bluuebunny/crossref_metadata_2025 huggingface dataset:
Reexamining the Role of the Accessory Plasmid pAtC58 in the Virulence of Agrobacterium tumefaciens Strain C58
Authors: Nair Gauri R. , Liu Zhenying , Binns Andrew N.
Published: November 2003

Isogenic strains of Agrobacterium tumefaciens carrying pTiC58, pAtC58, or both were constructed and assayed semiquantitatively and quantitatively for virulence and vir gene expression to study the effect of the large 542-kb accessory plasmid, pAtC58, on virulence. Earlier studies indicate that the att (attachment) genes of A. tumefaciens are crucial in the ability of this soil phytopathogen to infect susceptible host plants. Mutations in many att genes, notably attR and attD, rendered the strain avirulent. These genes are located on pAtC58. Previous work also has shown that derivatives of the wild-type strain C58 cured of pAtC58 are virulent as determined by qualitative virulence assays and, hence, pAtC58 was described as nonessential for virulence. We show here that the absence of pAtC58 in pTiC58-containing strains results in reduced virulence but that disruption of the attR gene does not result in avirulence or a reduction in virulence. Our studies indicate that pAtC58 has a positive effect on vir gene induction as revealed by immunoblot analysis of Vir proteins and expression of a PvirB::lacZ fusion.
Site-Specific Integration ofAgrobacterium tumefaciensT-DNA via Double-Stranded Intermediates
Authors: Tzfira Tzvi , Frankman Leah Renée , Vaidya Manjusha , Citovsky Vitaly
Published: November 2003

Agrobacterium tumefaciens-mediated genetic transformation involves transfer of a single-stranded T-DNA molecule (T strand) into the host cell, followed by its integration into the plant genome. The molecular mechanism of T-DNA integration, the culmination point of the entire transformation process, remains largely obscure. Here, we studied the roles of double-stranded breaks (DSBs) and double-stranded T-DNA intermediates in the integration process. We produced transgenic tobacco (Nicotiana tabacum) plants carrying an I-SceI endonuclease recognition site that, upon cleavage with I-SceI, generates DSB. Then, we retransformed these plants with two A. tumefaciens strains: one that allows transient expression of I-SceI to induce DSB and the other that carries a T-DNA with the I-SceI site and an integration selection marker. Integration of this latter T-DNA as full-length and I-SceI-digested molecules into the DSB site was analyzed in the resulting plants. Of 620 transgenic plants, 16 plants integrated T-DNA into DSB at their I-SceI sites; because DSB induces DNA repair, these results suggest that the invading T-DNA molecules target to the DNA repair sites for integration. Furthermore, of these 16 plants, seven plants incorporated T-DNA digested with I-SceI, which cleaves only double-stranded DNA. Thus, T-strand molecules can be converted into double-stranded intermediates before their integration into the DSB sites within the host cell genome.
Different flecainide sensitivity of hNav1.4 channels and myotonic mutants explained by state‐dependent block
Authors: Desaphy Jean‐François , Luca Annamaria D. E. , Didonna Maria Paola , George Alfred L. , Camerino Diana Conte
Published: November 2003

Flecainide, a class IC antiarrhythmic, was shown to improve myotonia caused by sodium channel mutations in situations where the class IB antiarrhythmic drug mexiletine was less efficient. Yet little is known about molecular interactions between flecainide and human skeletal muscle sodium (hNav1.4) channels. Whole‐cell sodium currents (INa) were recorded in tsA201 cells expressing wild‐type (WT) and mutant hNav1.4 channels (R1448C, paramyotonia congenita; G1306E, potassium‐aggravated myotonia). At a holding potential (HP) of –120 mV, flecainide use‐dependently blocked WT and G1306E INa equally but was more potent on R1448C channels. For WT, the extent of block depended on a holding voltage more negative than the activation threshold, being greater at –90 mV as compared to –120 and –180 mV. This behaviour was exacerbated by the R1448C mutation since block at –120 mV was greater than that at –180 mV. Thus flecainide can bind to inactivated sodium channels in the absence of channel opening. Nevertheless, all the channels showed the same closed‐state affinity constant (KR∼480 μm) and the same inactivated‐state affinity constant (KI∼18 μm). Simulations according to the modulated receptor hypothesis mimic the voltage‐dependent block of WT and mutant channels by flecainide and mexiletine. All the results suggest similar blocking mechanisms for the two drugs. Yet, since flecainide exerts use‐dependent block at lower frequency than mexiletine, it may exhibit greater benefit in all myotonic syndromes. Moreover, flecainide blocks hNav1.4 channel mutants with a rightward shift of availability voltage dependence more specifically than mexiletine, owing to a lower KR/KI ratio. This study offers a pharmacogenetic strategy to better address treatment in individual myotonic patients.
Influence of age and resistance exercise on human skeletal muscle proteolysis: a microdialysis approach
Authors: Trappe Todd , Williams Rick , Carrithers John , Raue Ulrika , Esmarck Birgitte , Kjaer Michael , Hickner Robert
Published: November 2003

We combined the interstitial sampling method of microdialysis with the natural tracer qualities (i.e. non‐recyclability) of the amino acid 3‐methylhistidine (3MH) to uniquely study in vivo degradation of the two most abundant skeletal muscle proteins, myosin and actin. Interstitial 3MH concentration was measured before and for 24 h following a single bout of resistance exercise in eight young (27 ± 2 years) and eight old (75 ± 4 years) men. The exercise bout consisted of four exercises (3 sets of 8 repetitions at 80% one‐repetition maximum (1RM) per exercise) emphasizing the quadriceps. Interstitial 3MH concentration was calculated using the internal reference method from microdialysate samples that were obtained from two microdialysis probes placed in the vastus lateralis. Resting interstitial 3MH concentration was 44% higher (P < 0.05) in the old (6.16 ± 0.56 nmol ml−1) as compared with the young (4.28 ± 0.27 nmol ml−1). Interstitial 3MH was not different (P > 0.05) from preexercise at any time point within the 24 h following exercise in both the young and the old. Leg arteriovenous exchange measurements in a separate group of young subjects also showed no increase in 3MH release during the 4 h following a resistance exercise bout compared with a non‐exercised control leg (control leg: –28 ± 6, exercise leg: –28 ± 11 nmol min−1). These results suggest that myosin and actin proteolysis are not increased in the first 24 h following a standard bout of resistance exercise, and this response is not altered with ageing. The higher interstitial 3MH concentration in the old suggests an increased proteolysis of the two main contractile proteins in the rested and fasted state, which is consistent with a decrease in muscle mass with ageing. Microdialysis is an appropriate methodology for use in ageing individuals and is compatible with high‐intensity resistance exercise.
Insulin resistance and elevated triglyceride in muscle: more important for survival than ‘thrifty’ genes?
Authors: Stannard S. R. , Johnson N. A.
Published: November 2003

Elevated intramyocellular triglyceride (IMTG) is strongly associated with insulin resistance, though a cause and effect relationship has not been fully described. Insulin sensitivity and IMTG content are both dynamic and can alter rapidly in response to dietary variation, physical activity and thermoregulatory response. Physically active humans (athletes) display elevated IMTG content, but in contrast to obese persons, are insulin sensitive. This paradox has created confusion surrounding the role of IMTG in the development of insulin resistance. In this review we consider the modern athlete as the physiological archetype of the Late Palaeolithic hunter–gatherer to whom the selection pressures of food availability, predation and fluctuating environmental conditions applied and to whom the genotype of modern man is virtually identical. As food procurement by the hunter–gatherer required physical activity, ‘thrifty’ genes that encouraged immediate energy storage upon refeeding after food deprivation (Neel, 1962) must have been of secondary importance in survival to genes that preserved physical capacity during food deprivation. Similarly genes that enabled survival during cold exposure whilst starved would be of primary importance. In this context, we discuss the advantage afforded by an elevated IMTG content, and how under these conditions, a concomitant muscle resistance to insulin‐mediated glucose uptake would also be advantageous. In sedentary modern man, adiposity is high and skeletal muscle appears to respond as if a state of starvation exists. In this situation, elevated plasma lipids serve to accrue lipid and induce insulin resistance in skeletal muscle. Reversal of this physiological state is primarily dependant on adequate contractile activity, however, in modern Western society, physical inactivity combined with abundant food and warmth has rendered IMTG a redundant muscle substrate.
Tidal volume, cardiac output and functional residual capacity determine end‐tidal CO2 transient during standing up in humans
Authors: Gisolf Janneke , Wilders Ronald , Immink Rogier V. , Van Lieshout Johannes J. , Karemaker John M.
Published: November 2003

In man assuming the upright position, end‐tidal PCO2 (PETCO2) decreases. With the rising interest in cerebral autoregulation during posture change, which is known to be affected by PETCO2, we sought to determine the factors leading to hypocapnia during standing up from the supine position. To study the contribution of an increase in tidal volume (VT) and breathing frequency, a decrease in stroke volume (SV), a ventilation–perfusion (V/Q) gradient and an increase in functional residual capacity (FRC) to hypocapnia in the standing position, we developed a mathematical model of the lung to follow breath‐to‐breath variations in PETCO2. A gravity‐induced apical‐to‐basal V/Q gradient in the lung was modelled using nine lung segments. We tested the model using an eight‐subject data set with measurements of VT, pulmonary O2 uptake and breath‐to‐breath lumped SV. On average, the PETCO2 decreased from 40 mmHg to 36 mmHg after 150 s standing. Results show that the model is able to track breath‐to‐breath PETCO2 variations (r2= 0.74, P < 0.05). Model parameter sensitivity analysis demonstrates that the decrease in PETCO2 during standing is due primarily to increased VT, and transiently to decreased SV and increased FRC; a slight gravity‐induced V/Q mismatch also contributes to the hypocapnia. The influence of cardiac output on hypocapnia in the standing position was verified in experiments on human subjects, where first breathing alone, and then breathing, FRC and V/Q were controlled.
Prostate cancer management: (1) an update on localised disease
Authors: Bott S R J , Birtle A J , Taylor C J , Kirby R S
Published: November 2003

Prostate cancer is receiving ever more publicity with the result that more men are having their prostate specific antigen checked and a greater proportion of men are diagnosed with potentially curable localised disease. Advances in the therapeutic modalities including radical surgery, external beam radiotherapy, and brachytherapy have reduced the incidence of side effects and now offer patients a choice of treatments depending on their tumour characteristics, age, and co-morbidity. A significant proportion of men do not need intervention and may be safely kept under a “watch and wait” policy. The use of genetic markers may in the future distinguish between patients most likely to benefit from radical therapy and those in who either palliation or observation is more appropriate. This review examines the potentially curative options, as well as expectant management, outlining the pros and cons of each. The use of adjuvant and neoadjuvant therapy is also discussed.
Inpatient management of diabetes: survey in a tertiary care centre
Authors: Deepak P J , Sunitha K , Nagaraj J , Sanjukta A , Bhattacharyya A
Published: November 2003

Aims

Good glycaemic control in hospitalised patients with diabetes mellitus improves wellbeing and aids recovery. This survey aimed to: (1) assess glycaemic control in patients with diabetes admitted to hospital for reasons other than diabetes, (2) compare the glycaemic control in patients treated in medical and surgical units, and (3) see the impact of specialists’ input on glycaemic control.

Methods

The first 150 patients admitted to hospital were identified; those with acute metabolic complications of diabetes mellitus, acute myocardial infarction, pregestational or gestational diabetes, and patients in different intensive care units were excluded. Case notes were reviewed with particular attention to glycaemic control, frequency of blood monitoring, complications, and the actions taken to improve glycaemic control.

Results

Four of the 150 patients died in hospital. When subcutaneous insulin was used glycaemic control was good in 48%, suboptimal in 15%, and poor in 37% of patients. The results were not significantly different with subcutaneous or intravenous insulin. There was also no difference in glycaemic control among medical and surgical patients. Patients managed by designated specialists had better control than those managed by physicians (p<0.001). Hypoglycaemia was documented in 20% and two patients developed non-ketotic hyperosmolar coma while in hospital. In a few cases treatment at discharge was not changed despite poor control while in hospital.

Conclusion

More attention should be given to improving glycaemic control in patients hospitalised for reasons other than diabetes. Particular care should be taken to modify the dose of insulin needed to get good glycaemic control; control was better with specialists’ input. A follow up survey will be conducted.
Examination of the hands: an insight into the health of a Welsh population
Authors: White H A , Alcolado R , Alcolado J C
Published: November 2003

When asked to examine a patient in a clinical examination, undergraduates and postgraduates characteristically begin with a painstaking observation of the hands. It was of concern that this is done mainly for the benefit of the examiners and that, in routine clinical practice, examination of the hands receives scant attention. The case notes of 70 general medical and surgical inpatients were reviewed and it was found that in only seven was there any mention of physical examination of the hands; in three of these “no clubbing” was the only entry. However, when the authors carefully examined the hands of 197 patients, at least one clinical sign was found in 87 (44%) cases. Heberden’s nodes, cigarette tar staining, and the spectrum of Dupuytren’s contractures were the most common findings. In this population in the South Wales valleys, coal deposits were also commonly seen in men.
Role of frozen section histology in diagnosis of infection during revision arthroplasty
Authors: Musso A D , Mohanty K , Spencer-Jones R
Published: November 2003

The accurate diagnosis of deep infection in total joint arthroplasty is difficult. No single test on its own is entirely reliable. Frozen section histology has been used for the last two decades as an adjunct to diagnose infection with variable results. In this retrospective analysis, experience of the use of frozen section histology as a diagnostic tool in 45 cases of suspected infected total joint arthroplasty is reported.

Taking intraoperative cultures as the “gold standard”, the results showed 50% sensitivity, 95% specificity, positive predictive value of 60%, negative predictive value of 92%, and an accuracy of 89%, which is similar to other existing reports in the literature. Based on these findings, the use of frozen section histology in diagnostic work-up of all suspected cases of total joint infection is recommended.
Multiple brain abscesses in a patient with bilateral pulmonary arteriovenous malformations and immunoglobulin deficiency
Authors: Tse K-C , Ooi G C , Wu A , Ho P L , Ip S K , Jim M H , Lam Y M , Fan Y W , Tso W K , Tsang K W
Published: November 2003

A 34 year old Chinese man presented with grand mal seizures complicating multiple brain abscesses caused by mixed oral flora. Because of persistent hypoxaemia contrast spiral thoracic computed tomography was done, which revealed bilateral pulmonary arteriovenous malformations (PAVMs). Concomitant IgA and IgG subclass deficiency was also found. The combination of these two conditions appears to have predisposed this patient to presumably paradoxical septic embolism. The patient’s cerebral condition responded to postoperative antibiotic treatment and he eventually received selective coil embolisation of right lower lobe PAVMs, which relieved his hypoxaemia and dyspnoea.
SOFTWARE PRODUCT AND PROCESS ASSESSMENT THROUGH PROFILE-BASED EVALUATION
Authors: MORISIO MAURIZIO , STAMELOS IOANNIS , TSOUKIAS ALEXIS
Published: November 2003

Software entities (software products or processes) are characterized by many attributes, each one in its turn can be measured by one or more measures. In several cases the software entities have to be evaluated as a whole, thus raising the problem of aggregating measures to give an overall, single view on the software entity. This paper presents a method to aggregate measures, which works by comparing the product/process with predefined, ideal entities, or profiles. Profiles are defined starting from ranges of values on measures of attributes. The method is based on two main phases, namely definition of the evaluation model and application of the evaluation model. It is presented through a simplified case study that deals with evaluating the level of quality of an asset to decide whether to accept it in a reuse repository. A plausible way of how the method could be applied to process maturity assessment is also provided. The advantages of the method are that it allows using ordinal scales, while it deals explicitly with preferences expressed, implicitly or explicitly, by the evaluator.
Homocysteine Status and Polymorphisms of Methylenetetrahydrofolate Reductase Are Not Associated With Restenosis After Stenting in Coronary Arteries
Authors: Koch Werner , Ndrepepa Gjin , Mehilli Julinda , Braun Siegmund , Burghartz Marc , Lengnick Harald , Kölling Klaus , Schömig Albert , Kastrati Adnan
Published: November 2003

Objective—

We investigated the influence of elevated homocysteine plasma levels and 2 polymorphisms, 677C/T and 1298A/C, of the methylenetetrahydrofolate reductase (MTHFR) gene on the risk of restenosis after stenting in patients with symptomatic coronary artery disease.

Methods and Results—

Homocysteine levels and MTHFR genotypes were determined in 800 consecutive patients treated with coronary artery stenting. Angiographic restenosis (≥50% diameter stenosis at 6-month follow-up) was present in 25.8% of the patients with low homocysteine levels (at or below the median of 11.6 μmol/L; n=400) and 24.1% of the patients with high homocysteine levels (>11.6 μmol/L; n=400;
P
=0.62). Rates of angiographic restenosis were 26.0%, 23.5%, and 26.9% in carriers of the 677CC, 677CT, and 677TT genotypes (
P
=0.75), respectively, and 24.4%, 25.9%, and 24.0% in patients with the 1298AA, 1298AC, and 1298CC genotypes (
P
=0.90), respectively. The need for restenosis-driven reintervention (clinical restenosis) was 18.8% in subjects with low homocysteine concentrations and 19.0% in subjects with high homocysteine concentrations during the first year after the intervention (
P
=0.93). Rates of clinical restenosis were 19.5%, 17.1%, and 23.3% in carriers of the 677CC, 677CT, and 677TT genotypes (
P
=0.37), respectively, and 17.6%, 18.6%, and 24.7% in patients with the 1298AA, 1298AC, and 1298CC genotypes (
P
=0.27), respectively.

Conclusions—

Elevated levels of homocysteine and 2 polymorphisms of the MTHFR gene are not associated with restenosis after stenting in coronary arteries.
Both Insulin Resistance and Diabetes inPsammomys obesusUpregulate the Hepatic Machinery Involved in Intracellular VLDL Assembly
Authors: Zoltowska M. , Ziv E. , Delvin E. , Lambert M. , Seidman E. , Levy E.
Published: November 2003

Objective—In the current study, we examined the mechanisms that regulate hepatic apolipoprotein B (apoB)–containing lipoprotein secretion inPsammomys obesus, a good animal model for the investigation of insulin resistance and diabetes.

Methods and Results—When fed chow ad libitum, 22% maintained normoglycemia and normoinsulinemia (group A), 33% exhibited normoglycemia and appreciable hyperinsulinemia (group B), and 45% developed overt diabetes (group C). Body weight gain, plasma free fatty acid elevation, hypertriglyceridemia, and hypercholesterolemia characterized groups B and C. Triton WR-1339 injection, at fasting, resulted in higher plasma VLDL-triglyceride and VLDL-apoB accumulation in groups B and C, suggesting increased VLDL production by the liver. Pulse-chase labeling experiments in cultured hepatocytes with [35S]methionine revealed reduced intracellular degradation and enhanced secretion of newly synthesized apoB in groups B and C. Concomitant with the raised triglyceride and cholesterol contents in the livers of groups B and C, there was an increase in lipogenesis and in the activity of microsomal triglyceride transfer protein, monoacylglycerol acyltransferase, and diacylglycerol transferase. Pretreatment of hepatocytes with proteasomal inhibitors eliminated the differences in apoB secretion among groups A, B, and C.

Conclusions—Our data indicate that both insulin resistance and diabetes triggered the intracellular machinery involved in VLDL assembly and secretion.
Expression, Regulation, and Function of IGF-1, IGF-1R, and IGF-1 Binding Proteins in Blood Vessels
Authors: Delafontaine Patrice , Song Yao-Hua , Li Yangxin
Published: November 2003

The vascular insulin-like growth factor (IGF)-1 system includes the IGFs, the IGF-1 receptor (IGF-1R), and multiple binding proteins. This growth factor system exerts multiple physiologic effects on the vasculature through both endocrine and autocrine/paracrine mechanisms. The effects of IGF-1 are mediated principally through the IGF-1R but are modulated by complex interactions with multiple IGF binding proteins that themselves are regulated by phosphorylation, proteolysis, polymerization, and cell or matrix association. During the last decade, a significant body of evidence has accumulated, indicating that expression of the components of the IGF system are regulated by multiple factors, including growth factors, cytokines, lipoproteins, reactive oxygen species, and hemodynamic forces. In addition, cross-talk between the IGF system and other growth factors and integrin receptors has been demonstrated. There is accumulating evidence of a role for IGF-1 in multiple vascular pathologies, including atherosclerosis, hypertension, restenosis, angiogenesis, and diabetic vascular disease. This review will discuss the regulation of expression of IGF-1, IGF-1R, and IGF binding proteins in the vasculature and summarize evidence implicating involvement of this system in vascular diseases.
Antioxidative, Antinitrative, and Vasculoprotective Effects of a Peroxisome Proliferator–Activated Receptor-γ Agonist in Hypercholesterolemia
Authors: Tao Ling , Liu Hui-Rong , Gao Erhe , Teng Zhi-Ping , Lopez Bernard L. , Christopher Theodore A. , Ma Xin-Liang , Batinic-Haberle Ines , Willette Robert N. , Ohlstein Eliot H. , Yue Tian-Li
Published: November 2003

Background—

Peroxisome proliferator–activated receptor (PPAR) signaling pathways have been reported to exert anti-inflammatory effects and attenuate atherosclerosis formation. However, the mechanisms responsible for their anti-inflammatory and antiatherosclerotic effects remain largely unknown. The present study tested the hypothesis that a PPARγ agonist may exert significant endothelial protection by antioxidative and antinitrative effects.

Methods and Results—

Male New Zealand White rabbits were randomized to receive a normal (control) or a high-cholesterol diet and treated with vehicle or rosiglitazone (a PPARγ agonist) 3 mg · kg
−1
· d
−1
for 5 weeks beginning 3 weeks after the high-cholesterol diet. At the end of 8 weeks of a high-cholesterol diet, the rabbits were killed, and the carotid arteries were isolated. Bioactive nitric oxide was determined functionally (endothelium-dependent vasodilatation) and biochemically (the phosphorylation of vasodilator-stimulated phosphoprotein, or P-VASP). Vascular superoxide production, PPARγ, gp91
phox
, and inducible nitric oxide synthase (iNOS) expression, and vascular ONOO
−
formation were determined. Hypercholesterolemia caused severe endothelial dysfunction and reduced P-VASP, despite a marked increase in iNOS expression and total NO
x
production. Treatment with rosiglitazone enhanced PPARγ expression, improved endothelium-dependent vasodilatation, preserved P-VASP, suppressed gp91
phox
and iNOS expression, reduced superoxide and total NO
x
production, and inhibited nitrotyrosine formation.

Conclusions—

The PPARγ agonist rosiglitazone exerted a significant vascular protective effect in hypercholesterolemic rabbits, most likely by attenuation of oxidative and nitrative stresses. The endothelial protective effects of PPARγ agonists may reduce leukocyte accumulation in vascular walls and contribute to their antiatherosclerotic effect.
Intravascular Ultrasound Assessment of Ulcerated Ruptured Plaques
Authors: Fujii Kenichi , Kobayashi Yoshio , Mintz Gary S. , Takebayashi Hideo , Dangas George , Moussa Issam , Mehran Roxana , Lansky Alexandra J. , Kreps Edward , Collins Michael , Colombo Antonio , Stone Gregg W. , Leon Martin B. , Moses Jeffrey W.
Published: November 2003

Background—

It is not clear why some plaque ruptures lead to acute coronary syndromes (ACS) but others do not.

Methods and Results—

We analyzed 80 plaque ruptures in 74 patients and compared culprit lesions of ACS patients with nonculprit lesions of ACS patients and lesions of non-ACS patients; both culprit and nonculprit plaque ruptures were studied in 6 of 54 ACS patients. Intravascular ultrasound findings suggesting thrombus were observed more frequently in culprit lesions of ACS patients (n=35) compared with nonculprit lesions of ACS patients (n=19) and lesions of non-ACS patients (n=26): 60% versus 32% versus 8% (
P
<0.001). At the minimal lumen site, smaller lumen areas (3.3±1.5 versus 5.4±2.6 versus 6.1±2.0 mm
2
,
P
<0.001) and greater area stenosis (61±15% versus 50±14% versus 46±18%,
P
=0.002) and plaque burden (80±8% versus 71±8% versus 69±10%,
P
<0.001) were observed in culprit lesions of ACS patients compared with nonculprit lesions of ACS patients and lesions of non-ACS patients. Lesions were longer (18.7±6.4 versus 154.9±6.1 versus 12.0±4.9 mm,
P
<0.001) and rupture site remodeling indices were greater (1.26±0.21 versus 1.24±0.21 versus 1.09±0.05,
P
=0.002). Independent predictors of culprit plaque ruptures in ACS patients were smaller minimum lumen areas (
P
=0.02) and presence of thrombus (
P
=0.01).

Conclusions—

Ruptured plaques in culprit lesions of ACS patients have smaller lumens; greater plaque burdens, area stenosis, and remodeling indices; and more thrombus. Plaque rupture itself does not lead to symptoms. The association of plaque rupture with a smaller lumen area and/or thrombus formation causes lumen compromise and leads to symptoms.
Randomized Study Comparing Combined Pulmonary Vein–Left Atrial Junction Disconnection and Cavotricuspid Isthmus Ablation Versus Pulmonary Vein–Left Atrial Junction Disconnection Alone in Patients Presenting With Typical Atrial Flutter and Atrial Fibrillation
Authors: Wazni Oussama , Marrouche Nassir F. , Martin David O. , Gillinov A. Marc , Saliba Walid , Saad Eduardo , Klein Allan , Bhargava Mandeep , Bash Dianna , Schweikert Robert , Erciyes Demet , Abdul-Karim Ahmad , Brachman Johannes , Gunther Jens , Pisano Ennio , Potenza Domenico , Fanelli Raffaele , Natale Andrea
Published: November 2003

Background—

Atrial flutter (AFL) and atrial fibrillation (AF) frequently coexist in the same patient. Recently it has been demonstrated that the triggers for both AF and AFL may originate in the pulmonary veins (PVs). We hypothesized that in patients with both AF and typical AFL, pulmonary vein–left atrial junction (PV-LAJ) disconnection may eliminate both arrhythmias.

Methods and Results—

Consecutive patients with documented symptomatic AF and typical AFL were randomly assigned to have PV-LAJ disconnection combined with cavotricuspid isthmus (CTI) ablation (group 1, n=49) or PV-LAJ disconnection alone (group 2, n=59). Within the first 8 weeks after ablation, 32 of the group 2 patients had typical AFL documented, whereas none was seen in group 1. Twenty of these 32 converted to sinus rhythm after initiating antiarrhythmic drugs (AADs). Twelve were cardioverted, and AADs were started. After 8 weeks, all AADS were stopped, and only 3 patients continued to have recurrent sustained typical AFL that was eliminated by CTI ablation. Beyond 8 weeks of follow-up, 7 patients in group 1 and 6 patients in group 2 (14% and 11%, respectively) continued to have AF. Ten of these 13 patients underwent a repeat PV-LAJ disconnection procedure and were cured. The remaining 3 remained in normal sinus rhythm while taking AADs.

Conclusions—

In patients with both AFL and AF, PV-LAJ disconnection alone may be sufficient to control both arrhythmias. CTI block reduced early postablation recurrence of arrhythmias, which in the majority of patients reflects a short-term clinical problem.
Sympathetic Augmentation in Hypertension
Authors: Schlaich Markus P. , Lambert Elisabeth , Kaye David M. , Krozowski Zygmunt , Campbell Duncan J. , Lambert Gavin , Hastings Jacqui , Aggarwal Anuradha , Esler Murray D.
Published: November 2003

There is growing evidence that essential hypertension is commonly neurogenic and is initiated and sustained by sympathetic nervous system overactivity. Potential mechanisms include increased central sympathetic outflow, altered norepinephrine (NE) neuronal reuptake, diminished arterial baroreflex dampening of sympathetic nerve traffic, and sympathetic neuromodulation by angiotensin II. To address this issue, we used microneurography and radiotracer dilution methodology to measure regional sympathetic activity in 22 hypertensive patients and 11 normotensive control subjects. The NE transport inhibitor desipramine was infused to directly assess the potential role of impaired neuronal NE reuptake. To evaluate possible angiotensin sympathetic neuromodulation, the relation of arterial and coronary sinus plasma concentrations of angiotensin II to sympathetic activity was investigated. Hypertensive patients displayed increased muscle sympathetic nerve activity and elevated total systemic, cardiac, and renal NE spillover. Cardiac neuronal NE reuptake was decreased in hypertensive subjects. In response to desipramine, both the reduction of fractional transcardiac
3
[H]NE extraction and the increase in cardiac NE spillover were less pronounced in hypertensive patients. DNA sequencing analysis of the NE transporter gene revealed no mutations that could account for reduced transporter activity. Arterial baroreflex control of sympathetic nerve traffic was not diminished in hypertensive subjects. Angiotensin II plasma concentrations were similar in both groups and were not related to indexes of sympathetic activation. Increased rates of sympathetic nerve firing and reduced neuronal NE reuptake both contribute to sympathetic activation in hypertension, whereas a role for dampened arterial baroreflex restraint on sympathetic nerve traffic and a peripheral neuromodulating influence of angiotensin II appear to be excluded.
Mnk1 Is Required for Angiotensin II–Induced Protein Synthesis in Vascular Smooth Muscle Cells
Authors: Ishida Mari , Ishida Takafumi , Nakashima Hidekatsu , Miho Narimasa , Miyagawa Kiyoshi , Chayama Kazuaki , Oshima Tetsuya , Kambe Masayuki , Yoshizumi Masao
Published: November 2003

Angiotensin II (Ang II) stimulates protein synthesis in vascular smooth muscle cells (VSMCs), possibly secondary to regulatory changes at the initiation of mRNA translation. Mitogen-activated protein (MAP) kinase signal–integrating kinase-1 (Mnk1), a substrate of ERK and p38 MAP kinase, phosphorylates eukaryotic initiation factor 4E (eIF4E), an important factor in translation. The goal of the present study was to investigate the role of Mnk1 in Ang II–induced protein synthesis and to characterize the molecular mechanisms by which Mnk1 and eIF4E is activated in rat VSMCs. Ang II treatment resulted in increased Mnk1 activity and eIF4E phosphorylation. Expression of a dominant-negative Mnk1 mutant abolished Ang II–induced eIF4E phosphorylation. PD98059 or introduction of kinase-inactive MEK1/MKK1, but not SB202190 or kinase-inactive p38 MAP kinase, inhibited Ang II–induced Mnk1 activation and eIF4E phosphorylation, suggesting that ERK, but not p38 MAP kinase, is required for Ang II–induced Mnk1-eIF4E activation. Further, dominant-negative constructs for Ras, but not for Rho, Rac, or Cdc42, abolished Ang II–induced Mnk1 activation. Finally, treatment of VSMCs with CGP57380, a novel specific kinase inhibitor of Mnk1, resulted in dose-dependent decreases in Ang II–stimulated phosphorylation of eIF4E, protein synthesis, and VSMC hypertrophy. In summary, these data demonstrated that (1) Ang II–induced Mnk1 activation is mediated by the Ras-ERK cascade in VSMCs, and (2) Mnk1 is involved in Ang II–mediated protein synthesis and hypertrophy, presumably through the activation of translation-initiation. The Mnk1-eIF4E pathway may provide new insights into molecular mechanisms involved in vascular hypertrophy and other Ang II–mediated pathological states.
Cervical Arterial Dissection
Authors: Beletsky Vadim , Nadareishvili Zurab , Lynch John , Shuaib Ashfaq , Woolfenden Andrew , Norris John W.
Published: November 2003

Background and Purpose—

Cervical arterial dissection is a major cause of stroke in young adults, yet despite standard treatment with anticoagulants or antiplatelet drugs, its management remains uncertain. The goal of this study was to assess the natural history of the disorder and to decide on the feasibility of a therapeutic trial.

Methods—

Collaborating members of the Canadian Stroke Consortium prospectively enrolled consecutively referred patients with angiographically proven acute vertebral or carotid arterial dissection. Data recorded included clinical and radiological details, recurrence of ischemic cerebral events, and medical or surgical treatment.

Results—

Of 116 patients, 67 had vertebral and 49 had carotid dissections, with no difference in age or sex. In 68 (59%), trauma occurred at the time of dissection. During the course of a 1-year follow-up, at least 17 patients (15%) had recurrent transient ischemic attacks, stroke, or death, mainly in the weeks immediately after the dissection. In 105 patients with complete follow-up, the event rate in those treated with anticoagulants was 8.3% and in those treated with aspirin was 12.4%, a nonsignificant difference of 4.1%. Using these data, we calculate that for a 2-arm trial (aspirin versus anticoagulants) with 80% power and 5% significance, 913 patients are needed in each group.

Conclusions—

From our data indicating an initial relatively high recurrence rate, a multicenter trial of anticoagulants versus aspirin involving a total of 2000 patients is feasible.
Tissue Inhibitor of Metalloproteinases-1, −2, and −3 Polymorphisms in a White Population With Intracranial Aneurysms
Authors: Krex Dietmar , Röhl Henning , König Inke R. , Ziegler Andreas , Schackert Hans K. , Schackert Gabriele
Published: November 2003

Background and Purpose—

Remodeling of the extracellular matrix seems to be a crucial event in the pathogenesis of cerebral aneurysms. Matrix metalloproteinases are the most important degrading enzymes in the extracellular matrix. Their activity is controlled predominantly by tissue inhibitors of metalloproteinases (TIMPs). To investigate the possible impact of genetic variants within the genes encoding TIMP-1, −2, and −3, we conducted this case-control study.

Methods—

A study sample was analyzed that comprised 44 patients with intracranial aneurysms and 44, 41, and 40 controls for the analysis of TIMP-1, −2, and −3, respectively. Differences in genotype and allele frequencies of identified polymorphisms were determined. The entire coding regions and parts of the promoter sequences of the TIMP-1, −2, and −3 genes were with using the automated laser fluorescence technique.

Results—

Nine polymorphisms were identified, 3 located in TIMP-1 (−19C>T, 261C>T, 372T>C), 4 in TIMP-2 (−621C>T, −596A>C, −261G>A, 303G>A), and 2 in TIMP-3 (249T>C, 261C>T), whereas −621C>T, −596A>C, and −261G>A of the TIMP-2 gene are newly identified polymorphisms. We detected no deviation from Hardy-Weinberg equilibrium in any of the groups. The C allele of the 372T>C polymorphism was more frequently found in female than in male controls (exact nominal
P
=0.0012). However, this finding could not be validated by analysis of a second sample of 113 controls (exact nominal
P
=1.0000). There were no differences in genotype and allele frequencies between any of the other groups.

Conclusions—

Our analysis of the entire coding region of 3 TIMPs, which are the main inhibitors of metalloproteinase activity in the extracellular matrix, failed to show an association between genetic polymorphisms and an intracranial aneurysm. These data do not support the hypothesis that genetic variants within these genes have an impact on aneurysm development in the white population.
Neonatal Hypoxia-Ischemia Differentially Upregulates MAGUKs and Associated Proteins in PSD-93–Deficient Mouse Brain
Authors: Jiang Xiangning , Mu Dezhi , Sheldon R. Ann , Glidden David V. , Ferriero Donna M.
Published: November 2003

Background and Purpose—

Postsynaptic density (PSD)-93 and PSD-95 are the major membrane-associated guanylate kinases (MAGUKs) at excitatory synapses of the brain linking the
N
-methyl-
d
-aspartate receptor (NMDAR) with neuronal nitric oxide synthase (nNOS), which contributes to cell death after neonatal hypoxia-ischemia (HI). We investigated whether deletion of PSD-93 would dissociate the NMDAR from nNOS and be neuroprotective.

Methods—

Postnatal day 7 wild-type (+/+), heterozygous (+/−), and homozygous (−/−) PSD-93 knockout mice were subjected to HI by permanent ligation of the right carotid artery, followed by exposure to 8% O
2
/92% N
2
for 1 hour. Brains were scored 5 days later for damage with cresyl violet and iron stains. Western blot and coimmunoprecipitation were used to determine the expression and association of the major PSD proteins.

Results—

There was no significant difference between PSD-93 (−/−) and (+/+) mice in mortality or degree of brain injury. In the absence of PSD-93, PSD-95 still interacted with NR2B and nNOS. Under physiological conditions, PSD-95, nNOS, NR2A, and NR2B were unaltered in the (−/−) pups. However, at 24 hours after HI, protein expression of PSD-95, nNOS, and NR2A but not NR2B was markedly higher in the (−/−) than in the (+/+) pups. In (+/+) pups, HI resulted in decreased expression of NR2A but not NR2B in cortex and decreased NR2A and NR2B expression in hippocampus, but this reduction was not observed in (−/−) pups.

Conclusions—

PSD-93 is not essential for baseline synaptic function but may participate in regulation of NMDAR-associated signaling pathways after HI injury. Deletion of PSD-93 alone does not provide neuroprotection after neonatal HI, possibly a result, in part, of upregulation of PSD-95. MAGUKs may substitute for one another, allowing normal NMDAR function in the postnatal period.
Could the Environment Acquire its Own Discourse?
Authors: Kaldis Byron
Published: November 2003

This article addresses the question as to whether it is logically possible to fashion a discourse exclusively for the natural environment. Could such a discourse emerge without colonization by other social spheres acting as proxy? The prospects appear to be rather bleak, for even in the case of two apparently non-human-directed or non-committal discourses, that of extensionist ethics and new sophisticated management (of environmental crises), the latent social-constructionism built into both renders them monistic discourses hegemonically mapping the territories of what they refer to. It becomes increasingly difficult to escape the human epistemic locatedness anti-anthropocentric critics demand. Despite this, such an exercise offers us the benefit of being mindful of what the crisis of social-scientific discourses amounts to as well as what to expect of discourse analysis as such. Furthermore, the prospects of the two discourses examined are being mapped onto two modified models drawing on Foucault and Deleuze thus helping us understand the pattern of our diverse environmental responses. Ecological thinking is perhaps the first subject-matter that transcends or shatters discourse boundaries and strains both imagination and human powers when selecting between conceptual frameworks, making us aware of the ineluctable feature of social-constructionism present in our social thought.
More than a Game? The Role of Sports Governing Bodies in the Development of Sport Education Programmes
Authors: Reid Paul
Published: November 2003

This article explores the extent to which young people can transfer the skills and knowledge gained from a sport education programme to contexts experienced outside the curriculum. Furthermore, it seeks to identify how and where governing bodies of sport can be influential in the promotion of sport education values outside the school context; that is to say, are governing bodies able to develop initiatives to encourage community clubs to adopt a supporting role in the promotion and delivery of sport education?
Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization
Authors: Papayannopoulou Thalia
Published: November 2003

Uncovering the molecular mechanisms governing the exit of stem/progenitor cells from bone marrow to peripheral blood at steady state or after their enforced migration has been an ongoing challenge. Recently, however, several new avenues or paradigms in mobilization have emerged from ever-expanding work in humans subjected to granulocyte colony-stimulating factor (G-CSF) mobilization, as well as from studies in normal and gene-deficient mouse models. Although these developments represent notable advances that met with considerable excitement, they have been quenched by surprising vacillations in subsequent research. This perspective highlights recent developments in mobilization along with their controversies. A full understanding of the directional cues that control the migratory behavior and the fate of stem/progenitor cells once they migrate out of bone marrow will await further experimentation, aiming to bridge our current gaps in knowledge.
Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells
Authors: Clark Fiona J. , Gregg Richard , Piper Karen , Dunnion Debbie , Freeman Lisa , Griffiths Mike , Begum Gulnaz , Mahendra Premini , Craddock Charles , Moss Paul , Chakraverty Ronjon
Published: November 2003

Chronic graft-versus-host disease (cGVHD) is characterized by a state of profound immunodeficiency in association with alloreactive and autoimmune phenomena. These observations indicate an impairment of immunologic tolerance that could involve both central and peripheral mechanisms. Defective thymic function may contribute to dysregulation of central tolerance, but few studies have addressed peripheral tolerance. Recently a population of CD4+CD25+ T cells (Treg cells) has been characterized, which controls immunologic reactivity in vivo and which on transfer can prevent experimental acute GVHD. We investigated the number and function of peripheral blood CD4+CD25high T cells in patients more than 100 days after allogeneic hematopoietic stem cell transplantation. Patients with cGVHD had markedly elevated numbers of CD4+CD25high T cells as compared to patients without GVHD. CD4+CD25high T cells derived from patients in both groups were of donor origin, lacked markers of recent activation, and expressed intracellular CD152. In contrast to controls, CD4+CD25high T cells derived from patients with cGVHD were characterized by lower surface CD62L expression. In vitro, CD4+CD25high T cells were hyporesponsive to polyclonal stimulation and suppressed the proliferation and cytokine synthesis of CD4+CD25- cells, an effect that was independent of interleukin 10. These results indicate that chronic graft-versus-host injury does not occur as a result of Treg cell deficiency.
Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection
Authors: De Milito Angelo , Nilsson Anna , Titanji Kehmia , Thorstensson Rigmor , Reizenstein Elisabet , Narita Mitsuo , Grutzmeier Sven , Sönnerborg Anders , Chiodi Francesca
Published: November 2003

Hypergammaglobulinemia and defective humoral immunity are hallmarks of HIV-1 infection. Naive B cells have been recently suggested as the major source of hypergammaglobulinemia in chronic viral infections. We recently reported that HIV-1–infected patients carry low levels of memory B cells. Here we studied whether defects in the naive and memory B cells in HIV-1–infected patients translated into hypergammaglobulinemia and defective humoral immunity against specific antigens. Naive B cells from HIV-1–infected patients exhibited abnormal expression of the activation/differentiation markers CD70 and leukocyte-associated Ig-like receptor (LAIR-1). Activated naive B cells from patients showed a significant increase in the intracellular immunoglobulin G (IgG) content ex vivo and this activated phenotype correlated to hypergammaglobulinemia and to the ability of naive B cells from patients to secrete IgG in vitro. We analyzed the levels of antibodies to tetanus toxoid, measles, and HIV-1 in relation to memory B cells and observed a significant reduction of antigen-specific antibodies in patients with low-memory B lymphocytes. Nevertheless, hypergammaglobulinemia and levels of polyspecific self-reactive antibodies were comparable in patients with normal and low memory B cells. We conclude that reduction of memory B lymphocytes in HIV-1 infection correlates with defective humoral immunity and that hyperactivated naive B cells may represent the source of abnormal IgG production in HIV-1 infection. Our results may be relevant to the design of HIV-1 therapeutical vaccines and to the clinical management of HIV-1–infected patients.