DING YU‐AN , CHEN SHIH‐ANN
Published: September 2004

Paroxysmal atrial fibrillation (PAF) can be initiated by ectopic activation from the crista terminalis. The crista terminalis conduction gap is also a critical isthmus in atrial reentrant arrhythmias like upper and lower loop reentry. The aim of this study was to investigate the mechanism and results of catheter ablation for complex atrial arrhythmias originating from the crista terminalis using the noncontact mapping system (NCM). The study population consisted of six patients (5 men, 1 woman; 70 ± 9 years) with drug refractory PAF and typical/atypical atrial flutter. NCM identified the earliest ectopic activation originating from the crista terminalis in these six patients. The reentry circuit of atypical atrial flutter propagated around the upper crista terminalis in five patients, and lower crista terminalis in one patient. The reentry circuit of atypical atrial flutter and the initial reentry circuit of AF conducted through the crista terminalis gap in all patients. Radiofrequency applications were delivered on the sites of ectopy, which initiated AF. Substrate modification was also performed over the crista terminalis gap (six patients) and cavotricuspid isthmus (three patients) responsible for the reentry. During a mean follow‐up of 9 ± 5 months (range 5–18 months), five patients were free of AF without antiarrhythmic drugs, and one patient did not have AF or atrial flutter using propafenone. NCM demonstrated the mechanism of crista terminalis ectopy‐initiating AF and associated typical/atypical atrial flutter. Catheter ablation of crista terminalis ectopy and substrate for the reentry guided by NCM successfully eliminated these atrial arrhythmias.
Electrophysiological Characteristics of Accessory Pathways with Prolonged Retrograde Conduction
Authors: LIN KUO‐HUNG , KUO CHI‐TAI , LUQMAN NAZAR , HSU KUANG‐HUNG , WANG CHIUN‐LI , HSU TSU‐SHIU , LEE YING‐SHIUNG
Published: September 2004

Electrophysiological characteristics of an accessory pathway (AP) with a long ventriculoatrial (VA) interval (arbitrarily defined as ≥ 50 ms and absence of continuous electrical activity) and no retrograde decremental property are described in this study. Fifteen patients (group 1) were compared with 171 patients with normal VA conduction (group 2). Mean VA conduction time was 77 ± 24 versus 34 ± 12 ms in group 1 versus group 2, respectively. Group 1 patients were older (55 ± 14 vs 40 ± 14 years), the male to female ratio was higher (2.8 vs 1.6), and APs were more prevalent on the right (60%) but manifest APs were lower (20% vs 54%) compared to group 2 patients (P < 0.05 in all cases). QRS morphology during induced atrioventricular reciprocating tachycardia was identical in both groups but the tachycardia cycle length was longer in group 1 (373 ± 29 vs 344 ± 50 ms, P < 0.05). Retrograde AP block cycle length and effective refractory period were greater in group 1 (362 ± 59 vs 293 ± 57 ms; 330 ± 58 vs 273 ± 55 ms, both P <0.05). Adenosine (up to 18 mg) and verapamil (5–10 mg) failed to block the VA conduction via AP during ventricular pacing. In group 1 the number of radiofrequency lesions for a successful ablation were significantly less (3 ± 2 vs 6 ± 5, P < 0.05). In conclusion, APs with a long VA interval and no decremental retrograde conduction have electrophysiological characteristics that are different from those with a short VA interval. Role of aging deserves further exploration.
Effects of Transvenous Pacing on Cardiac Troponin Release
Authors: BOOS CHRISTOPHER J. , GOUGH SOPHIE , WHEATHER MATTHEW , MEDBAK SAMI , MORE RANJIT
Published: September 2004

Cardiac troponins are invaluable tools for the detection of minimal myocardial injury. No study to date has analyzed the effect of permanent cardiac pacing on minimal myocardial injury detection by cardiac troponin I (cTnI) measurement. We investigated 76 clinically stable patients (mean age 75 years, range 31‐93 years, 59% men) listed for elective endocardial permanent pacemaker insertion. Patients were required to have normal levels of cardiac cTnI, aspartate transaminase (AST) and creatinine kinase (CK) on a venous blood sample taken immediately prior to elective pacemaker implantation. Repeat measurements of AST, CK, and cTnI were performed at a mean of 19.2 post implantation. There was a detectable small rise in cTnI levels above normal in 21% of patients in a second blood sample taken 18‐21 hours later (mean cTnI 0.39 ± 0.37 μg/L, normal < 0.15 μg/L). The only factor that correlated with this rise was prolonged x ray screening time for lead implantation.
Assessment of Regional Wall Motion by Strain Doppler During Biventricular Pacing in Patients with Conventional Indications for a Pacemaker
Authors: MATSUSHITA KOHEI , ISHIKAWA TOSHIYUKI , SUMITA SHINICHI , KOBAYASHI TSUKASA , YAMAKAWA YOHEI , KAWASAKI NORIKO , MATSUMOTO KATSUMI , OHKUSU YASUO , UCHINO KAZUAKI , KIMURA KAZUO , UMEMURA SATOSHI
Published: September 2004

Biventricular pacing therapy is effective in patients with severe congestive heart failure. Strain Doppler imaging (SDI) is a new tool for measuring regional myocardial deformation. We evaluated regional wall motion by strain Doppler imaging in 13 patients who had conventional indications for a pacemaker (74 ± 6 years old) and in six with NYHA Class III or IV heart failure with a biventricular pacemaker (HF‐RV: during right ventricular pacing, HF‐BV: during biventricular pacing). The other seven patients had normal LV function (N‐RV). Wall motion was assessed by strain of the myocardium, and the interval between the Q wave of the surface ECG and the peak strain (QPSI) was measured in three septal and three lateral segments. Interventricular contraction delay was determined as the interval between the onset of the left and right ventricular outflow waves. Intraventricular contraction delay was determined as the time difference between minimum and maximum QPSI. Strain of HF‐RV was significantly greater than that of N‐RV (−9.6%± 2.5% vs −14.4%± 2.3%, P < 0.0001). Intraventricular contraction delay of HF‐RV was significantly greater than that of N‐RV (273 ± 12 vs 151 ± 69 ms, P = 0.0004). Strain of HF‐RV was not significantly greater than that of HF‐BV (−9.6%± 2.5% vs –10.6%± 2.9%). Interventricular contraction delay of HF‐RV was greater than that of HF‐BV (37.2 ± 44.7 vs 16.2 ± 47.4 ms, P < 0.0001). Intraventricular contraction delay of HF‐RV was significantly greater than that of HF‐BV (322 ± 101 vs 209 ± 88 ms, P = 0.0006). In conclusion, biventricular pacing improves both interventricular contraction delay and intraventricular contraction delay in patients with conventional indications for a pacemaker with severe congestive heart failure, and SDI is useful to predict the efficacy of biventricular pacing.
Inappropriate Implantable Cardioverter Defibrillator Discharge Following Consumption of a Dietary Weight Loss Supplement
Authors: MCBRIDE BRIAN F. , GUERTIN DANETTE , WHITE C. MICHAEL , KLUGER JEFFREY
Published: September 2004

This report describes the clinical course of a 40‐year‐old female who experienced repetitive ICD firing after consuming Metabolife 356, a multicomponent dietary weight loss supplement. Following the initiation of Metabolife 356, the patient experienced four shocks over a 3 day period with two 30 J shocks being delivered sequentially. Interrogation of the device revealed atrial tachycardia with 1:1 AV conduction at a rate of 240 beats/min. Metabolife 356 was discontinued and the dosage of sotalol was increased to 120 mg twice daily without recurrence of ICD discharge.
Interference Between Pacemaker and Video Capsule Endoscopy
Authors: GUYOMAR YVES , VANDEVILLE LAURENT , HEULS SEBASTIEN , COVIAUX FRANÇOIS , GRAUX PIERRE , CORNAERT PIERRE , FILOCHE BERNARD
Published: September 2004

The wireless capsule video endoscopy is useful in patients with occult blood loss, but is contraindicated in patients with cardiac pacemaker (PM). No case of interference has been published. We report the case of a patient with a PM implanted in the abdominal wall. After capsule ingestion, cardiac monitoring showed no modification of the PM compartment (VOO, unipolar mode) but the capsule recording reveal more than 3 hours of loss of image. The wireless capsule endoscopy is safe in patients with PMs in VOO mode. Nevertheless important interference was noted in the recording when the capsule was near the PM.
Thebesian Valve Imaging with Electron Beam CT Angiography:
Authors: SHINBANE JEROLD S. , GIRSKY MARC J. , MAO SONGSHOU , BUDOFF MATTHEW J.
Published: September 2004

We report visualization of a prominent coronary sinus os valve (Thebesian valve), by electron beam computed tomographic angiography, which impeded an endocardial approach to left ventricular pacing. Resynchronization therapy was therefore performed with an epicardial approach to left ventricular lead placement. Electron beam computed tomographic angiography can provide detailed information for coronary sinus instrumentation, including anomalies potentially affecting the approach to resynchronization therapy.
Mental Health in Prison Populations. A review – with special emphasis on a study of Danish prisoners on remand
Authors: Andersen H. S.
Published: September 2004

Objective: To review the literature on mental health and psychiatric morbidity in prison populations and relate findings to a Danish study on remand prisoners.

Method: The literature is reviewed and subdivided in the following section: validity of psychometrics in prison populations, prevalence of psychiatric disorders prior to imprisonment, incidence of psychiatric disorders during imprisonment, psychopathy related to psychiatric comorbidity, dependence syndromes with special emphasis on different administrations of heroin use (smoke vs. injection). The results are compared with a longitudinal Danish study on remand prisoners in either solitary confinement (SC) or non‐SC.

Results: Many factors must be taken into consideration when dealing with prisoners and mental health, e.g. international differences, the prison setting, demographics and methodological issues. The prison populations in general are increasing worldwide. Psychometrics may perform differently in prison populations compared with general populations with the General Health Questionnaire‐28 having a low validity in remand prisoners. Psychiatric morbidity including schizophrenia is higher and perhaps increasing in prison populations compared with general populations with dependence syndromes being the most frequent disorders. The early phase of imprisonment is a vulnerable period with a moderately high incidence of adjustment disorders and twice the incidence in SC compared with non‐SC. Prevalence of psychopathy is lower in European than North American prisons. Medium to high scores of psychopathy is related to higher psychiatric comorbidity. Opioid dependence is the most frequent drug disorder with subjects using injection representing a more dysfunctional group than subjects using smoke administration. Many mentally ill prisoners remain undetected and undertreated.

Conclusion: There is a growing population of mentally ill prisoners being insufficiently detected and treated.
Experimental Human Pain Models: A Review of Standardised Methods for Preclinical Testing of Analgesics
Authors: Staahl Camilla , Drewes Asbjørn Mohr
Published: September 2004

Abstract: Treatment of pain is one of the major challenges in clinical medicine. However, it is often difficult to evaluate the effect of a treatment, as the many symptoms of the underlying diseases often confound this assessment. Furthermore, as the pain mechanisms in many diseases are poorly understood, the limited successful trial and error approach is most often used in the selection of analgesics. Hence, there is a need for new methods in the characterization and treatment of pain. Human experimental pain models offer the possibility to explore the pain system under controlled settings. The models can also be used to screen the analgesic profiles of drugs targeted to treat pain. This review gives a brief introduction to the methods used to evoke and assess pain in the skin, muscle and viscera. New methods using multimodal stimulation and activation of central pain mechanisms can to a higher degree mimic the clinical situation, and such methods are recommended in the future screening of analgesics. Examples of the use of experimental pain models in the testing of analgesics are given. With these models the therapeutic spectrum may be defined from a differentiated knowledge on the effect of drugs on the pain system. Such information may be used in the future guidelines for trials and clinical use of analgesics.
Effect of Nortriptyline on Intracellular Ca2+ Handling and Proliferation in Human Osteosarcoma Cells
Authors: Hsu Shu‐Shong , Huang Chun‐Jen , Chen Jin‐Shyr , Cheng He‐Hsiung , Chang Hong‐Tai , Jiann Bang‐Ping , Lin Ko‐Long , Wang Jue‐Long , Ho Chin‐Man , Jan Chung‐Ren
Published: September 2004

Abstract: The effect of the antidepressant nortriptyline, on bone cells is unknown. In human osteosarcoma MG63 cells, the effect of nortriptyline on intracellular Ca2+ concentration ([Ca2+]i) and proliferation was measured by using fura‐2 and tetrazolium, respectively. Nortriptyline (≥10 μM) caused a [Ca2+]i rise in a concentration‐dependent manner (EC50=200 μM). Nortriptyline‐induced [Ca2+]i rise was prevented by 60% by removal of extracellular Ca2+ but was not altered by voltage‐gated Ca2+ channel blockers. In Ca2+‐free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+‐ATPase, caused a monophasic [Ca2+]i rise, after which the increasing effect of nortriptyline on [Ca2+]i was abolished; also, pretreatment with nortriptyline abolished thapsigargin‐induced [Ca2+]i increase. U73122, an inhibitor of phospholipase C, did not affect nortriptyline‐induced [Ca2+]i rise; however, activation of protein kinase C decrease nortriptyline‐induced [Ca2+]i rise by 32%. Overnight incubation with 50 and 100 μM nortriptyline killed 78% and 97% of cells, respectively; while 10 μM nortriptyline had no effect. These data suggest that nortriptyline rapidly increases [Ca2+]i in human osteosarcoma cells by stimulating both extracellular Ca2+ influx and intracellular Ca2+ release, and is cytotoxic at high concentrations.
Effects of Perinatal Combined Exposure to 1,4‐Dichlorobenzene and 1,1‐Dichloro‐2, 2‐bis (p‐chlorophenyl) ethylene (p,p′‐DDE) on Rat Female Offspring
Authors: Makita Yuji
Published: September 2004

Abstract: 1,4‐Dichlorobenzene (DCB) is used as an air freshener and a moth repellent and 1, 1‐dichloro‐2, 2‐bis (p‐chlorophenyl) ethylene (p,p′‐DDE) is a persistent metabolite of 1, 1, 1‐trichloro‐2, 2‐bis (p‐chlorophenyl) ethane (DDT) previously used as a pesticide. DCB concentrations of residential air and oral p,p′‐DDE intake via marine products are demonstrated to be higher in Japan than elsewhere. Consequently, human foetuses and neonates may be exposed to DCB and p,p′‐DDE via the mother. Therefore, the combined effects of DCB and p,p′‐DDE have been investigated in rat female offspring of dams after ingestion of these contaminants. No deteriorated reproductive outcomes of dams and developmental effects on female offspring were observed following oral administration of 25 ppm DCB (approximately 2 mg/kg) and/or 125 ppm p,p′‐DDE (approximately 10 mg/kg) to dams. In this study, the thymus weight of female offspring was preserved by DCB at 6 weeks of age though the biological relevance remains unknown. Simultaneous administration of p,p′‐DDE with DCB inhibited this phenomenon, through a mechanism still to be elucidated.
In vitro Optimization of Structure Activity Relationships of Analogues of A‐331440 Combining Radioligand Receptor Binding Assays and Micronucleus Assays of Potential Antiobesity Histamine H3 Receptor Antagonists
Authors: Hancock Arthur A. , Diehl Marilyn S. , Faghih Ramin , Bush Eugene N. , Krueger Kathleen M. , Krishna Gopala , Miller Thomas R. , Denise M.  , Wilcox  , Nguyen Phong , Pratt John K. , Cowart Marlon D. , Esbenshade Timothy A. , Jacobson Peer B.
Published: September 2004

Abstract: A‐331440 {4′‐[3‐(3(R)‐(dimethylamino)‐pyrrolidin‐1‐yl)‐propoxy]‐biphenyl‐4‐carbonitrile}, a potent and selective antagonist of histamine H3 receptors, yielded positive results in an in vitro micronucleus assay, predictive of genotoxicity in vivo. Because this compound has highly favourable properties and potential as an antiobesity agent, new compounds of this general chemical class were sought that would retain or improve upon the high potency and selectivity of A‐331440 for H3 receptors, but would lack the potential for genotoxicity obtained with that compound. Our working hypothesis was that the biphenyl rings in A‐331440 might contribute to interactions with DNA and thereby predispose toward genotoxicity. Toward this end, several analogues were prepared, with substituents introduced onto the biaryl ring to alter the orientation, electronegativity, and polarity of this moiety, and were tested for their radioligand binding potency and selectivity and their propensity to induce genotoxicity in the in vitro micronucleus assay. Using this strategy, novel compounds were discovered that retained or improved upon the potency and selectivity of A‐331440 for H3 receptors and were devoid of genotoxicity in vitro. Of these, the simple mono‐ and di‐fluorinated analogues (A‐417022 [4′‐{3‐[(3R)‐3‐(dimethylamino)‐1‐pyrrolidinyl]propoxy}‐3′‐fluoro‐1,1′‐biphenyl‐4‐carbonitrile] and A‐423579 [4′‐{3‐[(3R)‐3‐(dimethylamino)‐1‐pyrrolidinyl]‐propoxy}‐3′,5′‐difluoro‐1,1′‐biphenyl‐4‐carbonitrile], respectively) were found to bind to H3 receptors at least as potently as A‐331440, while lacking genotoxicity in the micronucleus assay. The reason of the lack of genotoxicity of the fluorinated analogues is unclear, but is especially noteworthy in light of the general principle that fluorine and hydrogen are very similar in size. Therefore, these fluorinated analogues of A‐331440 represented the most potent and potentially safest compounds for further evaluation as antiobesity leads. Preliminary findings with one of these examples, A‐417022, in a mouse model of obesity are presented.
Arteriolar network architecture and vasomotor function with ageing in mouse gluteus maximus muscle
Authors: Bearden Shawn E. , Payne Geoffrey W. , Chisty Alia , Segal Steven S.
Published: September 2004

Physical diminishes with ageing, but little is known of how the microvascular supply to skeletal muscle fibres is affected. To test the hypothesis that ageing alters blood flow control, we investigated network architecture and vasomotor responses of arterioles in the gluteus maximus muscle of young (2–3 months), adult (12–14 months) and old (18–20 months) C57BL6 male mice (n= 83) (Young, Adult and Old, respectively). Microvascular casts revealed that the total number, length and surface area of arteriolar segments (diameter, 10–50 μm) were not significantly different across age‐groups. However, for arterioles with diameter of 30 μm, tortuosity and branch angles increased with age (P < 0.05). In anaesthetized mice, second‐order (2A) distributing arterioles had similar resting (17 ± 1 μm) and maximal (37 ± 1 μm) diameters and similar responsiveness to cumulative (10−10−10−4m) superfusion of acetylcholine or phenylephrine. With superfusate oxygen level raised from 0 to 21%, 2A arteriolar constriction in Young (11 ± 1 μm) was greater (P < 0.05) than Adult and Old (5 ± 1 μm). Observed 1 mm upstream from microiontophoresis of ACh (1 μA, 1 s), conducted vasodilatation was 10 ± 1 μm in Young, 17 ± 1 μm in Adult and 6 ± 1 μm in Old (P < 0.05). With muscle contractions (2, 4 and 8 Hz; 30 s) arteriolar diameter increased similarly across age‐groups (6 ± 1, 11 ± 1 and 18 ± 1 μm, respectively). Muscle mass and active tension were similar across age‐groups yet postcontraction vasodilatation recovered more rapidly in Old versus Adult and Young (P < 0.05). With arteriolar network architecture maintained during ageing, the impairment in conducted vasodilatation and attenuation of postcontraction vasodilatation may compromise exercise tolerance.
The effect of sensory input and attention on the sensorimotor organization of the hand area of the human motor cortex
Authors: Rosenkranz Karin , Rothwell John C.
Published: September 2004

Sensory input can remodel representations in the sensory cortex, and this effect is heavily influenced by attention to the stimulus. Here we ask whether pure sensory input can also influence the spatial distribution of sensory effects on motor cortical hand area (sensorimotor organization) and whether this is modulated by attention. Sensorimotor organization was tested by applying short (1.5 s) periods of low amplitude vibration to single intrinsic hand muscles and measuring motor cortex excitability with transcranial magnetic stimulation (TMS). In healthy subjects, sensorimotor organization in the hand is focal, with input from one hand muscle increasing motor‐evoked potentials (MEPs), decreasing short and increasing long‐interval intracortical inhibition (SICI and LICI) in the vibrated muscle (‘homotopic’ effects) and having opposite effects on neighbouring muscles (‘heterotopic’ effects). Here we show that a 15 min intervention of vibration applied simultaneously to two hand muscles can lead to long‐term (> 30 min) changes in the spatial pattern of sensorimotor interaction. The amount and direction of the effects depended on the subject's attention during the intervention: if subjects attended to both muscles when they were receiving simultaneous vibration, subsequent short‐term vibration applied to one of them produced ‘homotopic’ effects on both muscles. ‘Heterotopic’ effects on a muscle not vibrated during the intervention were unaffected. If subjects did not attend to simultaneous vibration, subsequent short‐term vibration of the muscles involved in the intervention no longer had any effect on them although the ‘heterotopic’ effects on a muscle not involved in the intervention were unchanged. We conclude that a 15 min period of pure sensory input can remodel the way that subsequent sensory inputs interact with motor output, that the effects are specific for the motor output to muscles involved in the intervention and that they are modulated by the subject's attention.
Neuropeptide Y stabilizes body temperature and prevents hypotension in endotoxaemic rats
Authors: Felies Melanie , Von Hörsten Stephan , Pabst Reinhard , Nave Heike
Published: September 2004

The on‐going high mortality from sepsis motivates continuous research for novel therapeutic strategies. Neuropeptide Y (NPY), a sympathetic neurotransmitter, has been shown to increase survival in experimental septic shock in rats. This protective effect might be due to immunological, cardiovascular or thermoregulatory effects. The aim of this study was to examine the in vivo effect of peripherally administered NPY on body temperature, blood pressure and heart rate in endotoxaemic animals. In order to obtain clinically relevant data, various physiological parameters were monitored in parallel via radio‐telemetry in chronically intravenously cannulated, freely behaving rats. Rats received a sublethal bolus of lipopolysaccharide (LPS, 100 μg kg−1i.v.) and the three parameters were continuously recorded for 72 h. Endotoxaemic rats showed a long‐lasting hypotension, an initial hypothermia (−0.5°C), followed by a prolonged febrile phase (+1.6°C 6 h after endotoxin challenge) associated with a decrease of the circadian rhythm amplitude of temperature. Pretreatment with NPY (160 pmol kg−1i.v. over 75 min) prevented hypotension and significantly stabilized body temperature immediately following the application. The febrile phase was effectively reduced for at least 72 h. These telemetrically obtained findings clearly demonstrate that pretreatment with NPY positively influences two life‐threatening symptoms in endotoxaemia and might be a future option for a successful clinical treatment regimen.
Unraveling Socs
Authors: Leslie Mitch
Published: September 2004

As the brain decides how much food we should eat and how much energy we should use, it listens to molecules exuded by fat. But this communication breaks down in obesity. A new study reveals a possible reason why the brain pays less attention to a weight-regulating hormone. The results might help researchers design drugs to slim down the world's increasingly rotund residents.
Sex-Specific Effects of Interventions That Extend Fly Life Span
Authors: Burger Joep M. S. , Promislow Daniel E. L.
Published: September 2004

Genetic and environmental interventions that extend life span are a current focus in research on the biology of aging. Most of this work has focused on differences among genotypes and species. A recent study on fruit flies shows that life span extension because of dietary restriction can be highly sex-specific. Here we review the literature on sex-specific effects of 56 genetic and 41 environmental interventions that extend life span in
Drosophila melanogaster
. We found that only one-sixth of the experiments provided statistical tests of differences in response between males and females, suggesting that sex-specific effects have been largely ignored. When measured, the life span extension was female-biased in 8 of 16 cases, male-biased in 5 of 16 cases, and not significantly different in only 3 of 16 cases. We discuss possible explanations for the sex-specific differences and suggest various ways in which we might test these hypotheses. We argue that understanding sex differences in the response to life span-extending manipulations should lead to new insights about the basic mechanisms that underlie the biology of aging in both sexes.
Aging Cartilage and Osteoarthritis--What's the Link?
Authors: Loeser Jr. Richard F.
Published: September 2004

Cartilage aging can contribute to the development of osteoarthritis (OA), the most common cause of chronic pain and disability in older adults. Articular cartilage is a unique tissue from the perspective of aging in that the cells (chondrocytes) and the majority of the extracellular matrix proteins experience little turnover, resulting in a tissue that must withstand years of use and can also accumulate years of aging-associated changes. Accumulation of advanced glycation end products (AGEs) occurs in cartilage, and the potential role of AGEs in the development of OA is being investigated. An age-associated reduction in growth factor signaling and an increase in oxidative stress may also play an important role in the age-OA connection. Further elucidation of mechanisms that affect chondrocyte function with aging should lead to novel interventions designed to slow the aging process in cartilage with the goal of preventing age-associated OA.
(Data)base Desires
Authors: Davenport R. John
Published: September 2004

A new online database can help researchers sort through a subset of longevity-associated genes. Launched 3 months ago and announced in print last week, GenAge offers a compendium of genes that are possibly linked to human aging. The new tool supplements SAGE KE's Genes/Interventions Database, which covers aging-related genes and life-stretching treatments in many organisms.
High Anxiety
Authors: Leslie Mitch
Published: September 2004

Childhood hardship forges wiser, tougher adults--or so parents tell their whining children. But in rats, early stress can cause lasting harm to the brain. A new study shows that separating rat pups from their mothers slashes the adult rodents' production of new cells in a brain region crucial for memory and response to stress.
Growing Pains
Authors: Davenport R. John
Published: September 2004

Widely touted as a panacea against aging, growth hormone does provide some benefits. The molecule helps the elderly build muscle and burn fat, according to some clinical studies, yet no one knows whether long-term therapy is safe--or if it improves a person's life. Furthermore, laboratory work suggests that less growth hormone is the secret to exceptional longevity. Researchers are sorting through the data and devising new approaches to understand the two sides of this molecule.
Suppressed RAGE
Authors: Leslie Mitch
Published: September 2004

A receptor protein that snares damaged molecules might spare cells from a sticky situation. According to a new study, the protein guards against harmful compounds that result from reactions between sugars and amino acids. This protective molecule helps cells absorb and destroy the ruinous sugar compounds and dampens inflammation.
The Thing That Wouldn't Leave
Authors: Davenport R. John
Published: September 2004

Like party guests who drink too much and crash on the couch, immune cells overstay their welcome in fat-laden blood vessels, new work reveals. The cells loiter in cholesterol-laden arterial plaques and cause the lesions to grow. Researchers have known that the cells flock there, but the study reveals that once they arrive, they don't leave.
Trouncing Tau
Authors: Beckman Mary
Published: September 2004

If the sheriff knocks off Bonnie, Clyde might hightail it out of town. Similarly, getting rid of β-amyloid plaques in Alzheimer's mice also clears out early-stage tau deposits, new research shows. However, late in the disease, tau switches into a form that resists this treatment. Despite the limitation, the results offer encouragement for human Alzheimer's vaccines and therapies.
Ticking Fast or Ticking Slow, Through Shc Must You Go?
Authors: Martin Florent M. , Friedman Jeffrey S.
Published: September 2004

Circumstantial evidence places the p66 isoform of the adapter protein Shc in a position to mediate the accelerated aging phenotype displayed by mice expressing shortened forms of the tumor suppressor protein p53. We present a model in which p66
shc
may be responsible for integrating signals from the p53 pathway with signals from the insulin-like growth factor-1/Daf pathway in mammals. A full understanding of how interactions between p53 and p66
shc
affect longevity will require the production of animals with mutations in the genes encoding both proteins.
Hardy Helper
Authors: Davenport R. John
Published: September 2004

Like the little devil who wheedles the conscience of a cartoon character contemplating a fateful decision, a worm protein guides another protein in shaping the animal's future, new work reveals. The molecule--called DIN-1--coaxes another protein to stretch longevity when a particular hormone is absent. The study might help clarify how pathways that kick in during hard times also delay aging.
Longevity Is Infectious
Authors: Davenport R. John
Published: September 2004

Nasty germs in fast-food burgers can kill, but a more cordial relationship with bacteria fosters longevity, a new study reveals. Now, research suggests that microbes help shape life span: Young flies need bacteria in order to maximize their adult survival.
Hastening Death to Delay Aging
Authors: Davenport R. John
Published: September 2004

To build a strong gymnastics squad, coaches select future superstars at a young age. Gerontologists also want to identify animals with exceptional potential, but they typically must wait until animals are old. Assessing whether genetic changes or experimental treatments prolong life means waiting for animals to die. A new strategy promises to accelerate the search by killing adolescent flies that are unlikely to live a long time. The approach might help researchers identify drugs that enhance longevity, although some scientists aren't sure whether the tactic will illuminate all aspects of aging.
Regenerating Regeneration
Authors: Davenport R. John
Published: September 2004

Humans possess a limited capacity to restore missing or injured body parts. Stimulating this capability might circumvent some of the tissue deterioration that accompanies old age. Other organisms, such as salamanders and planaria, boast remarkable regenerative powers, sprouting limbs or producing entire new individuals. Once a scientific backwater, study of these creatures is maturing. As researchers uncover the secrets behind regeneration, they hope to conjure up similar forces in people.
Not Wisely but Too Well: Aging as a Cost of Neuroendocrine Activity
Authors: Mobbs Charles V.
Published: September 2004

Progressive decline of some neuroendocrine signaling systems has long been assumed to cause age-related physiological impairments and limit life span. However, hypophysectomy--removal of the pituitary gland--can delay many aspects of the aging process, and recent genetic studies have confirmed that reducing the secretion of pituitary hormones can increase the life span of laboratory organisms. Most strikingly, reducing activity of the insulin/insulin-like growth factor-1 signaling system substantially increases life span. Conversely, activity of the reproductive system or activation of stress responses can curtail life span. Because caloric restriction also reduces the activity of several neuroendocrine systems while increasing life span, it now appears that the aging process is driven, at least in part, by neuroendocrine activity rather than by its decline with age.
Leashing
Leishmania
Authors: Davenport R. John
Published: September 2004

Most of the people who die from flu each winter are older than 65. But a new study suggests that sometimes age bolsters, rather than cripples, the immune system. In at least one strain of mice, geriatric rodents resist a parasitic skin infection better than youngsters do. The finding highlights the convoluted changes that time imparts on the immune system, although researchers don't yet know how the finding relates to human health.
Brown Norway Rat
Authors: Holmes Donna J.
Published: September 2004

This document contains a summary of the biological characteristics of the Brown Norway rat. This strain is available from the National Institute of Aging.