bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of antisense oligodeoxynucleotides for ICAM‐1 on renal ischaemia–reperfusion injury in the anaesthetised rat
Authors: Kiew Lik Voon , Munavvar Abdul Sattar , Law Chung Hiong , Azizan Abdullah Nor , Nazarina Abdul Rahman , Sidik Khalifah , Johns Edward J.
Published: March 2004

An antisense oligodeoxynucleotide (As‐ODN) to the 3′ untranslated region of the mRNA sequence expressing the intracellular adhesion molecule‐1 (ICAM‐1) was employed to determine ICAM‐1's role in renal ischaemia–reperfusion injury in the rat. Wistar‐Kyoto rats receivingi.v.either lipofectin–As‐ODN (As‐ODN group), lipofectin–reverse ODN (Rv‐ODN group) or lipofectin (ischaemia control group) 8 h prior to study were anaesthetized and subjected to 30 min of renal artery occlusion. Renal haemodynamic and excretory parameters were monitored before and after renal ischaemia. On termination of the study renal tissue was subjected to histological and Western blot analysis. Renal blood flow decreased in the 3 h post‐ischaemia period in the ischaemia control and Rv‐ODN groups, but was maintained in the As‐ODN group. Glomerular filtration rate was depressed initially but gradually increased to 10% above basal levels in the ischaemia control and Rv‐ODN groups, but was below basal levels (20%) in the As‐ODN group. There was a three‐ to fourfold increase in sodium and water excretion following ischaemia in the ischaemia control and reverse‐ODN groups but not in the As‐ODN treated group. The As‐ODN ameliorated the histological evidence of ischaemic damage and reduced ICAM‐1 protein levels to a greater extent in the medulla than cortex. These observations suggested that in the post‐ischaemic period afferent and efferent arteriolar tone was increased with a loss of reabsorptive capacity which was in part due to ICAM‐1. The possibility arises that the action of ICAM‐1 at vascular and tubular sites in the deeper regions of the kidney contributes to the ischaemia–reperfusion injury.
Rats exhibit aldosterone‐dependent sodium appetite during 24 h hindlimb unloading
Authors: Sullivan Margaret J. , Hasser Eileen M. , Moffitt Julia A. , Bruno Stacy B. , Cunningham J. Thomas
Published: March 2004

Hindlimb unloading (HU) is an animal model of microgravity and bed rest. In these studies, we examined the role of ingestive behaviours in regulating body fluid balance during 24 h HU. In the first experiment, all rats were given distilled water to drink while two groups were also given access to a sodium chloride solution (0.9% or 1.8%). Water and saline intakes were measured before, during and after 24 h of HU. Rats reduced water intake during 24 h HU in all conditions. During HU, rats increased their intakes of both saline solutions (0.9% NaCl (n= 11): control 7.8 ± 3 ml; HU 18.2 ± 4 ml; recovery 8.9 ± 2.5 ml; 1.8% NaCl (n= 7): control 1.0 ± 0.4 ml; HU 3.8 ± 0.3 ml; recovery 1.2 ± 0.5 ml). Although water intake decreased there was no reduction in total fluid intake when saline was available. Plasma volumes were reduced during HU compared to rats in a normal posture when only water was available to drink (control (n= 11) versus HU (n= 11): 4.0 ± 0.2 versus 3.4 ± 0.2 ml (100 g body weight)−1). When 0.9% saline was available in addition to water, plasma volumes after 24 h HU were not different from rats in a normal posture (control (n= 11) versus HU (n= 12): 4.3 ± 0.4 versus 4.3 ± 0.1 ml (100 g body weight)−1). Plasma aldosterone but not plasma renin activity was significantly elevated after 24 h HU. Central infusions of spironolactone blocked the increased intake of 1.8% saline that was associated with 24 h HU. Thus, HU results in an aldosterone‐dependent sodium appetite and the ingestion of sodium may help maintain plasma volume.
Paradoxical muscle movement in human standing
Authors: Loram Ian D. , Maganaris Constantinos N. , Lakie Martin
Published: March 2004

In human standing, gravity causes forward toppling about the ankle joint which is prevented by activity in the soleus and gastrocnemius muscles. It has long been assumed that when people sway forwards the calf muscles are stretched and conversely that they shorten with backward sway. Consequently, for many years, two explanations for standing stabilization have flourished. First, tonic muscle activity itself may generate adequate intrinsic ankle stiffness. Second, if intrinsic ankle stiffness is inadequate, the resistance to stretch of the calf muscles may be augmented by stretch reflexes or by central control. These explanations require that the passive tissue (Achilles' tendon, foot) transmitting the calf muscle tension is stiff. However, our recent measurements have indicated that this passive tissue is not stiff during standing. Accordingly, we predicted a counterintuitive mode of control where the muscles and body must, on average, move in opposite directions (paradoxical movements). Here we use dynamic ultrasound imaging in vivo with novel automated tracking of muscle length to test our hypothesis. We show that soleus and gastrocnemius do indeed move paradoxically, shortening when the body sways forward and lengthening when the body returns. This confirms that intrinsic ankle stiffness is too low to stabilize human standing. Moreover, it shows that the increase in active tension is associated with muscle shortening. This pattern cannot be produced by muscle stretch reflexes and can only arise from the anticipatory neural control of muscle length that is necessary for balance.
Episodic hypoxia evokes long‐term facilitation of genioglossus muscle activity in neonatal rats
Authors: McKay Leanne C. , Janczewski Wiktor A. , Feldman Jack L.
Published: March 2004

The aim of this study was to determine if episodic hypoxia evokes persistent increases of genioglossus muscle (GG) activity, termed long‐term facilitation (LTF), in neonatal rats in vivo. Experiments were performed on anaesthetized, spontaneously breathing, intubated neonatal rats (postnatal days (P) 3–7), divided into three groups. The first group (n= 8) was subjected to three 5‐min periods of hypoxia (5% O2–95% N2) alternating with 5 min periods of room air. The second group (n= 8) was exposed to 15 min of continuous hypoxia. The third (n= 4) group was not exposed to hypoxia and served as a control. GG EMG activity and airflow were recorded before, during and for 60 min after episodic and continuous hypoxic exposure. During hypoxia, GG EMG burst amplitude and tidal volume (VT) significantly increased compared to baseline levels (episodic protocol: mean ±s.e.m; 324 ± 59% of control and 0.13 ± 0.007 versus 0.09 ± 0.005 ml, respectively; continuous protocol: 259 ± 30% of control and 0.16 ± 0.005 versus 0.09 ± 0.007 ml, respectively; P < 0.05). After the episodic protocol, GG EMG burst amplitude transiently returned to baseline; over the next 60 min, burst amplitude progressively increased to levels significantly greater than baseline (238 ± 40% at 60 min; P < 0.05), without any significant increase in VT and respiratory frequency (P> 0.05). After the continuous protocol, there was no lasting increase in GG EMG burst amplitude. We conclude that LTF of upper airway muscles is an adaptive respiratory behaviour present from birth.
Complete Genome Sequence of the Apicomplexan,
Cryptosporidium parvum
Authors: Abrahamsen Mitchell S. , Templeton Thomas J. , Enomoto Shinichiro , Abrahante Juan E. , Zhu Guan , Lancto Cheryl A. , Deng Mingqi , Liu Chang , Widmer Giovanni , Tzipori Saul , Buck Gregory A. , Xu Ping , Bankier Alan T. , Dear Paul H. , Konfortov Bernard A. , Spriggs Helen F. , Iyer Lakshminarayan , Anantharaman Vivek , Aravind L. , Kapur Vivek
Published: March 2004

The apicomplexan
Cryptosporidium parvum
is an intestinal parasite that affects healthy humans and animals, and causes an unrelenting infection in immunocompromised individuals such as AIDS patients. We report the complete genome sequence of
C. parvum
, type II isolate. Genome analysis identifies extremely streamlined metabolic pathways and a reliance on the host for nutrients. In contrast to
Plasmodium
and
Toxoplasma
, the parasite lacks an apicoplast and its genome, and possesses a degenerate mitochondrion that has lost its genome. Several novel classes of cell-surface and secreted proteins with a potential role in host interactions and pathogenesis were also detected. Elucidation of the core metabolism, including enzymes with high similarities to bacterial and plant counterparts, opens new avenues for drug development.
Tunable Nonlocal Spin Control in a Coupled-Quantum Dot System
Authors: Craig N. J. , Taylor J. M. , Lester E. A. , Marcus C. M. , Hanson M. P. , Gossard A. C.
Published: March 2004

The effective interaction between magnetic impurities in metals that can lead to various magnetic ground states often competes with a tendency for electrons near impurities to screen the local moment (known as the Kondo effect). The simplest system exhibiting the richness of this competition, the two-impurity Kondo system, was realized experimentally in the form of two quantum dots coupled through an open conducting region. We demonstrate nonlocal spin control by suppressing and splitting Kondo resonances in one quantum dot by changing the electron number and coupling of the other dot. The results suggest an approach to nonlocal spin control that may be relevant to quantum information processing.
Personalization Tools: Organize, Customize, and Expedite Knowledge Acquisition
Authors: Gough Nancy R.
Published: March 2004

STKE offers several preset and customizable tools for enhancing access to STKE’s resources and converting information into knowledge. The personalization tools include Folders, Display Settings, Saved Searches, and Alerts, and they allow users to more efficiently identify and access information relevant to their field of interest. Various preset tools expedite information acquisition--for example, with downloadable citations or by providing access to external sites, such as PubMed, for identifying related materials.
Some observations on the measurement of haemoglobin A2and S percentages by high performance liquid chromatography in the presence and absence of α thalassaemia
Authors: Head C E , Conroy M , Jarvis M , Phelan L , Bain B J
Published: March 2004

Aims:To assess the accuracy and precision of measuring haemoglobin A2by high performance liquid chromatography (HPLC) in the presence and absence of sickle cell trait, with or without α thalassaemia trait.

Methods:The haemoglobin A2percentage and the haemoglobin A2plus S percentages were determined by HPLC on 82 normal controls and 78 patients with sickle cell trait, respectively; the α thalassaemia status of each patient was determined by polymerase chain reaction. Red cell indices and haemoglobin A2and S percentages were compared in patients with two, three, or four α genes.

Results:Of the 78 patients with sickle cell trait, 17 were heterozygous for α+thalassaemia (−α3.7/αα) and 13 were homozygous (−α3.7/−α3.7). Microcolumn chromatography showed that the haemoglobin A2percentage was slightly, but significantly, higher than normal in sickle cell trait. HPLC determinations of haemoglobin A2percentage in patients with sickle cell trait are precise but inaccurate, the percentage being appreciably overestimated. The measured haemoglobin A2percentage is stable for one week, but inaccuracy increases by two weeks in most samples. Despite this inaccuracy, there are significant differences in the HPLC “haemoglobin A2percentage” between groups of individuals with two, three, and four α genes.

Conclusions:Haemoglobin A2determinations by HPLC are precise but inaccurate. Nevertheless, there are significant differences in the haemoglobin A2percentage in subjects with two, three, and four α genes. Although there is some overlap between groups, this can be useful, together with the red cell indices, in predicting the likelihood of coexisting α thalassaemia.
My approach to oncocytic tumours of the thyroid
Authors: Asa S L
Published: March 2004

The traditional approach to oncocytic thyroid lesions classified these as a separate entity, and applied criteria that are somewhat similar to those used for follicular lesions of the thyroid. In general, the guidelines to distinguish hyperplasia from neoplasia, and benign from malignant were crude and unsubstantiated by scientific evidence. In fact, there is no basis to separate oncocytic lesions from other classifications of thyroid pathology. The factors that result in mitochondrial accumulation are largely unrelated to the genetic events that result in proliferation and neoplastic transformation of thyroid follicular epithelial cells. The concept of classifying oncocytic lesions, including follicular variant papillary carcinomas, based on nuclear morphology, immunohistochemical profiles, and molecular markers may pave the way for a better understanding of the biology of oncocytic lesions of the thyroid.
Recurrent aneurysmal fibrous histiocytoma
Authors: Sheehan K M , Leader M B , Sexton S , Cunningham F , Leen E
Published: March 2004

Aneurysmal fibrous histiocytoma is a rare variant of cutaneous fibrous histiocytoma that results from blood vessel proliferation and haemorrhage into a fibrous histiocytoma. The resulting lesion has a very different clinical appearance, hence the potential confusion with other skin lesions. This report describes the case of a 48 year old woman with a recurrent fibrous histiocytoma with prominent vasculature, which over a three year period recurred on two occasions, showing more progressive features of the aneurysmal variant. In addition, squamous lined cysts were present within this tumour, a finding that has not been described previously. The histological features of this rare lesion and the importance of the differential diagnosis from other similar appearing malignant lesions will be discussed.
Cutaneous T cell lymphoma and classic Hodgkin lymphoma of the B cell type within a single lymph node: composite lymphoma
Authors: Steinhoff M , Hummel M , Assaf C , Anagnostopoulos I , Treudler R , Geilen C C , Stein H , Orfanos C E
Published: March 2004

Composite lymphomas are defined as two unrelated, morphologically and genetically distinct lymphomas occurring at the same point in time within the same tissue or organ. Since their original definition, several composite lymphomas have been reported exclusively based on morphological grounds. However, with the application of immunhistological and molecular biological techniques it has become evident that many so called “composite” lymphomas do not fulfil the necessary criteria, because they merely represent two different morphological phenotypes of the same malignant clone. This report describes the manifestation of a true composite lymphoma within a single cervical lymph node, which is composed of a cutaneous T cell lymphoma and a classic Hodgkin lymphoma of B cell type—a very rare finding indeed.
Parathyroid invasion, nodal recurrence, and lung metastasis by papillary carcinoma of the thyroid
Authors: Kakudo K , Tang W , Ito Y , Nakamura Y , Yasuoka H , Morita S , Miyauchi A
Published: March 2004

Aims:Parathyroid invasion by papillary thyroid carcinoma (PTC) is found in a small proportion of surgical specimens, but the clinicopathological relevance of this phenomenon is not well understood. This study investigated the possible prognostic relevance of parathyroid invasion in PTC.

Method:Parathyroid involvement was seen in 14 patients with PTC, and the clinicopathological characteristics and follow up data of these patients were analysed and compared with 164 patients without parathyroid involvement, in whom histological parathyroid examination had been undertaken, and 177 other patients without parathyroid examination (341 patients without parathyroid involvement in total).

Results:Parathyroid invasion was found in older patients and there were more male patients in this group than in those without parathyroid invasion. These patients had more extrathyroid extension and were frequently in an advanced stage of disease. Lung metastasis was seen in two of the 14 patients, which was significantly more than that seen in control cases. Moreover, male patients with parathyroid invasion and those who were older than 55 years had reduced disease free survival compared with those without parathyroid invasion.

Conclusion:Parathyroid invasion seen in thyroid carcinoma may be an important histological feature indicating a greater chance of nodal recurrence and lung metastasis.
Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries
Authors: Belgore F , Blann A , Neil D , Ahmed A S , Lip G Y H
Published: March 2004

Background:Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. The existence of single or multiple VEGF isoforms and receptors suggests that these proteins may have overlapping but distinct functions, which may be reflected in their cell expression and distribution.

Methods:The localisation of VEGFs A–C and their receptors (VEGFRs 1–3, respectively) in 30 fresh human atherosclerotic arteries, 15 normal uterine arteries, and 15 saphenous veins using immunohistochemistry and western blotting.

Results:Saphenous veins showed no staining for VEGF-B or VEGFR-2. Smooth muscle cells (SMCs) showed the strongest staining for VEGF-A, VEGF-B, VEGFR-1, and VEGFR-2 in all specimens. Conversely, VEGFR-3 and VEGF-C were predominately localised to the endothelial vasa vasorum in normal arteries, whereas medial SMCs showed the strongest staining in atherosclerotic arteries. Western blotting showed variations in VEGF protein localisation, with lower amounts of VEGF-B and VEGF-C in saphenous veins, compared with arterial tissue. Amounts of VEGF-C were lower than those of VEGF-A and VEGF-B in all specimens.

Conclusion:This study provides direct evidence of the presence of VEGF proteins and receptors in human physiology and pathology, with variations in both the amounts of VEGF proteins expressed and their cellular distribution in normal arteries compared with atherosclerotic arteries. The presence of VEGFs A–C and their receptors in normal arterial tissue implies that VEGF functions may extend beyond endothelial cell proliferation. Reduced VEGFR-2 staining in atherosclerotic arteries may have implications for the atherosclerosis process and the development of vascular disease and its complications.
Sputum cytology of patients with severe acute respiratory syndrome (SARS)
Authors: Tse G M K , Hui P-K , Ma T K F , Lo A W I , To K-F , Chan W Y , Chow L T C , Ng H-K
Published: March 2004

Background:Severe acute respiratory syndrome (SARS) is a newly described form of atypical pneumonia linked to a novel coronavirus.

Aims:To review the sputum cytology of 15 patients who fulfilled the World Health Organisation clinical criteria for SARS in an attempt to evaluate whether early diagnosis is feasible with routine sputum examination.

Methods:All sputum samples from patients with SARS from the four major hospitals in Hong Kong were reviewed; abnormalities were sought in the cellular component, including abnormal numbers and morphology of the component cells compared with those from age matched controls taken over the same period one year ago.

Results:Fifteen sputum samples from patients were compared with 25 control samples. In the patients with SARS, loose aggregates of macrophages were seen more frequently in the sputum. These macrophages frequently showed morphological changes, such as cytoplasmic foaminess, vacuole formation, and nuclear changes (including multinucleation and a ground glass appearance) when compared with the control samples.

Conclusions:The cytological features of SARS are non-specific, but the observation of any of the described features should prompt further investigations, especially in patients with suspicious clinical features.
Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS)
Authors: Tse G M-K , To K-F , Chan P K-S , Lo A W I , Ng K-C , Wu A , Lee N , Wong H-C , Mak S-M , Chan K-F , Hui D S C , Sung J J-Y , Ng H-K
Published: March 2004

Background:Severe acute respiratory syndrome (SARS) became a worldwide outbreak with a mortality of 9.2%. This new human emergent infectious disease is dominated by severe lower respiratory illness and is aetiologically linked to a new coronavirus (SARS-CoV).

Methods:Pulmonary pathology and clinical correlates were investigated in seven patients who died of SARS in whom there was a strong epidemiological link. Investigations include a review of clinical features, morphological assessment, histochemical and immunohistochemical stainings, ultrastructural study, and virological investigations in postmortem tissue.

Results:Positive viral culture for coronavirus was detected in most premortem nasopharyngeal aspirate specimens (five of six) and postmortem lung tissues (two of seven). Viral particles, consistent with coronavirus, could be detected in lung pneumocytes in most of the patients. These features suggested that pneumocytes are probably the primary target of infection. The pathological features were dominated by diffuse alveolar damage, with the presence of multinucleated pneumocytes. Fibrogranulation tissue proliferation in small airways and airspaces (bronchiolitis obliterans organising pneumonia-like lesions) in subpleural locations was also seen in some patients.

Conclusions:Viable SARS-CoV could be isolated from postmortem tissues. Postmortem examination allows tissue to be sampled for virological investigations and ultrastructural examination, and when coupled with the appropriate lung morphological changes, is valuable to confirm the diagnosis of SARS-CoV, particularly in clinically unapparent or suspicious but unconfirmed cases.
Building Atomic Nuclei with the Dirac Equation
Authors: Serot Brian D.
Published: March 2004

The relevance of the Dirac equation for computations of nuclear structure is motivated and discussed. Quantitatively successful results for medium- and heavy-mass nuclei are described, and modern ideas of effective field theory and density functional theory are used to justify them.
Dirac's Magnetic Monopoles (Again)
Authors: Jackiw Roman W.
Published: March 2004

Dirac's quantization of magnetic monopole strength is derived without reference to a (singular, patched) vector potential.
Monopoles, Duality, and String Theory
Authors: Polchinski Joe
Published: March 2004

Dirac showed that the existence of magnetic monopoles would imply quantization of electric charge. I discuss the converse, and propose two 'principles of completeness' which I illustrate with various examples. Presented at the Dirac Centennial Symposium, Tallahassee, Dec. 6-7, 2002.
Changes in gene expression in gills of the euryhaline killifish Fundulus heteroclitus after abrupt salinity transfer
Authors: Scott Graham R. , Richards Jeff G. , Forbush Biff , Isenring Paul , Schulte Patricia M.
Published: March 2004

Maintenance of ion balance requires that ionoregulatory epithelia modulate ion flux in response to internal or environmental osmotic challenges. We have explored the basis of this functional plasticity in the gills of the euryhaline killifish Fundulus heteroclitus. The expression patterns of several genes encoding ion transport proteins were quantified after transfer from near-isosmotic brackish water [10 parts/thousand (ppt)] to either freshwater (FW) or seawater (SW). Many changes in response to SW transfer were transient. Increased mRNA expression occurred 1 day after transfer for Na+-K+-ATPase-α1a (3-fold), Na+-K+-2Cl−-cotransporter 1 (NKCC1) (3-fold), and glucocorticoid receptor (1.3-fold) and was paralleled by elevated Na+-K+-ATPase activity (2-fold). The transient increase in NKCC1 mRNA expression was followed by a later 2-fold rise in NKCC protein abundance. In contrast to the other genes studied in the present work, mRNA expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel generally remained elevated (2-fold) in SW. No change in protein abundance was detected, however, suggesting posttranscriptional regulation. The responses to FW transfer were quite different from those to SW transfer. In particular, FW transfer increased Na+-K+-ATPase-α1a mRNA expression and Na+-K+-ATPase activity to a greater extent than did SW transfer but had no effect on V-type H+-ATPase expression, supporting the current suggestion that killifish gills transport Na+ via Na+/H+ exchange. These findings demonstrate unique patterns of ion transporter expression in killifish gills after salinity transfer and illustrate important mechanisms of functional plasticity in ion-transporting epithelia.
Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model
Authors: Sahai Atul , Malladi Padmini , Melin-Aldana Hector , Green Richard M. , Whitington Peter F.
Published: March 2004

The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-α, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1–4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-α expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-β and TNF-α. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN−/−mice when compared with OPN+/+mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH.
Expression of apical membranel-glutamate transporters in neonatal porcine epithelial cells along the small intestinal crypt-villus axis
Authors: Fan Ming Z. , Matthews James C. , Etienne Nadege M. P. , Stoll Barbara , Lackeyram Dale , Burrin Douglas G.
Published: March 2004

Enteral l-glutamate is extensively utilized as an oxidative fuel by the gut mucosa in the neonate. To identify major uptake pathways and to understand uptake regulation, we examined transport kinetics and molecular identities of apical membrane l-glutamate transporters in epithelial cells sequentially isolated along the small intestinal crypt-villus axis from milk protein-fed, 16-day-old pigs. The distended intestinal sac method was used to isolate 12 sequential cell fractions from the tip villus to the bottom crypt. Initial rates and kinetics of l-glutamate uptake were measured with l-[G-3H]glutamate by fast filtration in apical membrane vesicles prepared by Mg2+precipitation and differential centrifugation, with membrane potential clamped by SCN−. Initial l-glutamate uptake results suggested the presence of Boand XAG−transport systems, but the XAG−system was predominant for uptake across the apical membrane. Kinetic data suggested that l-glutamate uptake through the XAG−system was associated with higher maximal transport activity but lower transporter affinity in crypt than in villus cells. Molecular identity of the XAG−glutamate transporter, based on immunoblot and RT-PCR analysis, was primarily the defined excitatory amino acid carrier (EAAC)-1. EAAC-1 expression was increased with cell differentiation and regulated at transcription and translation levels from crypt to upper villus cells. In conclusion, efficiency and capacity of luminal l-glutamate uptake across the apical membrane are regulated by changing expression of the XAG−system transporter gene EAAC-1 at transcription and translation levels as well as maximal uptake activity and transporter affinity along the intestinal crypt-villus axis in the neonate.
Expression of genes for B7-H3 and other T cell ligands by nasal epithelial cells during differentiation and activation
Authors: Saatian Bahman , Yu Xiao-Ying , Lane Andrew P. , Doyle Thanh , Casolaro Vincenzo , Spannhake Ernst Wm.
Published: March 2004

Epithelial cells of the human respiratory tract express human leukocyte antigen (HLA) and the costimulatory molecules B7-1 and B7-2. Little is known, however, about the constitutive expression of genes encoding for the more recently identified members of the B7 homolog family of costimulatory molecules or about the influence of cellular differentiation and cytokines on their activity or on that of HLA or B7-1 and B7-2. Human nasal epithelial (HNE) cells were grown at the air-liquid interface (ALI) for 2 or 21 days to model in vivo conditions. Expression of genes for HLA-B and HLA-DR1 increased during mucociliary differentiation during this period and became more similar to HNE cells obtained fresh by brush biopsy from nasal turbinates. Gene transcripts for B7-H3 and B7-H2 were abundantly expressed in cells cultured at the ALI, but neither their activities nor that of B7-2 was significantly altered during differentiation. IFN-γ and TNF-α upregulated mRNA encoding for both HLA molecules, but not for the B7 molecules. This study describes, for the first time, the expression of B7-H3 and B7-H2 by HNE cells and thus expands the range of potential costimulatory signals through which these cells may interact with activated mucosal T lymphocytes. In addition, the results suggest that the extent of mucociliary differentiation of cultured cells may influence this capability.
Differential expression of PDE4 cAMP phosphodiesterase isoforms in inflammatory cells of smokers with COPD, smokers without COPD, and nonsmokers
Authors: Barber Rachael , Baillie George S. , Bergmann Reinhard , Shepherd Malcolm C. , Sepper Ruth , Houslay Miles D. , Heeke Gino Van
Published: March 2004

The expression profile of a panel of 15 cAMP phosphodiesterase isoforms was determined for inflammatory cell types of relevance to chronic obstructive pulmonary disease (COPD). In particular, the expression profiles for bronchoalveolar macrophages, peripheral blood monocytes, T lymphocytes, and neutrophils from smokers with and without COPD were compared. The phosphodiesterase expression profile was also analyzed for peripheral blood monocytes, T lymphocytes, and neutrophils from nonsmokers and compared with smokers. Qualitative RT-PCR identified transcripts for PDE4A10, PDE4A7, PDE4B1, PDE4B2, PDE4D1, and PDE4D2 isoforms as well as transcripts for both PDE3B and PDE7A in T cells, monocytes, and macrophages in all subjects. Transcripts for PDE4B3 and PDE4D4 were not observed in any of the cell types investigated. PDE4C was detected in all cells analyzed except for T cells. The long PDE4A4, PDE4D3, and PDE4D5 isoforms exhibited cell type-specific expression patterns. Semiquantitative and real-time quantitative RT-PCR were used to analyze differential expression between disease states and between cell types. PDE4A4 was found significantly upregulated in lung macrophages from smokers with COPD when compared with control smokers. Furthermore, PDE4A4 as well as PDE4B2 transcripts were detected in higher amounts in peripheral blood monocytes of smokers when compared with nonsmokers. Finally, PDE4D5 and PDE4C were differentially regulated in lung macrophages when compared with monocytes of the same subjects, irrespective of the disease state. The data obtained suggest that PDE4A4 may be relevant as a macrophage-specific anti-inflammatory target for COPD.
Rosuvastatin treatment reverses impaired coronary artery vasodilation in fructose-fed, insulin-resistant rats
Authors: Miller Allison W. , Tulbert Christina D. , Busija David W.
Published: March 2004

Insulin resistance (IR) impairs vascular responses in coronary arteries, but mechanisms of dysfunction and approaches to treatment remain unclear. We examined the ability of a new 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, rosuvastatin, to reverse reduced dilator responses in rats made IR by feeding a fructose-rich diet (FF). Sprague-Dawley rats were randomized to control (normal rat diet) or FF. After 1 wk, rats received rosuvastatin (2 mg/kg) or placebo (saline) subcutaneously for 5 wk. Biochemical measurements and in vitro functional studies of small coronary arteries were performed. Fasting insulin and triglyceride (TG) levels were markedly increased in FF-placebo rats compared with other groups. Rosuvastatin treatment of FF rats normalized TG and modestly decreased insulin levels. ACh-induced dilator responses were depressed in arteries from FF-placebo rats. This impairment was due to decreased responses via calcium-dependent K channels (KCa). Rosuvastatin treatment of FF rats completely reversed the response to ACh to normal levels. Moreover, this recovery in function was due to an improvement in vasodilation via KCa. Thus rosuvastatin treatment of IR rats normalizes coronary vascular dilator responses by improving the KCa function.
Stimulation of the Parasubiculum Modulates Entorhinal Cortex Responses to Piriform Cortex Inputs In Vivo
Authors: Caruana Douglas A. , Chapman C. Andrew
Published: March 2004

Although a major output of the hippocampal formation is from the subiculum to the deep layers of the entorhinal cortex, the parasubiculum projects to the superficial layers of the entorhinal cortex and may therefore modulate how the entorhinal cortex responds to sensory inputs from other cortical regions. Recordings at multiple depths in the entorhinal cortex were first used to characterize field potentials evoked by stimulation of the parasubiculum in urethan-anesthetized rats. Current source density analysis showed that a prominent surface-negative field potential component is generated by synaptic activation in layer II. The surface-negative field potential was also observed in rats with chronically implanted electrodes. The response was maintained during short stimulation trains of ≤125 Hz, suggesting that it is generated by activation of monosynaptic inputs to the entorhinal cortex. The piriform cortex also projects to layer II of the entorhinal cortex, and interactions between parasubicular and piriform cortex inputs were investigated using double-site stimulation tests. Simultaneous activation of parasubicular and piriform cortex inputs with high-intensity pulses resulted in smaller synaptic potentials than were expected on the basis of summing the individual responses, consistent with the termination of both pathways onto a common population of neurons. Paired-pulse tests were then used to assess the effect of parasubicular stimulation on responses to piriform cortex stimulation. Responses of the entorhinal cortex to piriform cortex inputs were inhibited when the parasubiculum was stimulated 5 ms earlier and were enhanced when the parasubiculum was stimulated 20–150 ms earlier. These results indicate that excitatory inputs to the entorhinal cortex from the parasubiculum may enhance the propagation of neuronal activation patterns into the hippocampal circuit by increasing the responsiveness of the entorhinal cortex to appropriately timed inputs.
Second-Order Vestibular Neurons Form Separate Populations With Different Membrane and Discharge Properties
Authors: Straka H. , Beraneck M. , Rohregger M. , Moore L. E. , Vidal P.-P. , Vibert N.
Published: March 2004

Membrane and discharge properties were determined in second-order vestibular neurons (2°VN) in the isolated brain of grass frogs. 2°VN were identified by monosynaptic excitatory postsynaptic potentials after separate electrical stimulation of the utricular nerve, the lagenar nerve, or individual semicircular canal nerves. 2°VN were classified as vestibulo-ocular or -spinal neurons by the presence of antidromic spikes evoked by electrical stimulation of the spinal cord or the oculomotor nuclei. Differences in passive membrane properties, spike shape, and discharge pattern in response to current steps and ramp-like currents allowed a differentiation of frog 2°VN into two separate, nonoverlapping types of vestibular neurons. A larger subgroup of 2°VN (78%) was characterized by brief, high-frequency bursts of up to five spikes and the absence of a subsequent continuous discharge in response to positive current steps. In contrast, the smaller subgroup of 2°VN (22%) exhibited a continuous discharge with moderate adaptation in response to positive current steps. The differences in the evoked spike discharge pattern were paralleled by differences in passive membrane properties and spike shapes. Despite these differences in membrane properties, both types, i.e., phasic and tonic 2°VN, occupied similar anatomical locations and displayed similar afferent and efferent connectivities. Differences in response dynamics of the two types of 2°VN match those of their pre- and postsynaptic neurons. The existence of distinct populations of 2°VN that differ in response dynamics but not in the spatial organization of their afferent inputs and efferent connectivity to motor targets suggests that frog 2°VN form one part of parallel vestibulomotor pathways.
On Cauchy problems for fuzzy differential equations
Authors: Georgiou D. N. , Kougias I. E.
Published: March 2004

Existence and uniqueness theorems are proved for Cauchy problems
of second‐order fuzzy differential equations.
Analysis of Cause-Specific Mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study
Authors: Steinberg Jonathan S. , Sadaniantz Ara , Kron Jack , Krahn Andrew , Denny D. Marty , Daubert James , Campbell W. Barton , Havranek Edward , Murray Katherine , Olshansky Brian , O’Neill Gearoid , Sami Magdi , Schmidt Stanley , Storm Randle , Zabalgoitia Miguel , Miller John , Chandler Mary , Nasco Elaine M. , Greene H. Leon ,   the AFFIRM Investigators
Published: March 2004

Background—

Expectations that reestablishing and maintaining sinus rhythm in patients with atrial fibrillation might improve survival were disproved in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. This report describes the cause-specific modes of death in the AFFIRM treatment groups.

Methods and Results—

All deaths in patients enrolled in AFFIRM underwent blinded review by the AFFIRM Events Committee, and a mode of death was assigned. In AFFIRM, 2033 patients were randomized to a rhythm-control strategy and 2027 patients to a rate-control strategy. During a mean follow-up of 3.5 years, there were 356 deaths in the rhythm-control patients and 310 deaths in the rate-control patients (
P
=0.07). In the rhythm-control group, 129 patients (9%) died of a cardiac cause, and in the rate-control group, 130 patients (10%) died (
P
=0.95). Both groups had similar rates of arrhythmic and nonarrhythmic cardiac deaths. The numbers of vascular deaths were similar in the 2 groups: 35 (3%) in the rhythm-control group and 37 (3%) in the rate-control group (
P
=0.82). There were no differences in the rates of ischemic stroke and central nervous system hemorrhage. In the rhythm-control group, there were 169 noncardiovascular deaths (47.5% of the total number of deaths), whereas in the rate-control arm, there were 113 noncardiovascular deaths (36.5% of the total number of deaths) (
P
=0.0008). Differences in noncardiovascular death rates were due to pulmonary and cancer-related deaths.

Conclusions—

Management of atrial fibrillation with a rhythm-control strategy conferred no advantage over a rate-control strategy in cardiac or vascular mortality and may be associated with an increased noncardiovascular death rate.
Comparing the Efficacy and Safety of a Novel Monophasic Waveform Delivered by the Passive Implantable Atrial Defibrillator With Biphasic Waveforms in Cardioversion of Atrial Fibrillation
Authors: Manoharan Ganesh , Evans Noel , Allen Desmond , Anderson John , Adgey Jennifer
Published: March 2004

Background—

The passive implantable atrial defibrillator (PIAD) (with no battery or discharging capacitor and powered transcutaneously by radio-frequency energy) delivering a novel monophasic low-tilt waveform is more efficacious than the standard monophasic waveform at atrial defibrillation. Standard biphasic (STB) waveforms, however, are more efficacious and safer than monophasic waveforms. This study compared the efficacy and safety of the PIAD waveform with biphasic waveforms.

Methods and Results—

Sustained atrial fibrillation (AF) was induced by rapid atrial pacing. Cardioversion was attempted via 2 atrial defibrillation leads. The efficacy of the PIAD was compared with 3 biphasic waveforms (standard, single rounded, and double rounded) at varying voltage settings in 10 pigs. After a synchronized shock, hemodynamic changes between the PIAD, standard biphasic, and monophasic waveforms were compared at 1.5 and 3.0 J in 12 pigs. Myocardial injury (biochemical and histological) after ten 5-J PIAD shocks was compared with a no-shock group in 14 pigs. The PIAD 100-V setting was significantly more efficacious than the STB (100/−50 V: 100% [1.88±0.02 J] versus 90% [0.89±0.0 J];
P
=0.025). No arrhythmic, hemodynamic, or myocardial injury was observed with the PIAD waveform.

Conclusions—

Defibrillation with the PIAD is more efficacious than with the STB waveform and appears safe. This device could provide a more effective option for cardioversion.
Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-α–Induced Cardiomyopathy
Authors: Higuchi Yoshihiro , McTiernan Charles F. , Frye Carole B. , McGowan Brian S. , Chan Tung O. , Feldman Arthur M.
Published: March 2004

Background—

Tumor necrosis factor (TNF)-α plays a pathophysiological role in heart failure. Although both TNF receptor 1 (TNFR1) and 2 (TNFR2) are present in the heart, comparatively little is known about the role of TNFR2.

Methods and Results—

We bred TNFR1-knockout (KO) or TNFR2KO mice to transgenic (TG) mice with cardiac-specific overexpression of TNF-α and analyzed resultant progeny. Six groups of male and female mice were studied: wild type (WT) with wild receptors (WT/W), TG with wild receptors (TG/W), TG with heterozygous receptor KO (TG/R1
+/−
or TG/R2
+/−
), and TG with homozygous receptor KO (TG/R1
−/−
or TG/R2
−/−
). Both male and female TG mice displayed cardiac hypertrophy, dilation, and reduced cardiac function. Male TG mice were more severely affected than genotypically matched females and died of heart failure at a younger age. Survival, cardiac function, and remodeling of TG/R1
+/−
and TG/R1
−/−
mice were improved relative to TG/W mice in both males and females. However, the survival of female TG/R2
+/−
and TG/R2
−/−
mice was worse than that of TG/W mice, with increased left ventricular dimension and left ventricular weight/body weight ratios. The cardiac TNF-α protein level was upregulated in TG/R1
−/−
and TG/R2
−/−
compared with TG/W mice, whereas the level of TNF receptors was not downregulated in TG/W relative to WT/W mice.

Conclusions—

Ablation of the TNFR2 gene exacerbates heart failure and reduces survival, whereas ablation of TNFR1 blunts heart failure and improves survival. Signaling via TNFR2 may play a cardioprotective role in the pathogenesis of cytokine-mediated heart failure.
Metabolic and Functional Protection by Selective Inhibition of Nitric Oxide Synthase 2 During Ischemia-Reperfusion in Isolated Perfused Hearts
Authors: Ramasamy Ravichandran , Hwang Yuying C. , Liu Yulin , Son Ni Huiping , Ma Ningsheng , Parkinson John , Sciacca Robert , Albala Arline , Edwards Niloo , Szabolcs Matthias J. , Cannon Paul J.
Published: March 2004

Background—

Drugs that selectively block nitric oxide synthase (NOS) 2 enzyme activity by inhibiting dimerization of NOS2 monomers have recently been developed.

Methods and Results—

To investigate whether selective inhibition of NOS2 is cardioprotective, rats were pretreated for 2 days with BBS2, an inhibitor of NOS2 dimerization, at 15 mg/kg SC. Isolated buffer-perfused hearts from treated (n=9) and control (n=7) hearts were subjected to 20 minutes of ischemia followed by 60 minutes of reperfusion. NOS2 protein was upregulated in all hearts at the end of ischemia and of reperfusion; NOS2 enzyme activity was 60% lower in hearts from the treated animals. In the treated hearts, the increase in end-diastolic pressure was significantly attenuated at the end of ischemia, and the return of developed pressure at reperfusion was greater (
P
<0.05). Creatine kinase release at reperfusion was lower in treated hearts than in controls (
P
=0.02). At the end of ischemia and of reperfusion, myocardial ATP levels were significantly higher in the treated hearts than in controls (
P
<0.05). In the treated hearts under ischemic conditions, lactate content was higher and the lactate/pyruvate ratio was lower than in controls (
P
<0.05); GAPDH activity was higher; and G-3-P and aldose reductase activity were lower. At reperfusion, in the treated hearts, there was less histological damage and less apoptosis of cardiac muscle cells.

Conclusions—

Pretreatment with BBS2, a selective inhibitor of NOS2, improves contractile performance, preserves myocardial ATP, and reduces damage and death of cardiac myocytes during ischemia and reperfusion of isolated buffer-perfused rat hearts.
Increased Expression of Interleukin-1 in Coronary Artery Disease With Downregulatory Effects of HMG-CoA Reductase Inhibitors
Authors: Wæhre Torgun , Yndestad Arne , Smith Camilla , Haug Terje , Tunheim Siv Haugen , Gullestad Lars , Frøland Stig S. , Semb Anne G. , Aukrust Pål , Damås Jan K.
Published: March 2004

Background—

Inflammation is important in atherogenesis. Interleukin (IL)-1 is the prototypic inflammatory cytokine. We hypothesized a dysbalance between inflammatory and anti-inflammatory mediators in the IL-1 family in coronary artery disease (CAD) and a possible modulation of these mediators by HMG-CoA inhibitors (statins).

Methods and Results—

In a microarray screening experiment examining peripheral blood mononuclear cells (PBMCs) from 6 CAD patients and 4 healthy control subjects, IL-1β was identified as 1 of 25 genes whose expression were upregulated in CAD and downregulated by statins. In the following, we studied the role of IL-1β and related mediators in CAD. Our major findings were as follows. (1) Although mRNA levels of IL-1α and IL-1β were markedly reduced in PBMCs from CAD patients after 6 months of simvastatin (20 mg/d, n=15) and atorvastatin (80 mg/d, n=15) therapy, the reduction in IL-1 receptor antagonist (IL-1Ra) was more modest. Statins also reduced the spontaneous release of IL-1β and IL-1Ra from PBMCs in CAD patients. (2) mRNA levels of IL-1α, IL-1β, and IL-1Ra were increased in PBMCs from patients with stable (n=20) and unstable (n=20) angina compared with healthy control subjects (n=15). Although the unstable patients had particularly high levels of IL-1β and IL-1α, IL-1Ra was not correspondingly increased. (3) IL-1β induced release of proatherogenic cytokines from PBMCs, whereas atorvastatin partly abolished this effect.

Conclusions—

Our findings suggest that cytokines in the IL-1 family may represent therapeutic targets in CAD. The ability of statins to modulate these cytokines in an anti-inflammatory direction underscores their immunomodulatory potential.