bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced Hepatitis B Virus (HBV)-Specific CD4+T-Cell Responses in Human Immunodeficiency Virus Type 1-HBV-Coinfected Individuals Receiving HBV-Active Antiretroviral Therapy
Authors: Chang J. Judy , Wightman Fiona , Bartholomeusz Angeline , Ayres Anna , Kent Stephen J. , Sasadeusz Joseph , Lewin Sharon R.
Published: February 2005

Functional hepatitis B virus (HBV)-specific T cells are significantly diminished in individuals chronically infected with HBV compared to individuals with self-limiting HBV infection or those on anti-HBV therapy. In individuals infected with human immunodeficiency virus type 1 (HIV-1), coinfection with HBV is associated with an increased risk of worsening liver function following antiviral therapy and of more rapid HBV disease progression. Total HBV-specific T-cell responses in subjects with diverse genetic backgrounds were characterized by using a library of 15-mer peptides overlapping by 11 amino acids and spanning all HBV proteins. The magnitude and breadth of CD4+and CD8+T-cell responses to HBV in peripheral blood were examined by flow cytometry to detect gamma interferon production following stimulation with HBV peptide pools. Chronic HBV carriers (n= 34) were studied, including individuals never treated for HBV infection (n= 7), HBV-infected individuals receiving anti-HBV therapy (n= 13), and HIV-1-HBV-coinfected individuals receiving anti-HBV therapy (n= 14). CD4+and CD8+HBV-specific T-cell responses were more frequently detected and the CD8+T-cell responses were of greater magnitude and breadth in subjects on anti-HBV treatment than in untreated chronic HBV carriers. There was a significant inverse correlation between detection of a HBV-specific T-cell response and HBV viral load. HBV-specific CD4+and CD8+T-cell responses were significantly (fivefold) reduced compared with HIV-specific responses. Although, the frequency and breadth of HBV-specific CD8+T-cell responses were comparable in the monoinfected and HIV-1-HBV-coinfected groups, HBV-specific CD4+T-cell responses were significantly reduced in HIV-1-HBV-coinfected individuals. Therefore, HIV-1 infection has a significant and specific effect on HBV-specific T-cell immunity.
Human Cytomegalovirus Tegument Protein ppUL35 Is Important for Viral Replication and Particle Formation
Authors: Schierling Karina , Buser Christopher , Mertens Thomas , Winkler Michael
Published: February 2005

The tegument proteins ppUL35 and ppUL82 (pp71) of human cytomegalovirus (HCMV) physically interact and cooperatively activate the major immediate-early transcription. While an HCMV mutant lacking UL82 displayed a multiplicity of infection (MOI)-dependent growth, the biological significance of ppUL35 has not been addressed so far. We generated a mutant virus with a deletion of the UL35 gene. Using an MOI of 0.1, the progeny virus yield of this mutant was reduced by a factor of 1,000; however, when infected at a low MOI (0.01), the gene was essential. Characterization of the replication cycle showed that the mutant virus had two defects: when virus inoculum was standardized by the amount of viral DNA, a reduced immediate-early gene expression was observed, leading to a strongly delayed expression of lytic genes. A second defect was apparent in the virus assembly, as fewer enveloped particles and no dense bodies were present in cells infected with the mutant virus. However, the particles produced by wild-type and mutant viruses did not show significant ultrastructural differences. These results suggest an important role for ppUL35 in immediate-early gene expression and virus assembly.
Equine Herpesvirus 1 Utilizes a Novel Herpesvirus Entry Receptor
Authors: Frampton Arthur R. , Goins William F. , Cohen Justus B. , von Einem Jens , Osterrieder Nikolaus , O'Callaghan Dennis J. , Glorioso Joseph C.
Published: February 2005

The well-described herpesvirus entry receptors HveA (TNFRSF14), HveB (nectin 2), and HveC (nectin 1) have been shown to mediate the entry of alphaherpesviruses. Our findings showed that the alphaherpesvirus equine herpesvirus 1 (EHV-1) efficiently entered and replicated in CHO-K1 cells that lack the entry receptors HveA, HveB, and HveC, demonstrating that EHV-1 utilizes a unique entry receptor. As with other alphaherpesviruses, efficient EHV-1 entry was dependent on glycoprotein D and cell surface glycosaminoglycans.
Severe Acute Respiratory Syndrome Coronavirus 3a Protein Is a Viral Structural Protein
Authors: Ito Naoto , Mossel Eric C. , Narayanan Krishna , Popov Vsevolod L. , Huang Cheng , Inoue Taisuke , Peters Clarence J. , Makino Shinji
Published: February 2005

The present study showed the association of a severe acute respiratory syndrome coronavirus (SCoV) accessory protein, 3a, with plasma membrane and intracellular SCoV particles in infected cells. 3a protein appeared to undergo posttranslational modifications in infected cells and was incorporated into SCoV particles, establishing that 3a protein was a SCoV structural protein.
Mutational Analysis of Hepatitis C Virus Nonstructural Protein 5A: Potential Role of Differential Phosphorylation in RNA Replication and Identification of a Genetically Flexible Domain
Authors: Appel Nicole , Pietschmann Thomas , Bartenschlager Ralf
Published: February 2005

Nonstructural protein 5A of the hepatitis C virus (HCV) is a highly phosphorylated molecule implicated in multiple interactions with the host cell and most likely involved in RNA replication. Two phosphorylated variants of NS5A have been described, designated according to their apparent molecular masses (in kilodaltons) as p56 and p58, which correspond to the basal and hyperphosphorylated forms, respectively. With the aim of identifying a possible role of NS5A phosphorylation for RNA replication, we performed an extensive mutation analysis of three serine clusters that are involved in phosphorylation and hyperphosphorylation of NS5A. In most cases, alanine substitutions for serine residues in the central cluster 1 that enhanced RNA replication to the highest levels led to a reduction of NS5A hyperphosphorylation. Likewise, several highly adaptive mutations in NS4B, which is also part of the replication complex, resulted in a reduction of NS5A hyperphosphorylation too, arguing that alterations of the NS5A phosphorylation pattern play an important role for RNA replication. On the other hand, a deletion encompassing all highly conserved serine residues in the C-terminal region of NS5A that are involved in basal phosphorylation did not significantly affect RNA replication but reduced formation of p56. This region was found to tolerate even large insertions with only a moderate effect on replication. Based on these results, we propose a model of the role of NS5A phosphorylation in the viral life cycle.
Chimeric Human Immunodeficiency Virus Type 1 Virions That Contain the Simian Immunodeficiency Virus
nef
Gene Are Cyclosporin A Resistant
Authors: Khan Mahfuz , Jin Lingling , Miles Lesa , Bond Vincent C. , Powell Michael D.
Published: February 2005

We have previously shown that human immunodeficiency virus type 1 (HIV-1) virions which have their own
nef
gene deleted and are
trans
complemented to contain HIV-2 or simian immunodeficiency virus (SIV) Nef become resistant to treatment with cyclosporin A. To expand and confirm these studies, we have tested an HIV-1 isolate in which the HIV-1
nef
gene has been replaced by the
nef
gene from SIV in a multiround infectivity assay using more physiologically relevant cell types. Our results confirm that HIV-1 virions that contain SIV
nef
can replicate in a cyclophilin-independent fashion.
Can we evaluate population screening strategies in UK general practice? A pilot randomised controlled trial comparing postal and opportunistic screening for genital chlamydial infection
Authors: Senok Abiola , Wilson Phil , Reid Margaret , Scoular Anne , Craig Neil , McConnachie Alex , Fitzpatrick Bridie , MacDonald Alison
Published: February 2005

Study objective:To assess whether opportunistic and postal screening strategies forChlamydia trachomatiscan be compared with usual care in a randomised trial in general practice.

Design:Feasibility study for a randomised controlled trial.

Setting:Three West of Scotland general medical practices: one rural, one urban/deprived, and one urban/affluent.

Participants:600 women aged 16–30 years, 200 from each of three participating practices selected at random from a sample of West of Scotland practices that had expressed interest in the study. The women could opt out of the study. Those who did not were randomly assigned to one of three groups: postal screening, opportunistic screening, or usual care.

Results:38% (85 of 221) of the approached practices expressed interest in the study. Data were collected successfully from the three participating practices. There were considerable workload implications for staff. Altogether 124 of the 600 women opted out of the study. During the four month study period,55% (81 of 146) of the control group attended their practice but none was offered screening.Some 59% (80 of 136) women in the opportunistic group attended their practice of whom 55% (44 of 80) were offered screening. Of those, 64% (28 of 44) accepted, representing 21% of the opportunistic group. Forty eight per cent (59 of 124) of the postal group returned samples.

Conclusion:A randomised controlled trial comparing postal and opportunistic screening for chlamydial infection in general practice is feasible, although resource intensive. There may be problems with generalising from screening trials in which patients may opt out from the offer of screening.
Study of familial Parkinson’s disease in Russia, Uzbekistan, and Zambia
Authors: Atadzhanov M , Zumla A , Mwaba P
Published: February 2005

Objective

The aims of this study were (A) to determine inheritance patterns of familial Parkinson’s disease in three different geographical areas (Russia, Uzbekistan, and Zambia); (B) compare clinical characteristics of familial with sporadic Parkinson’s disease; and (C) assess whether there were ethnic differences in clinical manifestations of the disease.

Methods

Fifty two index cases of familial Parkinson’s disease in Moscow, 55 in Tashkent, and 27 in Lusaka were selected on the basis of the typical clinical features of Parkinson’s disease with a familial history. The sex ratio, transmission patterns, and segregation ratio were determined by pedigree analysis.

Results

Familial Parkinson’s disease was found in all three countries (30 families in Russia, 12 in Uzbekistan, and seven in Zambia), and appeared more common in Russia. Both autosomal dominant and autosomal recessive patterns of inheritance were seen, but autosomal dominance was more common in all countries.

Conclusions

In all three countries men have a higher risk of developing Parkinson’s disease than women and there are ethnic differences in clinical manifestations of the disease. The onset of both familial and sporadic Parkinson’s disease in Zambian patients occurs at a younger age and is associated with slow progression and a benign course, and generally responds well to levodopa treatment.
Modified electrode placement must be recorded when performing 12-lead electrocardiograms
Authors: Jowett N I , Turner A M , Cole A , Jones P A
Published: February 2005

Background

Local observation has suggested that placing limb leads on the torso when recording the standard 12-lead resting electrocardiogram (ECG) has become commonplace. This non-standard modification has the important advantages of ease and speed of application, and in an emergency may be applied with minimal undressing. Limb movement artefact is also reduced. It is believed that ECGs obtained with torso electrodes are interchangeable with standard ECGs and any minor electrocardiographic variations do not affect diagnostic interpretation.

Study design

The study compared 12-lead ECGs in 100 patients during routine electrocardiography, one being taken in the approved way and one taken with modified limb electrodes.

Results

It was found that the use of torso leads produced important amplitude and waveform changes associated with a more vertical and rightward shift of the QRS frontal axis, particularly in those with abnormal standard ECGs. Such changes generated important ECG abnormalities in 36% of patients with normal standard ECGs, suggesting “heart disease of electrocardiographic origin”. In those with abnormal standard ECGs, moving the limb leads to the torso made eight possible myocardial infarcts appear and five inferior infarcts disappeared. Twelve others developed clinically important T wave or QRS frontal axis changes.

Conclusions

It is vital that ECGs should be acquired in the standard way unless there are particular reasons for not doing so, and that any modification of electrode placement must be reported on the ECG itself. Marking the ECG “torso-positioned limb leads” or “non-standard” should alert the clinician to its limitations for clinical or investigative purposes, as any lead adaptation may modify the tracing and could result in misinterpretation.
CELL BIOLOGY OF ANTIGEN PROCESSING IN VITRO AND IN VIVO
Authors: Trombetta E. Sergio , Mellman Ira
Published: February 2005

▪ Abstract  The conversion of exogenous and endogenous proteins into immunogenic peptides recognized by T lymphocytes involves a series of proteolytic and other enzymatic events culminating in the formation of peptides bound to MHC class I or class II molecules. Although the biochemistry of these events has been studied in detail, only in the past few years has similar information begun to emerge describing the cellular context in which these events take place. This review thus concentrates on the properties of antigen-presenting cells, especially those aspects of their overall organization, regulation, and intracellular transport that both facilitate and modulate the processing of protein antigens. Emphasis is placed on dendritic cells and the specializations that help account for their marked efficiency at antigen processing and presentation both in vitro and, importantly, in vivo. How dendritic cells handle antigens is likely to be as important a determinant of immunogenicity and tolerance as is the nature of the antigens themselves.
ROLE OF C5A IN INFLAMMATORY RESPONSES
Authors: Guo Ren-Feng , Ward Peter A.
Published: February 2005

▪ Abstract  The complement system not only represents an effective innate immune mechanism of host defense to eradicate microbial pathogens, but it is also widely involved in many forms of acute and chronic inflammatory diseases including sepsis, acute lung injury, ischemia-reperfusion injury, and asthma, to give just a few examples. The complement-activated product, C5a, displays powerful biological activities that lead to inflammatory sequelae. C5a is a strong chemoattractant and is involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, in activation of phagocytic cells and release of granule-based enzymes and generation of oxidants, all of which may contribute to innate immune functions or tissue damage. Accumulating data suggest that C5a provides a vital bridge between innate and adaptive immune functions, extending the roles of C5a in inflammation. Herein, we review human and animal data describing the cellular and molecular mechanisms of C5a in the development of inflammatory disorders, sepsis, acute lung injury, ischemia-reperfusion injury, and asthma.
Overdrive pacing of early ischemic ventricular tachycardia: evidence for both reentry and triggered activity
Authors: Arnar David O. , Xing Dezhi , Martins James B.
Published: February 2005

Entrainment can be a useful method to identify reentry as a mechanism of ventricular tachycardia (VT). In this study, we evaluated the effect of gradually decreasing cycle lengths of overdrive pacing for stable VT induced in a canine model 1–3 h after coronary occlusion. Intact dogs underwent anterior descending coronary artery occlusion after instrumentation of the risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms. Overdrive pacing was attempted if the animals had sustained hemodynamically stable VT, looking for evidence of entrainment. Subsequent three-dimensional mapping determined the mechanism of VT. Fifteen of the 21 dogs studied demonstrated entrainment with overdrive pacing by progressive QRS fusion alone ( 1 ), the first nonpaced QRS entrained to the paced cycle length only ( 7 ), or both ( 7 ). Five of these 15 dogs also had postpacing acceleration of the VT at a subsequent faster pacing cycle length. The mechanism of acceleration in four was a change to a VT with a focal origin. The prepacing mechanism in all 15 dogs was subsequently mapped to reentry. Regarding the six VTs, which demonstrated no evidence for entrainment, the site of earliest activity was mapped to a focal origin in all. These data showing entrainment of inducible reentrant VTs and lack of such for focal VTs support that the focal VTs seen in this study are unlikely the result of microreentry but possibly a mechanism as triggered activity.
Cariporide enables hemodynamically more effective chest compression by leftward shift of its flow-depth relationship
Authors: Kolarova Julieta D. , Ayoub Iyad M. , Gazmuri Raúl J.
Published: February 2005

When given during closed-chest resuscitation, cariporide (4-isopropyl-methylsulfonylbenzoyl-guanidine methanesulfonate; a selective inhibitor of the Na+/H+ exchanger isoform-1) enables generation of viable perfusion pressures with less depth of compression. We hypothesized that this effect results from greater blood flows generated for a given depth of compression. Two series of 14 rats each underwent 10 min of untreated ventricular fibrillation followed by 8 min of chest compression before defibrillation was attempted. Compression depth was adjusted to maintain an aortic diastolic pressure (ADP) between 26 and 28 mmHg in the first series and between 36 and 38 mmHg in the second series. Within each series, rats were randomized to receive cariporide (3 mg/kg) or NaCl (0.9%; control) before chest compression was started. Blood flow was measured using 15-μm fluorescent microspheres. Less depth of compression was required to maintain the target ADP when cariporide was present in both series 1 (13.6 ± 1.2 vs. 16.6 ± 1.2 mm; P < 0.001) and series 2 (15.3 ± 1.0 vs. 18.9 ± 1.5 mm; P < 0.001). Despite less compression depth, the cardiac index in cariporide-treated rats was comparable to control rats in series 1 (11.1 ± 0.7 vs. 11.3 ± 1.4 ml·min−1·kg−1; P = not significant) but higher in series 2 (15.5 ± 2.3 vs. 9.9 ± 1.4 ml·min−1·kg−1; P < 0.05). Increases in compression depth (from series 1 to series 2) increased myocardial, cerebral, and adrenal blood flow in cariporide-treated rats. We conclude that cariporide enhances the efficacy of closed-chest resuscitation by leftward shift of the flow-depth relationship.
Prediction of circulatory equilibrium in response to changes in stressed blood volume
Authors: Uemura Kazunori , Kawada Toru , Kamiya Atsunori , Aiba Takeshi , Hidaka Ichiro , Sunagawa Kenji , Sugimachi Masaru
Published: February 2005

Accurate prediction of cardiac output (CO), left atrial pressure (PLA), and right atrial pressure (PRA) is a prerequisite for management of patients with compromised hemodynamics. In our previous study (Uemura et al. Am J Physiol Heart Circ Physiol 286: H2376–H2385, 2004), we demonstrated a circulatory equilibrium framework, which permits the prediction of CO, PLA, and PRA once the venous return surface and integrated CO curve are known. Inasmuch as we also showed that the surface can be estimated from single-point CO, PLA, and PRA measurements, we hypothesized that a similar single-point estimation of the CO curve would enable us to predict hemodynamics. In seven dogs, we measured the PLA-CO and PRA-CO relations and derived a standardized CO curve using the logarithmic function CO = SL[ln(PLA − 2.03) + 0.80] for the left heart and CO = SR[ln(PRA − 2.13) + 1.90] for the right heart, where SL and SR represent the preload sensitivity of CO, i.e., pumping ability, of the left and right heart, respectively. To estimate the integrated CO curve in each animal, we calculated SL and SR from single-point CO, PLA, and PRA measurements. Estimated and measured CO agreed reasonably well. In another eight dogs, we altered stressed blood volume (−8 to +8 ml/kg of reference volume) under normal and heart failure conditions and predicted the hemodynamics by intersecting the surface and the CO curve thus estimated. We could predict CO [ y = 0.93 x + 6.5, r 2 = 0.96, standard error of estimate (SEE) = 7.5 ml·min−1·kg−1], PLA ( y = 0.90 x + 0.5, r 2 = 0.93, SEE = 1.4 mmHg), and PRA ( y = 0.87 x + 0.4, r 2 = 0.91, SEE = 0.4 mmHg) reasonably well. In conclusion, single-point estimation of the integrated CO curve enables accurate prediction of hemodynamics in response to extensive changes in stressed blood volume.
Diastolic dysfunction in volume-overload hypertrophy is associated with abnormal shearing of myolaminar sheets
Authors: Ashikaga Hiroshi , Covell James W. , Omens Jeffrey H.
Published: February 2005

Diastolic dysfunction in volume-overload hypertrophy by aortocaval fistula is characterized by increased passive stiffness of the left ventricle (LV). We hypothesized that changes in passive properties are associated with abnormal myolaminar sheet mechanics during diastolic filling. We determined three-dimensional finite deformation of myofiber and myolaminar sheets in the LV free wall of six dogs with cineradiography of implanted markers during development of volume-overload hypertrophy by aortocaval fistula. After 9 ± 2 wk of volume overload, all dogs developed edema of extremities, pulmonary congestion, elevated LV end-diastolic pressure (5 ± 2 vs. 21 ± 4 mmHg, P < 0.05), and increased LV volume. There was no significant change in systolic function [dP/d tmax: 2,476 ± 203 vs. 2,330 ± 216 mmHg/s, P = not significant (NS)]. Diastolic relaxation was significantly reduced (dP/d tmin: −2,466 ± 190 vs. −2,076 ± 166 mmHg/s, P < 0.05; time constant of LV pressure decline: 32 ± 2 vs. 43 ± 1 ms, P < 0.05), whereas duration of diastolic filling was unchanged (304 ± 33 vs. 244 ± 42 ms, P = NS). Fiber stretch and sheet shear occur predominantly in the first third of diastolic filling, and chronic volume overload induced remodeling in lengthening of the fiber and reorientation of the laminar sheet architecture. Sheet shear was significantly increased and delayed at the subendocardial layer ( P < 0.05), whereas magnitude of fiber stretch was not altered in volume overload ( P = NS). These findings indicate that enhanced filling in volume-overload hypertrophy is achieved by enhanced sheet shear early in diastole. These results provide the first evidence that changes in motion of radially oriented laminar sheets may play an important functional role in pathology of diastolic dysfunction in this model.
Islet cell response in the neonatal rat after exposure to a high-fat diet during pregnancy
Authors: Cerf M. E. , Williams K. , Nkomo X. I. , Muller C. J. , Du Toit D. F. , Louw J. , Wolfe-Coote S. A.
Published: February 2005

Although pancreatic β-cells are capable of adapting their mass in response to insulin requirements, evidence has shown that a dietary insult could compromise this ability. Fetal malnutrition has been linked to low birth weight and the development of type 2 diabetes later in life, while reduced β-cell mass has been reported in adult rats fed a high-fat diet (HFD). Reported here are the effects of exposure to a HFD, during different periods of gestation, on neonatal rat weight and β- and α-cell development. The experimental groups were composed of neonatal offspring obtained from Wistar rats fed a high-fat (40% as energy) diet for either the first (HF1), second (HF2), or third (HF3) week, or all three (HF1–3) weeks of gestation. Neonatal weights and circulating glucose and insulin concentrations were measured on postnatal day 1, after which the pancreata were excised and processed for histological immunocytochemical examination and image analysis. HF1 and HF2 neonates were hypoglycemic, whereas HF1–3 neonates were hyperglycemic. Low birth weights were observed only in HF1 neonates. No significant differences were detected in the circulating insulin concentrations in the neonates, although β-cell volume and numbers were reduced in HF1–3 neonates. β-cell numbers also declined in HF1 and HF3 neonates. α-cell volume, number and size were, however, increased in HF1–3 neonates. α-cell size was also increased in HF1 and HF3 neonates. In neonates, exposure to a maternal HFD throughout gestation was found to have the most adverse effect on β-cell development and resulted in hyperglycemia.
D1-dopamine receptor agonists prevent and reverse opiate depression of breathing but not antinociception in the cat
Authors: Lalley Peter M.
Published: February 2005

Opioids depress respiration and decrease chest wall compliance. A previous study in this laboratory showed that dopamine-D1receptor (D1R) agonists restored phrenic nerve activity after arrest by fentanyl in immobilized, mechanically ventilated cats. The reinstated phrenic nerve rhythm was slower than control, so it was not known whether D1R agonists can restore spontaneous breathing to levels that provide favorable alveolar gas exchange and blood oxygenation. It was also not known whether the agonists counteract opioid analgesia. In the present study, anesthetized, spontaneously breathing cats were given intravenous doses of fentanyl (18.0 ± 3.4 μg/kg) that severely depressed depth and rate of respiration, lowered arterial hemoglobin oxygenation (HbO2), elevated end-tidal carbon dioxide (ETCO2), and abolished the nociceptive hind limb crossed-extensor reflex. Fentanyl (30 μg/kg) also evoked tonic discharges of caudal medullary expiratory neurons in paralyzed mechanically ventilated cats, which might explain decreased chest compliance. The selective D1R agonists 6-chloro APB (3 mg/kg) or dihydrexidine (DHD, 1 mg/kg) increased depth and rate of spontaneous breathing after opioid depression and returned HbO2and ETCO2to control levels. Opioid arrest of the nociceptive reflex remained intact. Pretreatment with DHD prevented significant depression of spontaneous breathing by fentanyl (17.5 ± 4.3 μg/kg). Tonic firing evoked by fentanyl in expiratory neurons was converted to rhythmic respiratory discharges by DHD (1 mg/kg). The results suggest that D1R agonists might be therapeutically useful for the treatment of opioid disturbances of breathing without impeding analgesia.
Effect of sustained hypobaric hypoxia during maturation and aging on rat myocardium. II. mtNOS activity
Authors: Zaobornyj Tamara , Valdez Laura B. , La Padula Pablo , Costa Lidia E. , Boveris Alberto
Published: February 2005

Mitochondrial nitric oxide (NO) production was assayed in rats submitted to hypobaric hypoxia and in normoxic controls (53.8 and 101.3 kPa air pressure, respectively). Heart mitochondria from young normoxic animals produced 0.62 and 0.37 nmol NO·min−1·mg protein−1in metabolic states 4 and 3, respectively. This production accounts for a release to the cytosol of 29 nmol NO·min−1·g heart−1and for 55% of the NO generation. The mitochondrial NO synthase (mtNOS) activity measured in submitochondrial membranes at pH 7.4 was 0.69 nmol NO·min−1·mg protein−1. Rats exposed to hypobaric hypoxia for 2–18 mo showed 20–60% increased left ventricle mtNOS activity compared with their normoxic siblings. Left ventricle NADH-cytochrome- c reductase and cytochrome oxidase activities decreased by 36 and 12%, respectively, from 2 to 18 mo of age, but they were not affected by hypoxia. mtNOS upregulation in hypoxia was associated with a retardation of the decline in the mechanical activity of papillary muscle upon aging and an improved recovery after anoxia-reoxygenation. The correlation of left ventricle mtNOS activity with papillary muscle contractility (determined as developed tension, maximal rates of contraction and relaxation) showed an optimal mtNOS activity (0.69 nmol·min−1·mg protein−1). Heart mtNOS activity is regulated by O2in the inspired air and seems to play a role in NO-mediated signaling and myocardial contractility.
Constitutive and Induced Neurogenesis in the Adult Mammalian Brain: Manipulation of Endogenous Precursors toward CNS Repair
Authors: Mitchell Bartley D. , Emsley Jason G. , Magavi Sanjay S.P. , Arlotta Paola , Macklis Jeffrey D.
Published: February 2005

Over most of the past century of modern neuroscience, it was thought that the adult brain was completely incapable of generating new neurons. During the past 3 decades, research exploring potential neuronal replacement therapies has focused on replacing lost neurons by transplanting cells or grafting tissue into diseased regions of the brain. However, in the last decade, the development of new techniques has resulted in an explosion of new research showing that neurogenesis, the birth of new neurons, normally occurs in two limited and specific regions of the adult mammalian brain and that there are significant numbers of multipotent neural precursors in many parts of the adult mammalian brain. Recent advances in our understanding of related events of neural development and plasticity, including the role of radial glia in developmental neurogenesis and the ability of endogenous precursors present in the adult brain to be induced to produce neurons and partially repopulate brain regions affected by neurodegenerative processes, have led to fundamental changes in the views about how the brain develops as well as to approaches by which endogenous precursors might be recruited to repair the adult brain. Recruitment of new neurons can be induced in a region-specific, layer-specific and neuronal-type-specific manner, and, in some cases, newly recruited neurons can form long-distance connections to appropriate targets. Elucidation of the relevant molecular controls may both allow control over transplanted precursor cells and potentially allow the development of neuronal replacement therapies for neurodegenerative disease and other CNS injuries that do not require transplantation of exogenous cells.
SOX2, a Persistent Marker for Multipotential Neural Stem Cells Derived from Embryonic Stem Cells, the Embryo or the Adult
Authors: Ellis Pam , Fagan B. Matthew , Magness Scott T. , Hutton Scott , Taranova Olena , Hayashi Shigemi , McMahon Andrew , Rao Mahendra , Pevny Larysa
Published: February 2005

Multipotent neural stem cells are present throughout the development of the central nervous system (CNS), persist into adulthood in defined locations and can be derived from more primitive embryonic stem cells. We show that SOX2, an HMG box transcription factor, is expressed in multipotent neural stem cells at all stages of mouse ontogeny. We have generated transgenic mice expressing enhanced green fluorescent protein (EGFP) under the control of the endogenous locus-regulatory regions of the Sox2 gene to prospectively identify neural stem/progenitor cells in vivo and in vitro. Fluorescent cells coexpress SOX2 protein, and EGFP fluorescence is detected in proliferating neural progenitor cells of the entire anterior-posterior axis of the CNS from neural plate stages to adulthood. SOX2-EGFP cells can form neurospheres that can be passaged repeatedly and can differentiate into neurons, astrocytes and oligodendrocytes. Moreover, prospective clonal analysis of SOX2- EGFP-positive cells shows that all neurospheres, whether isolated from the embryonic CNS or the adult CNS, express SOX2-EGFP. In contrast, the pattern of SOX2-EGFP expression using randomly integrated Sox2 promoter/reporter construct differs, and neurospheres are heterogeneous for EGFP expression. These studies demonstrate that SOX2 may meet the requirements of a universal neural stem cell marker and provides a means to identify cells which fulfill the basic criteria of a stem cell: self-renewal and multipotent differentiation.
Fibroblast Growth Factor 2 Is Required for Maintaining the Neural Stem Cell Pool in the Mouse Brain Subventricular Zone
Authors: Zheng Wei , Nowakowski Richard S. , Vaccarino Flora M.
Published: February 2005

Cells within the subventricular zone (SVZ) express basic Fgf (Fgf2) and Fgf receptor proteins. We show that the absence of Fgf2 gene products reduces by 50% the dividing progenitor population of the anterior SVZ (SVZa) without changing their cell cycle time. Every 2–3 cell cycles of the SVZa progenitor cell population, 30,000 newly generated neurons capable of long-term survival are added to the glomerular layer of the olfactory bulb. Fgf2 knockout mice have smaller olfactory bulbs due to decreased output of these newly generated cells into the bulbs. A population of slow-dividing neural stem cells (NSCs) residing in the SVZa is identified by its slow cell cycle kinetics (cell cycle approx. 20 days); these cells, called ‘S’ cells, are negative for glial fibrillary acidic protein and occasionally express brain-lipid-binding protein, a molecular marker of radial glia. The number of these dividing NSCs is reduced from about 13,000 in wild-type to 8,500 cells in Fgf2 knockout mice. Thus, FGF2 regulates the number of proliferative cells and olfactory bulb neurogenesis by maintaining a slow-dividing stem cell pool within the SVZa.
The Short-Term Effects of a Hurricane on the Diet and Activity of Black Howlers (Alouatta pigra) in Monkey River, Belize
Authors: Behie Alison M. , Pavelka Mary S.M.
Published: February 2005

The diet and activity of a population of Alouatta pigra were compared before and immediately after a major hurricane to begin to explore how the monkeys cope with severe habitat destruction. Focal animal data were collected from January to April (dry season) for two seasons before (368 h) and one season after the storm (149 h) on a population of black howlers in Monkey River, Belize. During the first dry season after the storm, the monkeys changed their diet in direct accordance with the availability of food. The absence of fruit and flower production and the increase in new leaf availability forced the monkeys to adopt a completely folivorous diet. The activity budget of the monkeys also changed, and they spent more time inactive, which may be linked to the change in the distribution and type of food available. They also spent less time in social interactions, which may be due to the lower number of juveniles in the population or to the formation of new groups between unfamiliar individuals following the hurricane. The ability to live for long periods of time on leaves alone has allowed the remaining population to survive in the short term.
Certain Aspects of Bonobo Female Sexual Repertoire Are Related to Urinary Testosterone Metabolite Levels
Authors: Sannen Adinda , Van Elsacker Linda , Heistermann Michael , Eens Marcel
Published: February 2005

We examined the unknown relationship between testosterone and sexual behaviour in female bonobos (Pan paniscus) on a daily and long-term level. In most animal species, sexual behaviours mainly focus on reproduction. Bonobos, however, also use sexual interactions to a large extent to maintain and restore social relationships. They display an elaborate sexual repertoire that is expressed during fertile as well as non-fertile periods in life and exhibit a high degree of female control over sexual interactions. Using urinary testosterone metabolite levels of cycling and non-cycling females, we found no relationship between daily differences in testosterone metabolite concentrations and any of the sexual behaviours. However, long-term differences in the variables partially confirm the hypothesis of Jurke et al. [2001] stating that in bonobos testosterone is primarily related to non-reproductive sexual interactions. Furthermore, remarkably, a negative correlation of testosterone metabolite levels with the frequency of the females’ sexual inspections was demonstrated. No correlation was found with the frequency of sexual presentations performed by the females and with the frequency of masturbation. We present a case study on this topic in an immigrating female.
Severe Hypothyroidism Caused by Hepatic Hemangioendothelioma in an Infant of a Diabetic Mother
Authors: Güven Ayla , Aygun Canan , İnce Hülya , Aydın Murat , Pınarlı F. Güçlü , Baysal Kemal , Küçüködük Sükrü
Published: February 2005

Hemangioendotheliomas can express type 3 iodothyronine deiodinase and cause severe hypothyroidism. The risk of congenital malformations such as vertebral and cardiac abnormalities in infants of diabetic mothers is higher than babies of healthy women. Here we report an infant of a diabetic mother with hypothyroidism caused by liver hemangioendothelioma. Consumptive hypothyroidism should be an indicator to search for a vascular tumor in infants. Supranormal doses of L-thyroxine might be required for normalization of thyroid function until the tumor involutes or is resected.
Comparative Anatomy of the Electrosensory Lateral Line Lobe of Mormyrids: The Mystery of the Missing Map in the Genus Stomatorhinus (Family: Mormyridae)
Authors: McNamara Ann Marie , Denizot Jean-Pierre , Hopkins Carl D.
Published: February 2005

Fish in the family Mormyridae produce weak electric organ discharges that are used in orientation and communication. The peripheral and central anatomy of the electrosensory system has been well studied in the species Gnathonemus petersii, but comparative studies in other species are scarce. Here we report on one genus of mormyrid that displays a remarkable change in the electrosensory lateral line lobe (ELL), the hypertrophied rhombencephalic structure that receives primary electroreceptor input. Although all other mormyrids studied have three distinct zones on each side of the ELL, fish of the genus Stomatorhinus exhibit only two. Therefore, the two-zone ELL is a unique derived characteristic shared by Stomatorhinus. We examined the cutaneous electroreceptors that project to the ELL in Stomatorhinus. All three types of electroreceptors previously described for G. petersii were present, but there was a significant change in one type, the mormyromast. Both mormyromast sensory cell types (A- and B-cells) are present, but the B-cell is not innervated in Stomatorhinus. We conclude that, although all cutaneous sensory cells are present, the missing B-cell afferents account for the loss of the dorsolateral zone of the ELL, and therefore the loss of an entire sensory map. Because mormyromasts are involved in electrolocation behavior, this anatomical difference is probably related to differences in electrolocation abilities. Stomatorhinus could prove to be an excellent system for linking evolutionary changes in behavior with modifications in their neural substrates.
Differential Effects of Transforming Growth Factor-Beta on the Synthesis of Connective Tissue Growth Factor and Vascular Endothelial Growth Factor by Peritoneal Mesothelial Cell
Authors: Szeto Cheuk-Chun , Lai Ka-Bik , Chow Kai-Ming , Szeto Carol Yi-Ki , Wong Teresa Yuk-Hwa , Li Philip Kam-Tao
Published: February 2005

Background: Previous studies found that transforming growth factor-β (TGF-β) plays a conflicting role in peritoneal fibrosis. We hypothesise that TGF-β acts on peritoneal mesothelial cells (PMC) via VEGF and CTGF as downstream mediators. Methods: The effect of TGF-β in primary culture of rat PMC was studied. VEGF and CTGF mRNA expression was examined by real time quantitative polymerase chain reaction (RT-QPCR), and VEGF antigen level in cell supernatant by ELISA. Results: Incubation of rat PMC with TGF-β resulted in a time- (3–72 h) and concentration- (0–50 pg/ml) dependent increase in VEGF mRNA expression, and VEGF protein level in the cell supernatant. When stimulated with TGF-β 100 pg/ml, there was a 20-fold up-regulation of VEGF mRNA expression (p < 0.001). The CTGF mRNA expression and protein level of PMC was slightly increased at low concentration of TGF-β (50 pg/ml) but decreased at a higher concentration (100 pg/ml or above). The effect of TGF-β on PMC CTGF, but not VEGF, gene expression was inhibited by Smad decoy oligodeoxynucleotide. The effect of TGF-β on PMC VEGF gene expression and protein synthesis was inhibited by PD98059 (a specific MAP kinase inhibitor) and chelerythrine (a specific protein kinase C inhibitor), but not cholera toxin (activator of cyclic AMP) or herbimycin A (inhibitor of protein tyrosine kinase). The up-regulation of CTGF mRNA expression was inhibited by PD98059, but not chelerythrine, cholera toxin or herbimycin A. Furthermore, CTGF gene expression in TGF-β-stimulated PMC was inhibited by co-administration of recombinant VEGF. Conclusions: Our data demonstrate that TGF-β induces PMC production of VEGF and CTGF via different signalling pathways. At high concentration of TGF-β, VEGF production predominates and CTGF production was inhibited. Since CTGF and VEGF have different biologic effects, our results may explain the complex activity of TGF-β in peritoneal physiology.
c-Jun N-Terminal Kinase Is Involved in Mercuric Ions-Mediated Interleukin-4 Secretion in Mast Cells
Authors: Walczak-Drzewiecka Aurelia , Wyczółkowska Janina , Dastych Jarosław
Published: February 2005

Background: Interleukin (IL)-4 plays a prominent role in immune response. Mercuric compounds upregulate IL-4 expression in animal tissues, and this upregulation plays a role in mercuric-mediated immunomodulation. Mercuric ions-mediated IL-4 expression was observed in vitro in T lymphocytes and mast cells. In the present study, we investigated molecular mechanisms responsible for this effect of mercuric ions in mast cells. Methods: C1.MC/C57.1 mouse mast cells were exposed in vitro to increasing concentrations of Hg2+ in the absence or presence of the specific c-Jun N-terminal kinase (JNK) inhibitor SP600125. The level of phosphorylated c-Jun in mast cells was determined by Western blotting, JNK activity assessed with in vitro kinase assay and the amount of secreted IL-4 determined by ELISA. Results: We observed that Hg2+ upregulated c-Jun phosphorylation on Ser 73 at concentrations which overlapped concentrations mediating IL-4 secretion. Phosphorylation of c-Jun in mast cells was associated with an increase in JNK activity. The specific JNK inhibitor SP600125 abolished both mercuric-induced c-Jun phosphorylation and IL-4 secretion in mast cells. Conclusions: These observations are consistent with the hypothesis that JNK is one of the signaling proteins mediating the effect of Hg2+ on IL-4 expression in mast cells and is engaged in environmentally mediated immunomodulation.
Recent Highlights in the Pathophysiology of Atopic Eczema
Authors: Allam J.-P. , Bieber T. , Novak N.
Published: February 2005

Atopic eczema (AE) belongs to the group of atopic diseases that have become increasingly prevalent over the last decades. The pathophysiology of AE has long remained enigmatic, but much scientific effort has been invested in elucidating the genetic background and the immunological mechanisms underlying AE, leading to a better understanding of this complex disease and to new therapeutic strategies. This review provides an update on the scientific progress that has been achieved in clarifying the pathophysiological mechanisms of AE.
Atopy and Asthma in Migrants
Authors: Rottem Menachem , Szyper-Kravitz Martine , Shoenfeld Yehuda
Published: February 2005

Atopy and asthma result from the effects of environmental factors on genetically susceptible persons, and different prevalence rates have been documented worldwide. In developed and industrialized countries a higher prevalence of atopy and asthma is observed as compared with undeveloped and less affluent countries. Migration involves exposure to a new set of pollutants and allergens. In addition, it involves several socioeconomic and cultural issues such as housing conditions, diet and accessibility to medical services, all of which are likely to affect migrants’ health. Migration studies provide information on the role of environmental factors in the development of atopy and asthma. Immigration to allergy-prevalent countries causes more allergies and asthma in immigrants as compared to the prevalence of atopy in their countries of origin. The increase in allergy and asthma is usually not related to ethnicity, but in certain populations may play an important role. Studies on migrants support the notion that lifestyle and environmental factors in western industrialized countries facilitate atopy and asthma. The effect is time-dependent. Acquiring allergy is influenced by the age at the time of immigration. Migrants, in general, are more prone to the development of allergies than the local population. Low hygiene prior to immigration does not seem to protect against the development of atopy or asthma. Vaccinations do not affect the development of atopy or asthma in the general population and in migrants. Migrants should be aware of the potential of developing allergies and/or asthma. Strategies for primary prevention in high-risk atopic individuals and secondary prevention guidelines should be developed both for populations in developing countries as well as for immigrants from such countries to atopy-prevalent developed countries.
GNAS Locus and Pseudohypoparathyroidism
Authors: Bastepe Murat , Jüppner Harald
Published: February 2005

Pseudohypoparathyroidism (PHP) is characterized by hypocalcemia and hyperphosphatemia due to resistance to parathyroid hormone (PTH). Patients with PHP-Ia often present with additional hormonal resistance and show characteristic physical features that are collectively termed Albright’s hereditary osteodystrophy (AHO). These features are also present in pseudopseudohypoparathyroidism (PPHP), but patients affected by this disorder do not show hormone resistance. PHP-Ib patients, on the other hand, present predominantly with renal PTH resistance and lack any features of AHO. Most of these PHP forms are caused by defects in GNAS (20q13.3), an imprinted gene locus with multiple transcriptional units. PHP-Ia and PPHP are caused by heterozygous inactivating mutations in those exons of GNAS encoding the α subunit of the stimulatory guanine nucleotide-binding protein (Gsα), and the autosomal dominant form of PHP-Ib (AD-PHP-Ib) is caused by heterozygous mutations disrupting a long-range imprinting control element of GNAS. Expressed nearly in all cells, Gsα plays essential roles in a multitude of physiological processes. Its expression in renal proximal tubules occurs predominantly from the maternal allele, and this tissue- and parent-specific imprinting of Gsα is an important determinant of hormone resistance in kindreds with PHP-Ia/PPHP and AD-PHP-Ib.