bluuebunny/crossref_metadata_2025 huggingface dataset:
Innate Immune Recognition of Invasive Bacteria Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice
Authors: Gibson Frank C. , Hong Charlie , Chou Hsin-Hua , Yumoto Hiromichi , Chen Jiqiu , Lien Egil , Wong Jodie , Attardo Genco Caroline
Published: May 2004

Background—

Infectious diseases have emerged as potential risk factors for cardiovascular disease (CVD). Epidemiological studies support a connection between periodontal disease, a chronic inflammatory disease of the supporting tissues of the teeth, and CVD.

Methods and Results—

To directly test the connection between periodontal disease and atherosclerosis, apoE
−/−
mice were orally challenged with the periodontal disease pathogen
Porphyromonas gingivalis
or an invasion-impaired
P gingivalis
fimbriae-deficient mutant (FimA−). Both wild-type
P gingivalis
and the FimA− mutant were detected in blood and aortic arch tissue of apoE
−/−
mice by PCR after challenge. ApoE
−/−
mice challenged with wild-type
P gingivalis
presented with increased atherosclerotic plaque and expressed the innate immune response markers Toll-like receptor (TLR)-2 and TLR-4 in aortic tissue. Despite detection of the FimA− mutant in the blood and in aortic arch tissue, apoE
−/−
mice challenged with the FimA− mutant did not present with periodontal disease, upregulation of TLRs, or accelerated atherosclerosis. Furthermore, we demonstrate that immunization to control
P gingivalis
-elicited periodontal disease concomitantly prevents
P gingivalis
-accelerated atherosclerosis.

Conclusions—

We conclude that invasive
P gingivalis
accelerates atherosclerosis.
Insulin Resistance and Hypertension
Authors: Saad Mohammed F. , Rewers Marian , Selby Joseph , Howard George , Jinagouda Sujata , Fahmi Salwa , Zaccaro Dan , Bergman Richard N. , Savage Peter J. , Haffner Steven M.
Published: May 2004

The association between insulin resistance and insulinemia and hypertension is controversial. We examined the relation between insulin resistance and hypertension in 564 non-Hispanic whites (NHW), 505 Hispanics (H), and 413 African Americans (AA) who participated in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity was measured with a frequently sampled intravenous glucose tolerance test with minimal model analysis. The prevalence of hypertension was 32.5%, 49.4%, and 32.3% in NHW, AA, and H, respectively (
P
<0.001). When subjects without diabetes in all ethnic groups were combined, age, male sex, race (AA), body mass index (BMI), and insulin resistance, but not fasting insulin, were significantly associated with hypertension. When each ethnic group was analyzed separately, insulin resistance was significantly associated with hypertension in NHW and H, but not AA. After excluding subjects taking antihypertensive medications, male sex, BMI, fasting glucose, and insulin resistance, but not fasting insulin, were significant determinants of blood pressure. When the 3 ethnic groups were analyzed separately, insulin resistance was significantly associated with blood pressure in H, but not NHW, or AA. Neither insulin resistance nor fasting insulin was significantly associated with hypertension or blood pressure in subjects with diabetes of the 3 ethnic groups after adjusting for age, sex, BMI, and waist. In conclusion, insulin resistance, but not insulinemia, was related to hypertension and blood pressure in subjects without diabetes, but ethnic differences in these relations appear to exist. Neither insulin resistance nor insulinemia was related to hypertension or blood pressure in patients with type 2 diabetes in the 3 ethnic groups.
Changes in Arterial Stiffness and Wave Reflection With Advancing Age in Healthy Men and Women
Authors: Mitchell Gary F. , Parise Helen , Benjamin Emelia J. , Larson Martin G. , Keyes Michelle J. , Vita Joseph A. , Vasan Ramachandran S. , Levy Daniel
Published: May 2004

With advancing age, arterial stiffness and wave reflections increase and elevate systolic and pulse pressures. An elevated central pulse pressure is generally ascribed to increased wave reflection and portends an unfavorable prognosis. Using arterial tonometry, we evaluated central (carotid-femoral) and peripheral (carotid-brachial) pulse wave velocity, amplitudes of forward and reflected pressure waves, and augmentation index in 188 men and 333 women in the Framingham Heart Study offspring cohort who were free of clinical cardiovascular disease, hypertension, diabetes, smoking within the past 12 months, dyslipidemia, and obesity. In multivariable linear regression models, advancing age was the predominant correlate of higher carotid-femoral pulse wave velocity; other correlates were higher mean arterial pressure, heart rate, and triglycerides and walk test before tonometry (model
R
2
=0.512,
P
<0.001). A similar model was obtained for carotid-brachial pulse wave velocity (model
R
2
=0.227,
P
<0.001), although the increase with advancing age was smaller. Owing to different relations of age to central and peripheral stiffness measures, carotid-femoral pulse wave velocity was lower than carotid-brachial pulse wave velocity before age 50 years but exceeded it thereafter, leading to reversal of the normal central-to-peripheral arterial stiffness gradient. In this healthy cohort with a minimal burden of cardiovascular disease risk factors, an age-related increase in aortic stiffness, as compared with peripheral arterial stiffness, was associated with increasing forward wave amplitude and pulse pressure and reversal of the arterial stiffness gradient. This phenomenon may facilitate forward transmission of potentially deleterious pressure pulsations into the periphery.
Left Ventricle Mass Index and the Common, Functional, X-Linked Angiotensin II Type-2 Receptor Gene Polymorphism (−1332 G/A) in Patients With Systemic Hypertension
Authors: Alfakih Khaled , Maqbool Azhar , Sivananthan Mohan , Walters Kevin , Bainbridge Gavin , Ridgway John , Balmforth Anthony J. , Hall Alistair S.
Published: May 2004

A common intronic polymorphism, (−1332 G/A) of the angiotensin type-2 receptor gene, located on the X-chromosome, has been reported to be functional. The aim of our study was to evaluate this polymorphism for an association with left ventricular hypertrophy. Left ventricle (LV) mass was measured in 197 patients with systemic hypertension and 60 normal volunteers using a 1.5-Tesla Philips MRI system. Genotyping was performed using a restriction enzyme digestion of an initial 310-bp polymerase chain reaction product that included the angiotensin type-2 (−1332 G/A) locus. The mean LV mass index for the male patients was 94.3±19.6 g/m
2
(n=125) and for the female patients was 71.2±12.0 g/m
2
(n=72). Seventy-three (37.1%) of all patients had an elevated LV mass index, defined as the mean LV mass index for normal volunteers plus 2 SD (males 77.8±9.1 g/m
2
, n=30; females 61.5±7.5g/m
2
, n=30). Comparison of LV mass index of the A_/AA genotype (mean LV mass index=82.4±21.1 g/m
2
; n=123) against that of the G_/GG genotype (mean LV mass index=88.1±19.0 g/m
2
; n=89) as a continuous variable was significant by ANOVA (
P
=0.044). χ
2
Comparison between subjects with and subjects without left ventricular hypertrophy revealed an excess of the G_/GG genotype among the group with LV hypertrophy (
P
=0.031). We observed an association between the angiotensin type-2 receptor (−1332 G) allele and the presence of left ventricular hypertrophy in hypertensive subjects.
Thrombosis and Neointima Formation in Vein Grafts Are Inhibited by Locally Applied Aspirin Through Endothelial Protection
Authors: Torsney Evelyn , Mayr Ursula , Zou Yiping , Thompson W. Douglas , Hu Yanhua , Xu Qingbo
Published: May 2004

Vein graft failure within the first month after bypass surgery is largely because of thrombosis. However, systemic study of thrombus formation in vein grafts is still lacking, and few effective techniques are available to prevent this event. Herein, we analyzed the kinetics of thrombosis and tested the effectiveness of locally applied aspirin on prevention of the disease in a mouse model. En face analysis of vein grafts revealed that 67±12% and 54±17% of the surface areas were covered by microthrombi at 1 and 3 days, respectively. Thrombus generation was also identified by labeling of platelets and fibrin, which occurred in 35 grafts examined at 1 and 3 days and 1, 2, 4, and 8 weeks. In a fifth of grafts, the thrombus occluded the vessel lumen by ≥1/4. Furthermore, a significant loss of endothelial cells was evidenced by β-gal staining for vein grafts in transgenic mice expressing LacZ gene controlled by TIE2-endothelial specific gene promoter. Following thrombosis, neointimal lesions were significantly increased by 4-fold 2 weeks after the operation. When vein grafts were treated locally with aspirin in pluronic gel-127, the thrombus area was significantly reduced (
P
<0.005) at 1, 4, and 8 weeks. Interestingly, neointimal lesions were markedly reduced in the local, but not oral, aspirin-treated group at 4 and 8 weeks by 50% to 70% (
P
<0.005). The mechanism of reduced lesions by locally applied aspirin involved the protection of vein graft endothelium. Thus, we provide strong evidence that thrombus formation occurs before the development of neointimal lesions in vein grafts and that local aspirin treatment successfully reduces vein graft arteriosclerosis through endothelial protection, resulting in reduction of thrombosis.
Thioredoxin-2 Inhibits Mitochondria-Located ASK1-Mediated Apoptosis in a JNK-Independent Manner
Authors: Zhang Rong , Al-Lamki Rafia , Bai Lanfang , Streb Jeffrey W. , Miano Joseph M. , Bradley John , Min Wang
Published: May 2004

Apoptosis signal-regulating kinase 1 (ASK1) mediates cytokines and oxidative stress (ROS)-induced apoptosis in a mitochondria-dependent pathway. However, the underlying mechanism has not been defined. In this study, we show that ASK1 is localized in both cytoplasm and mitochondria of endothelial cells (ECs) where it binds to cytosolic (Trx1) and mitochondrial thioredoxin (Trx2), respectively. Cys-250 and Cys-30 in the N-terminal domain of ASK1 are critical for binding of Trx1 and Trx2, respectively. Mutation of ASK1 at C250 enhanced ASK1-induced JNK activation and apoptosis, whereas mutation of ASK1 at C30 specifically increased ASK1-induced apoptosis without effects on JNK activation. We further show that a JNK-specific inhibitor SP600125 completely blocks TNF induced JNK activation, Bid cleavage, and Bax mitochondrial translocation, but only partially inhibits cytochrome
c
release and EC death, suggesting that TNF induces both JNK-dependent and JNK-independent apoptotic pathways in EC. Mitochondria-specific expression of a constitutively active ASK1 strongly induces EC apoptosis without JNK activation, Bid cleavage, and Bax mitochondrial translocation. These data suggest that mitochondrial ASK1 mediates a JNK-independent apoptotic pathway induced by TNF. To determine the role of Trx2 in regulation of mitochondrial ASK1 activity, we show that overexpression of Trx2 inhibits ASK1-induced apoptosis without effects on ASK1-induced JNK activation. Moreover, specific knockdown of Trx2 in EC increases TNF/ASK1-induced cytochrome
c
release and cell death without increase in JNK activation, Bid cleavage, and Bax translocation. Our data suggest that ASK1 in cytoplasm and mitochondria mediate distinct apoptotic pathways induced by TNF, and Trx1 and Trx2 cooperatively inhibit ASK1 activities.
Endothelial Lipase Promotes the Catabolism of ApoB-Containing Lipoproteins
Authors: Broedl Uli C. , Maugeais Cyrille , Millar John S. , Jin Weijun , Moore Ryan E. , Fuki Ilia V. , Marchadier Dawn , Glick Jane M. , Rader Daniel J.
Published: May 2004

Endothelial lipase (EL) has been found to be a key enzyme in high-density lipoprotein (HDL) metabolism in mice, leading to the concept that inhibition of EL could be a novel strategy for raising HDL cholesterol levels. However, mice are “HDL animals” and the effect of EL on atherogenic apoB-containing lipoproteins has not been elucidated. We previously found that EL is capable of hydrolyzing very low-density lipoprotein (VLDL) and LDL lipids ex vivo. To investigate the role of EL in the metabolism of apoB-containing lipoproteins in vivo, we expressed human EL in three mouse models of elevated apoB-containing lipoproteins: apoE-deficient, LDL receptor–deficient, and human apoB transgenic mice. Unexpectedly, hepatic expression of EL resulted in markedly decreased levels of VLDL/LDL cholesterol, phospholipid, and apoB accompanied by significantly increased LDL apolipoprotein and phospholipid catabolism. To determine whether lipolytic activity is required for this effect, we also expressed a catalytically inactive form of human EL (EL
S149A
); unexpectedly, expression of EL
S149A
did not lower and in fact increased plasma lipids. Coexpression and coimmunoprecipitation studies suggested that catalytically inactive EL
S149A
inhibits endogenous mouse EL, accounting for the increased lipid levels. We conclude that (1) in addition to its known effects on HDL metabolism, EL influences the metabolism of apoB-containing particles; (2) catalytic activity of EL is required for its effects on apoB-containing lipoproteins; and (3) overexpressed catalytically inactive EL inhibits endogenous mouse EL, resulting in increased levels of plasma lipids. In light of these results, inhibition of EL has the potential to raise levels of atherogenic lipoproteins in addition to HDL-C levels.
White Matter Hyperintensities Are Associated With Impairment of Memory, Attention, and Global Cognitive Performance in Older Stroke Patients
Authors: Burton Emma J. , Kenny Rose Anne , O’Brien John , Stephens Sally , Bradbury Michael , Rowan Elise , Kalaria Raj , Firbank Michael , Wesnes Keith , Ballard Clive
Published: May 2004

Background—

The importance of white matter hyperintensities (WMH) for cognitive performance in older stroke patients is largely unknown. We hypothesized that processing speed and executive dysfunction will be associated with frontal WMH whereas impaired memory will be associated with temporal WMH.

Methods—

Neuropsychological assessments using the Cambridge Cognitive Examination (CAMCOG) and the Cognitive Drug Research (CDR) were completed for 96 stroke survivors aged older than 75 and 23 age-matched controls. Magnetic resonance imaging whole-brain axial FLAIR images were undertaken to visualize WMH and an automated threshold technique was used to determine their volume.

Results—

In comparison to controls, the stroke patients had significantly greater volume of WMH in all key areas. Within the stroke group, a consistent pattern of significant association was identified between total and frontal WHM volumes and attention and processing speed tasks (eg, choice reaction time [right:
R
=0.24
P
=0.02; left:
R
=0.26,
P
=0.01]), but not with executive function. There were significant associations between memory and temporal WMH volumes (right:
R
=0.27,
P
=0.008; left:
R
=0.20,
P
=0.047).

Conclusion—

In older stroke patients, cognitive processing speed and performance on measures of attention are significantly associated with WMH volume, particularly in the frontal lobe regions, whereas memory impairment is associated with the volume of temporal lobe WMH.
Predictive Values of Lacunar Transient Ischemic Attacks
Authors: Hervé Dominique , Gautier-Bertrand Marion , Labreuche Julien , Amarenco Pierre
Published: May 2004

Background and Purpose—

We postulated that a lacunar syndrome occurring with transient ischemic attacks (TIAs) or progressive nonsudden onset predicts a brain infarction (BI), presumably caused by a small artery disease (ie, lacunar BI) better than a lacunar syndrome with sudden onset.

Methods—

We included 510 patients with BI. BI was classified into etiologic groups including lacunar BI group. We identified the patients with lacunar or nonlacunar syndrome, and those with TIAs preceding the BI or with symptoms of nonsudden onset.

Results—

Nonlacunar syndrome had a negative predictive value for a lacunar BI of 95%. A lacunar syndrome had a positive predictive value (PPV) of 57% for lacunar infarction (n=109), and the PPV increased to 79% in the case of recent TIAs preceding the lacunar syndrome. Hypertension was present in 95% of cases with lacunar TIAs (odds ratio: 10.69; 95% confidence interval: 1.34 to 84.82;
P
=0.02).

Conclusions—

Lacunar TIAs are almost always associated with history of arterial hypertension and have a high PPV for lacunar BI. This subgroup of patients may reflect different underlying mechanisms than the group of patient with lacunar syndrome of sudden onset.
Role of p38 Mitogen-Activated Protein Kinase on Cerebral Vasospasm After Subarachnoid Hemorrhage
Authors: Sasaki Toshiyuki , Kasuya Hidetoshi , Onda Hideaki , Sasahara Atsushi , Goto Shin , Hori Tomokatsu , Inoue Ituro
Published: May 2004

Background and Purpose—

Inflammatory cytokines are involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to examine the role of p38 mitogen-activated protein kinase (MAPK) in the development of vasospasm and cytokine production.

Methods—

We measured the expression levels of genes and proteins related to inflammation in human vascular smooth muscle cells (hVSMCs) treated with hemolysate and FR167653 (FR) (1μmol/L), a selective p38MAPK inhibitor, for 48 hours by TaqMan real-time reverse transcription-polymerase chain reaction (RT-PCR) and ELISA. Twenty-one dogs were assigned to 3 groups of 7 animals: control, placebo, and FR-treated (1 mg/kg/d) groups in a double-hemorrhage model. The effects were assessed through the caliber of the basilar artery, and the changes in gene expressions and the activation of p38MAPK were assessed by Western blot analysis.

Results—

Treatment of hVSMCs with hemolysate induced significant upregulation of interleukin (IL)-1α, IL-1β, and IL-8 gene and protein expressions, which was suppressed significantly with FR. The mean vessel caliber on day 7, as a percentage of that of day 0, was 49% in the placebo, and 74% in the FR group (
P
=0.0001). The gene expression levels of IL-1α, IL-1β, and IL-8 in the arterial wall were extremely elevated in the placebo, and significantly suppressed in the FR group (
P
=0.0027, 0.0002, and 0.0073). p38MAPK phosphorylation was stimulated in the placebo and hemolysate in vitro, and suppressed in the FR group.

Conclusions—

These results suggest that p38MAPK is activated in the arterial wall after SAH, leading to the development of vasospasm, possibly through the upregulation of inflammatory cytokines.
Critical Closing Pressure in Subarachnoid Hemorrhage
Authors: Soehle Martin , Czosnyka Marek , Pickard John D. , Kirkpatrick Peter J.
Published: May 2004

Background and Purpose—

Critical closing pressure (CCP) is thought to be jointly influenced by intracranial pressure and cerebrovascular tone. We examined how CCP is affected by cerebral vasospasm after subarachnoid hemorrhage (SAH).

Methods—

In 15 patients with vasospasm of the middle cerebral artery, CCP was calculated using 2 methods previously reported (ad modem Aaslid and Michel, indexed CCP
Aaslid
and CCP
Michel
, respectively) based on data of arterial blood pressure and flow velocity (FV) as assessed by transcranial Doppler.

Results—

CCP decreased significantly (
P
<0.05) during vasospasm (CCP
Aaslid
=6.3±22.9 mm Hg, CCP
Michel
=14.9±16.5 mm Hg, mean±SD) as compared with baseline (CCP
Aaslid
=24.4±20.3 mm Hg, CCP
Michel
=27.8±19.4 mm Hg). This was not attributable to ICP, which remained unaffected by vasospasm. In addition, CCP was significantly lower on the side of vasospasm (CCP
Aaslid
=11.9±24.2 mm Hg, CCP
Michel
=18.4±19.6 mm Hg) as compared with the contralateral nonvasospastic side (CCP
Aaslid
=24.7±22.3 mm Hg, CCP
Michel
=28.2±18.0 mm Hg).

Conclusions—

Assuming that autoregulation-related distal vasodilatation outweighs proximal vasospasm, CCP should decrease. Alternatively, CCP might have increased during vasospasm as the tension of big vessels increase, but the turbulence occurring during vasospasm may have impaired the linear relationship between pressure and FV, thus leading to a marked underestimation of CCP. In conclusion, interpretation of CCP in vasospasm is difficult and may be overshadowed by nonlinear hemodynamic effects.
Oxidative Stress Is Associated With XIAP and Smac/DIABLO Signaling Pathways in Mouse Brains After Transient Focal Cerebral Ischemia
Authors: Saito Atsushi , Hayashi Takeshi , Okuno Shuzo , Nishi Tatsuro , Chan Pak H.
Published: May 2004

Background and Purpose—

The interaction of X chromosome-linked inhibitor-of-apoptosis protein (XIAP) with second mitochondria-derived activator of caspase (Smac)/direct inhibitor-of-apoptosis protein-binding protein with low pI (DIABLO) contributes to regulation of apoptosis after a variety of cell death stimuli, and in our reported in vivo transient focal cerebral ischemia (tFCI) model. We have also reported that overexpression of copper/zinc superoxide dismutase (SOD1) reduces apoptotic cell death after tFCI. Our present study was designed to clarify the relationship between the XIAP signaling pathway and oxidative stress in the regulation of apoptosis after tFCI.

Methods—

We used a tFCI model of SOD1 transgenic mice and wild-type littermates to examine the expression of XIAP and Smac/DIABLO by Western blotting and the interaction of XIAP with Smac/DIABLO (XIAP/Smac) or caspase-9 (XIAP/caspase-9) by coimmunoprecipitation. The direct oxidation of carbonyl groups, an indication of oxidative injury to total and individual proteins caused by tFCI, was examined using a 2,4-dinitrophenylhydrazone reaction assay.

Results—

Direct oxidative injury to cytosolic and mitochondrial proteins was reduced by SOD1 after tFCI. The individual oxidized carbonyls in XIAP, mitochondrial Smac/DIABLO, and caspase-9 were also reduced by SOD1. Expression of XIAP and XIAP/caspase-9 was promoted, whereas translocation of Smac/DIABLO and XIAP/Smac was reduced, by SOD1 after tFCI.

Conclusions—

These results suggest that overexpression of SOD1 may affect the XIAP pathway after tFCI by reducing the direct oxidative reaction to XIAP regulators after reperfusion injury.
Effects of Urban Community Intervention on 3-Year Survival and Recurrence After First-Ever Stroke
Authors: Jiang Bin , Wang Wen-zhi , Wu Sheng-ping , Du Xiao-li , Bao Qiu-ju
Published: May 2004

Background and Purpose—

For the past 2 decades, stroke has been a principal cause of death in China, and stroke incidence tends to increase with the increase of stroke-related risk factors. The purpose of this study was to evaluate the effects of urban community-based intervention on 3-year survival and recurrence after first-ever stroke.

Methods—

Two communities with a registered population of ≈50 000 each were selected as either intervention or control communities in Beijing during 1991 to 2000. Comprehensive intervention measures including the management of high-risk population and the health education of whole community population were regularly implemented. Then the influence of community intervention on 3-year survival and recurrence after initial stroke was evaluated.

Results—

Within 3 years, 41.85% of 736 patients in the intervention community died whereas 40.34% of 818 patients in the control community died. Of 223 cases from the intervention community, 26 (11.66%) had a recurrent stroke within 3 years versus 52 (20.80%) of 250 cases from the control community. The statistical difference was found. Compared with the control community, the death risk of first-ever stroke in the intervention community decreased by 26% (relative risk [RR]=0.74; 95% confidence interval [CI]: 0.61 to 0.89;
P
=0.002); especially, that of hemorrhagic stroke decreased by 39% (RR=0.61; 95%CI: 0.46 to 0.81;
P
=0.001). Compared with the control community, the recurrence risk of first-ever stroke from the intervention community decreased by 42% (RR=0.58; 95% CI: 0.34 to 1.00;
P
=0.048).

Conclusion—

Community intervention may be effective and beneficial to the recurrence prevention and survival improvement of stroke, especially hemorrhagic stroke.
Recurrent Stroke in Patients With Symptomatic Carotid Artery Occlusion Is Associated With High-Volume Flow to the Brain and Increased Collateral Circulation
Authors: Rutgers D.R. , Klijn C.J.M. , Kappelle L.J. , van der Grond J.
Published: May 2004

Background and Purpose—

To investigate whether the risk of recurrent ipsilateral ischemic stroke in patients with symptomatic carotid artery occlusion (CAO) is related to (1) volume flow in the contralateral internal carotid artery (ICA), basilar artery (BA), and middle cerebral arteries (MCAs), and (2) intracranial collateral flow to the symptomatic side, measured in the first 6 months after the qualifying symptoms occurred.

Methods—

We prospectively studied 112 patients with symptomatic CAO. Quantitative volume flow was measured with magnetic resonance angiography (MRA) and collateral flow via the circle of Willis with MRA, via the ophthalmic artery (OA) with transcranial Doppler sonography, and via leptomeningeal anastomoses with conventional angiography.

Results—

During 49±14 months of follow-up (mean±SD), 7 patients had recurrent ipsilateral ischemic stroke. Compared with patients without recurrent stroke, these patients had significantly higher total flow to the brain, ie, ICA+BA flow (mean 536 mL/min versus 410 mL/min;
P
<0.05), and significantly higher contralateral ICA flow (355 mL/min versus 209 mL/min;
P
<0.001), whereas BA and MCA flow showed no significant differences. Also, they more often had Willisian collateral flow (
P
<0.05), mainly caused by increased collateral flow via the posterior communicating artery (PCoA; 71% versus 28%;
P
<0.05), whereas collateral flow via the OA and leptomeningeal anastomoses did not differ significantly.

Conclusions—

Recurrent ipsilateral ischemic stroke in patients with symptomatic CAO is associated with high volume flow to the brain and increased collateral PCoA flow.
Impact of Surgical Clipping on Survival in Unruptured and Ruptured Cerebral Aneurysms
Authors: Britz Gavin W. , Salem Leon , Newell David W. , Eskridge Joseph , Flum David R.
Published: May 2004

Background and Purpose—

The management of aneurysms is controversial because little is known about the impact of clipping on long-term outcome. This study was designed to evaluate long-term survival of patients with aneurysms undergoing clipping in a statewide population.

Methods—

We used a retrospective design using an administrative database to identify patients hospitalized with aneurysms (1987 to 2001). Time-to-event analysis was used to determine the risk of death from all causes and from neurological causes.

Results—

4619 patients (mean age 54.7±15.3, 66.3% female) were hospitalized with cerebral aneurysms. Survival among patients with ruptures was significantly lower compared with patients with unruptured aneurysm (
P
<0.001) with adjusted hazard ratio (HR) of death after clipping 40% higher (HR: 1.4; 95% CI: 1.2, 1.7) in patients with rupture compared with those that were unruptured. Survival estimates for unruptured patients who underwent clipping were significantly higher than among those unruptured patients who did not undergo clipping (
P
<0.001), with adjusted HR of death 30% higher in patients with unruptured aneurysm that were not clipped compared with unruptured patients who were clipped (HR: 1.3; 95% CI: 1.1, 1.6). Patients with unruptured aneurysm who underwent clipping and survived beyond the 30-day postoperative period were less likely to die from neurologically related causes (5.6 versus 2.3%,
P
<0.001). Patients with ruptures and aneurysms who underwent clipping have a higher rate of death compared with the general population in the long-term.

Conclusions—

Short-term and long-term mortality after clipping of cerebral aneurysms is higher than previously reported. Patients with unruptured aneurysms who undergo clipping have improved survival compared with those who do not undergo clipping. This study supports the use of early intervention in the management of patients with unruptured aneurysms.
Cigarette Smoking and Risk of Stroke and its Subtypes Among Middle-Aged Japanese Men and Women
Authors: Mannami Toshifumi , Iso Hiroyasu , Baba Shunroku , Sasaki Satoshi , Okada Katsutoshi , Konishi Masamitsu , Tsugane Shoichiro
Published: May 2004

Background and Purpose—

We examined sex-specific relationships of smoking with risk of total stroke and stroke subtypes in Asian populations because of the limited data available.

Methods—

A total of 19 782 men and 21 500 women aged 40 to 59 years who were free of prior diagnosis of stroke, coronary heart disease, or cancer and reported their smoking status were followed in the Japan Public Health Center–based Prospective Study on Cancer and Cardiovascular Disease (JPHC Study) from 1990 to 1992 to the end of 2001.

Results—

During a 461 761 person-year follow-up, 702 total strokes were documented among men, of which 619 were confirmed by imaging studies, including 219 intraparenchymal hemorrhages, 73 subarachnoid hemorrhages, and 327 ischemic strokes. The respective numbers of cases among women were 447, 411, 129, 106, and 176. Multivariate relative risks (95% CIs) for current smokers compared with never-smokers after adjustment for cardiovascular risk factors and public health center were 1.27 (1.05 to 1.54) for total stroke, 0.72 (0.49 to 1.07) for intraparenchymal hemorrhage, 3.60 (1.62 to 8.01) for subarachnoid hemorrhage, and 1.66 (1.25 to 2.20) for ischemic stroke. The respective multivariate relative risks among women were 1.98 (1.42 to 2.77), 1.53 (0.86 to 4.25), 2.70 (1.45 to 5.02), and 1.57 (0.86 to 2.87). There was a dose-response relation between the number of cigarettes smoked and risks of ischemic stroke for men. A similar positive association was observed between smoking and risks of lacunar infarction and large-artery occlusive infarction, but not embolic infarction.

Conclusions—

Smoking raises risks of total stroke and subarachnoid hemorrhage for both men and women and risk of ischemic stroke, either lacunar or large-artery occlusive infarction, for men.
Blood Pressure Management in Acute Intracerebral Hemorrhage
Authors: Ohwaki Kazuhiro , Yano Eiji , Nagashima Hiroshi , Hirata Masafumi , Nakagomi Tadayoshi , Tamura Akira
Published: May 2004

Background and Purpose—

The association between elevated blood pressure (BP) and hematoma enlargement in acute intracerebral hemorrhage (ICH) has not been clarified. We investigated the association between maximum systolic BP (SBP) and hematoma enlargement, measuring SBP between a baseline and a second CT scan in patients with hypertensive ICH.

Methods—

We assessed 76 consecutive patients with hypertensive ICH retrospectively. We usually attempted to lower SBP below targets of 140, 150, or 160 mm Hg. Recordings of serial BP from admission until the second CT scan were assessed. A neuroradiologist, who was not informed of the aim of this study, reviewed CT films. Hematoma enlargement was defined as an increase in volume of ≥140% or 12.5 cm
3
.

Results—

Hematoma enlargement occurred in 16 patients. Maximum SBP was significantly associated with hematoma enlargement (
P
=0.0074). A logistic regression model for predicting hematoma enlargement was constructed with the use of maximum SBP, hematoma volume, and Glasgow Coma Scale score at admission. After adjustment for these factors, maximum SBP was independently associated with hematoma enlargement (odds ratio per mm Hg, 1.04; 95% CI, 1.01 to 1.07). Target SBPs of ≥160 mm Hg were significantly associated with hematoma enlargement compared with those of ≤150 mm Hg (
P
=0.025).

Conclusions—

Our findings suggest that elevated BP increases the risk of hematoma enlargement. Efforts to lower SBP below 150 mm Hg may prevent this risk.
LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells
Authors: Perez Omar D. , Mitchell Dennis , Jager Gina C. , Nolan Garry P.
Published: May 2004

Leukocyte function antigen 1 (LFA-1) is essential for the formation of immune cell synapses and plays a role in the pathophysiology of various autoimmune diseases. We investigated the molecular details of LFA-1 activation during adhesion between cytotoxic cells and a target model leukemia cell. The cytolytic activity of a CD3–CD8+CD56+ natural killer (NK) subset was enhanced when LFA-1 was activated. In a comparison of LFA-1 ligands, intercellular adhesion molecule 2 (ICAM-2) and ICAM-3 promoted LFA-1–directed perforin release, whereas ICAM-1 had little effect. Ligand-induced LFA-1 clustering facilitated perforin release, demonstrating LFA-1 could regulate degranulation mechanisms. LFA-1 induced the activation of src family kinases, Vav1 and p44/42 mitogen-activated protein kinase (MAPK), in human CD56+ NK cells as evidenced by intracellular phospho-epitope measurements that correlated with effector-target cell binding and perforin-granzyme A–mediated cytolytic activity. These results identify novel, specific functional consequence of LFA-1–mediated cytolytic activity in perforin-containing human NK subsets.
Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load
Authors: Deeks Steven G. , Kitchen Christina M. R. , Liu Lea , Guo Hua , Gascon Ron , Narváez Amy B. , Hunt Peter , Martin Jeffrey N. , Kahn James O. , Levy Jay , McGrath Michael S. , Hecht Frederick M.
Published: May 2004

Although generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation “set point” is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4+ and CD8+ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviral-treated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8+ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10 000 copies/mL. Among untreated patients, the level of CD8+ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8+ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4+ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4+ T cells are lost over time.
Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IκB kinase activity
Authors: Bhattacharyya Sandip , Sen Pradip , Wallet Mark , Long Brian , Baldwin Albert S. , Tisch Roland
Published: May 2004

Interleukin-10 (IL-10) has potent immunoregulatory effects on the maturation and the antigen-presenting cell (APC) function of dendritic cells (DCs). The molecular basis underlying these effects in DCs, however, is ill defined. It is well established that the transcription factor NF-κB is a key regulator of DC development, maturation, and APC function. This study was initiated to determine the effects of IL-10 on the NF-κB signaling pathway in immature DCs. IL-10 pretreatment of myeloid DCs cultured from bone marrow resulted in reduced DNA binding and nuclear translocation of NF-κB after anti-CD40 antibody or lipopolysaccharide (LPS) stimulation. Furthermore, inhibited NF-κB activation was characterized by reduced degradation, phosphorylation, or both of IκBα and IκBϵ but not IκBβ and by reduced phosphorylation of Ser536, located in the trans-activation domain of p65. Notably, IL-10–mediated inhibition of NF-κB coincided with suppressed IκB kinase (IKK) activity in vitro. Furthermore, IL-10 blocked inducible Akt phosphorylation, and inhibitors of phosphatidylinositol 3-kinase (PI3K) effectively suppressed the activation of Akt, IKK, and NF-κB. These findings demonstrate that IL-10 targets IKK activation in immature DCs and that suppressing the PI3K pathway in part mediates blockade of the pathway.
Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
Authors: Ho Vincent T. , Zahrieh David , Hochberg Ephraim , Micale Eileen , Levin Jesse , Reynolds Carol , Steckel Steve , Cutler Corey , Fisher David C. , Lee Stephanie J. , Alyea Edwin P. , Ritz Jerome , Soiffer Robert J. , Antin Joseph H.
Published: May 2004

Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 μg/kg intravenously on days 1 and 15; 18 received 9 μg/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 μg/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (12 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD. (Blood. 2004;104:1224-1226)
The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain
Authors: Donnelly Raymond P , Sheikh Faruk , Kotenko Sergei V , Dickensheets Harold
Published: May 2004

Several novel interleukin (IL)-10-related cytokines have recently been discovered. These include IL-22, IL-26, and the interferon-λ (IFN-λ) proteins IFN-λ1 (IL-29), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B). The ligand-binding chains for IL-22, IL-26, and IFN-λ are distinct from that used by IL-10; however, all of these cytokines use a common second chain, IL-10 receptor-2 (IL-10R2; CRF2-4), to assemble their active receptor complexes. Thus, IL-10R2 is a shared component in at least four distinct class II cytokine-receptor complexes. IL-10 binds to IL-10R1; IL-22 binds to IL-22R1; IL-26 binds to IL-20R1; and IFN-λ binds to IFN-λR1 (also known as IL-28R). The binding of these ligands to their respective R1 chains induces a conformational change that enables IL-10R2 to interact with the newly formed ligand-receptor complexes. This in turn activates a signal-transduction cascade that results in rapid activation of several transcription factors, particularly signal transducer and activator of transcription (STAT)3 and to a lesser degree, STAT1. Activation by IL-10, IL-22, IL-26, or IFN-λ can be blocked with neutralizing antibodies to the IL-10R2 chain. Although IL-10R2 is broadly expressed on a wide variety of tissues, only a subset of these tissues expresses the ligand-binding R1 chains. The receptors for these cytokines are often present on cell lines derived from various tumors, including liver, colorectal, and pancreatic carcinomas. Consequently, the receptors for these cytokines may provide novel targets for inhibiting the growth of certain types of cancer.
Increased numbers of committed myeloid progenitors but not primitive hematopoietic stem/progenitors in mice lacking STAT6 expression
Authors: Bunting Kevin D , Yu Wen-Mei , Bradley Heath L , Haviernikova Eleonora , Kelly-Welch Ann E , Keegan Achsah D , Qu Cheng-Kui
Published: May 2004

Signal transducer and activator of transcription-6 (STAT6) plays important roles in cytokine signaling via interleukin-4 and -13 receptors (IL-4R and IL-13R). Mice in which STAT6 has been disrupted by homologous recombination show defects in T helper cell type 2 (Th2) lymphocyte production, resulting in an accumulation of Th1 cells. In addition to defects in differentiation and proliferation of T lymphocytes, STAT6-deficient mice show increased cell-cycle activation and frequency of myeloid progenitors. Although this has been shown to be mediated through Oncostatin M production by T cells, IL-4Rα and STAT6 have also recently been found to be enriched for expression in primitive hematopoietic stem cells (HSCs) in gene expression-profiling studies. Therefore, we have investigated whether defects in hematopoietic function in mice lacking STAT6 expression extended into the primitive hematopoietic compartments of the bone marrow. Here, we report that STAT6 deficiency increased bone marrow-committed myeloid progenitors but did not alter the number of cells enriched for HSC/multipotent progenitors, primitive cobblestone area-forming cells assayed in vitro, or bone marrow short-term or long-term repopulating cells assayed in vivo. Therefore, the requirement for STAT6 activation during hematopoiesis is limited, and primitive hematopoietic cell types are insulated against possible effects of cytokine stimulation by Th1 cells.
CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice
Authors: Lomas-Neira Joanne L , Chung Chun-Shiang , Grutkoski Patricia S , Miller Edmund J , Ayala Alfred
Published: May 2004

Polymorphonuclear neutrophil (PMN) extravasation/sequestration in the lung and a dysregulated inflammatory response characterize the pathogenesis of acute lung injury (ALI). Previously, we have shown that hemorrhage (Hem) serves to prime PMN such that subsequent septic challenge [cecal ligation and puncture (CLP)] produces a pathological, inflammatory response and consequent lung injury in mice. Keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) are murine CXC chemokines found elevated in the lungs and plasma following Hem/CLP and have been reported by others to share a common receptor (CXCR2). Based on these data, we hypothesize that blockade of CXCR2 immediately following Hem would suppress KC and MIP-2 priming of PMN, thereby reducing the inflammatory injury observed following CLP. To assess this, Hem mice (90 min at 35±5 mmHg) were randomized to receive 0, 0.4, or 1 mg antileukinate (a hexapeptide inhibitor of CXCRs) in 100 μl phosphate-bufferd saline (PBS)/mouse subcutaneously, immediately following resuscitation (Ringer's lactate-4× drawn blood volume). Twenty-four hours post-Hem, mice were subjected to CLP and killed 24 h later. The results show that blockade of CXCR2 significantly (P<0.05, Tukey's test) reduced PMN influx, lung protein leak, and lung-tissue content of interleukin (IL)-6, KC, and MIP-2 and increased tissue IL-10 levels. Plasma IL-6 was significantly decreased, and IL-10 levels increased in a dose-dependent manner compared with PBS-treated mice. A differential effect was observed in plasma levels of KC and MIP-2. KC showed a significant reduction at the 0.4 mg antileukinate dose. In contrast, plasma MIP-2 was significantly elevated at both doses compared with the PBS-treated controls. Together, these data demonstrate that blockade of CXCR2 signaling attenuates shock-induced priming and ALI observed following Hem and subsequent septic challenge in mice.
Cross-linking of MHC class I molecules on human NK cells inhibits NK cell function, segregates MHC I from the NK cell synapse, and induces intracellular phosphotyrosines
Authors: Rubio Gonzalo , Férez Xavier , Sánchez-Campillo María , Gálvez Jesús , Martí Salvador , Verdú Rocío , Hernández-Caselles Trinidad , García-Peñarrubia Pilar
Published: May 2004

Engagement of major histocompatibility complex (MHC) class I molecules on immune cells, where they are usually highly expressed, induces signal transduction events of unclear significance. We show here that antibody-mediated cross-linking of MHC-I molecules on human natural killer (NK) cells inhibits their cytotoxic activity against tumor target cells. Inhibition by anti-MHC class I monoclonal antibody exhibits molecular specificity and is an isotype and Fc-independent process. Physical hindrance of specific molecular recognition, induction of apoptosis, or reciprocal NK cell killing, which could be induced by cross-linking of MHC I molecules, has also been ruled out as putative mechanisms of inhibition. Confocal microscopy analysis revealed that MHC class I molecules on the surface of NK cells colocalize constitutively with GM1, a marker of lipid rafts. Cross-linking of MHC class I resulted in the asymmetric redistribution of GM1-enriched raft domains, which are concentrated to the immunological synapse, and MHC I molecules, which segregate to the opposite pole. Also, the cross-linking of MHC I on NK cells induced intracellular tyrosine phosphorylations. These results suggest that MHC I molecules on NK cells could transmit inhibitory signals upon engagement with putative ligands expressed on the surface of those cells that need to be protected from natural cytotoxicity.
CCL2, a product of mice early after systemic inflammatory response syndrome (SIRS), induces alternatively activated macrophages capable of impairing antibacterial resistance of SIRS mice
Authors: Tsuda Yasuhiro , Takahashi Hitoshi , Kobayashi Makiko , Hanafusa Toshiaki , Herndon David N , Suzuki Fujio
Published: May 2004

Infection associated with systemic inflammatory response syndrome (SIRS) is a major cause of morbidity and mortality in patients with major surgery, polytrauma, and severe burn injury. In previous studies, mice with severe pancreatitis (a mouse model of SIRS, SIRS mice) have been shown to be greatly susceptible to various infections. In the present study, a mechanism involved in the impaired resistance of SIRS mice to infectious complications was investigated. Sera from SIRS mice impaired the resistance of normal mice to infectious complications induced by cecal ligation and puncture (CLP). CC chemokine ligand 2 (CCL2) was detected in sera of SIRS mice. Resident macrophages (RMφ) cultured with SIRS mouse sera converted to alternatively activated macrophages (AAMφ), which were also demonstrated in mice treated with recombinant murine CCL2. However, AAMφ were not demonstrated in mice injected with SIRS mouse sera and anti-CCL2 monoclonal antibody (mAb) in combination. Furthermore, normal mice that received SIRS mouse sera and anti-CCL2 mAb resisted CLP-induced infectious complications. These results indicate that the resistance of SIRS mice to infectious complications is impaired by AAMφ generated from RMφ in response to SIRS-associated CCL2 production.
Working with grieving adults
Authors: Clark Andrew
Published: May 2004

Despite the dearth of recent psychiatric literature on the subject of grief, mental health professionals continue to see patients suffering from complex responses to grief. This article reviews psychological theories about normal and abnormal grief, drawing particularly on the work of Freud, Klein, Bowlby and Parkes. It describes the principles of grief work, using as illustration clinical examples of adults grieving as a result of bereavement. These principles also apply to work with adults grieving other forms of loss (e.g. breakdown of a love relationship, loss of employment or loss of physical health).
Supported accommodation for people with severe mental illness: a review
Authors: Macpherson Rob , Shepherd Geoff , Edwards Tom
Published: May 2004

The authors describe the main forms of supported accommodation available to people with mental health problems in the UK. They address the questions of who needs supported accommodation and how people may be selected for the differing types of unit. Historical trends and policy in this area are reviewed and the general research evidence and evidence of cost-effectiveness are considered. A ‘total system’ approach to assessing accommodation need in a locality is advocated. The authors also consider key quality issues that should be addressed for supported accommodation to be effective.