bluuebunny/crossref_metadata_2025 huggingface dataset:
The Efficacy of Hourly Prophylactic Steroids in Diffuse Lamellar Keratitis Epidemic
Authors: Cosar C. Banu , Sener A. Bozkurt , Sen Nursen , Coskunseven Efekan
Published: August 2004

Purpose: To investigate the inciting agent, clinical features, and the efficacy of hourly steroids in the prophylaxis in a diffuse lamellar keratitis (DLK) epidemic. Methods: One hundred and five eyes of 58 patients that had DLK after LASIK were included in the study. To identify the cause of the epidemic, some interventions were made: irrigation solution was changed from BSS to Ringer lactate (week 5), wiping of the interface with a sponge was discontinued (week 6), the air conditioner in the LASIK room was checked (week 6), the routine postoperative topical regimen was changed from fluoromethalone and fluoroquinolones 4 times a day to hourly prednisolone acetate or dexamethasone sodium and fluoroquinolones (week 7), and the trademark of the drape used was changed (week 12). Results: There was no statistical difference in any of the attack rates associated with variables including BSS versus Ringer lactate (9.9 vs. 14%, p = 0.4), and air conditioner check with wiping versus not wiping the interface with the microsurgical sponge (14.0 vs. 18.2%, p = 0.6). There was a significant decrease in the attack rate from 18.2 to 5.3% with use of the hourly prophylactic topical steroids (p = 0.012). After introduction of a new trademark of the drape, the incidence of DLK was further reduced from 5.3 to 0.7% (p = 0.016). Conclusion: The cause in a particular DLK epidemic should be identified and eliminated adopting a scientific approach. Hourly steroid use for prophylaxis is recommended until the etiologic agent responsible has been identified.
The HIV RNA Levels of Plasma and Ocular Fluids in AIDS Patients with Ophthalmic Infections
Authors: Hsu Wen-Ming , Chiou Shih-Hwa , Chen Steve S.-L. , Shyong Mon-Ping , Ho Chi-Kung , Chen Shih-Jen , Wu Chih-Chiau , Kung Szu-Hao , Chi Chin-Wen
Published: August 2004

The aim of the present study was to evaluate the impact of highly active antiretroviral therapy (HAART) on HIV viral load of plasma and intraocular fluids in AIDS patients with ophthalmic opportunistic infections. We further compared the treatment effect of HAART on these patients. From June 1997 to July 2003, we examined and followed up the ophthalmic conditions of 49 patients receiving HAART with ophthalmic diseases during this period. The method of reverse-transcriptase polymerase chain reaction was used to detect and monitor HIV load in plasma and/or aqueous humor of AIDS patients. Before HAART, the HIV levels in the plasma and aqueous humor in 8 AIDS patients with ophthalmic opportunistic infections were significantly higher than those in 6 patients with HIV-related retinopathy (p < 0.05). Compared to the eye findings and clinical improvement, HIV loads of aqueous humor in 10 of 14 AIDS patients (6 with HIV-related retinopathy, 5 with cytomegalovirus retinitis, 2 with toxoplasmic retinitis and 1 with cryptococcal chorioretinitis) declined to undetectable levels (<400 copies/ml) after 4–8 months of HAART. HIV virus levels in the plasma of AIDS patients were significantly decreased, and the CD4 counts of these patients were significantly increased (Wilcoxon test) after initiation of HAART.
Complete Nonvisualization of Basilar Artery on MR Angiography in Patients with Vertebrobasilar Ischemic Stroke: Favorable Outcome Factors
Authors: Kim H.Y. , Chung C.S. , Moon S.Y. , Lee K.H. , Han S.H.
Published: August 2004

Background: In vertebrobasilar ischemic stroke, magnetic resonance angiography (MRA) occasionally fails to visualize the basilar artery, but in these patients, little attention has been given to establishing correlations between the clinical and the radiological findings. Our aim was to identify clinical or radiological measures that could assist in predicting a favorable clinical outcome. Methods: Risk factors, clinicoradiological features, and functional outcomes were assessed in 40 patients with vertebrobasilar ischemic stroke whose basilar arteries were absent on MRA. The presence of potential feeding arteries to the posterior circulation was recorded from a review of the MRA data. To permit quantitative analysis of the images, a potential feeding artery score (PFAS; range: 0–8) was established. One point was assigned when a signal was seen from an intracranial vertebral artery, a posterior inferior cerebellar artery, a superior cerebellar artery, or a posterior cerebral artery. On MRI, the location of the infarction was classified as involving the proximal, middle, and distal territories of the intracranial posterior circulation. The infarctions were also categorized as single- or multi-sector infarctions, and according to whether more than one penetrating or branch artery was involved. Clinical outcomes were classified as favorable (modified Rankin Scale = 0–2) or poor (modified Rankin Scale = 3–6). Results: The clinical outcome was favorable in 30% (n = 12) of patients, and poor in 70% (n = 28). A transient ischemic attack preceded the stroke in 48% of patients, especially those with a favorable outcome (67%). Patients with a favorable outcome had a higher PFAS (p = 0.036) and an increased incidence of single-sector infarction (p = 0.049). Conclusions: Our study suggests that a higher PFAS, accompanied by a single-sector infarction, is a predictor of improved clinical outcome in patients with vertebrobasilar ischemic stroke in which the basilar artery was absent on MRA.
Unilateral Impairment of Leg Blood Flow in Chronic Stroke Patients
Authors: Ivey Frederick M. , Gardner Andrew W. , Dobrovolny C. Lynne , Macko Richard F.
Published: August 2004

Background: Previous studies comparing paretic limb blood flow with the unaffected limb have been contradictory and have often omitted comparisons of peak reactive hyperemic flow. Our objective was to perform bilateral measurements of resting and reactive hyperemic blood flow in the lower legs of chronic (>6 months) stroke patients. A secondary purpose was to determine the extent to which any unilateral changes in limb blood flow were a function of decreases in lean tissue mass on the affected side. We hypothesized that the chronic hemiparesis accompanying ischemic stroke creates an altered metabolic environment in the tissues of the affected side that ultimately impairs vasomotor function. Methods: The study used a single-visit cross-sectional design. All tests were performed at the Baltimore VA Medical Center. Nineteen chronic hemiparetic stroke patients (15 male, 4 female) who had mild to moderate hemiparetic gait after ischemic stroke were recruited for observation. Bilateral measurements of resting and reactive hyperemic blood flow were made using venous occlusion strain gauge plethysmography. Paired t-tests were used for the between leg comparison. Regression analysis and analysis of covariance were utilized to determine the strength of the relationship between lower leg lean tissue mass and blood flow. Results: Resting and reactive hyperemic blood flows were significantly reduced in the paretic compared with the non-paretic limb (32 and 35%, respectively, p < 0.001). Lean tissue mass was also significantly lower in the affected limb (p < 0.01). However, neither resting nor reactive hyperemic blood flows were significantly correlated with lower leg lean tissue mass by dual energy X-ray absorptiometry. The difference in blood flow between limbs remained after covarying for lean tissue mass. Conclusion: Hemiparesis causes impairments in vasomotor function under both resting and hyperemic conditions that are independent of the muscle atrophy on the affected side.
Delayed Occlusion after Internal Carotid Artery Dissection under Heparin
Authors: Dreier Jens P. , Lürtzing Frank , Kappmeier Melanie , Bohner Georg , Klingebiel Randolf , Leistner Stefanie , Einhäupl Karl M. , Schielke Eva , Valdueza José M.
Published: August 2004

Internal carotid artery dissection (ICAD) is a frequent etiology of stroke in the young. Immediate anticoagulation with unfractionated heparin is the most frequent treatment. A theoretical side effect of unfractionated heparin is an increase in the intramural hematoma resulting in hemodynamic cerebral infarction. We studied 20 patients with ICAD. All patients were immediately treated with unfractionated heparin. Activated partial thromboplastin time (aPTT) ratios were measured twice daily. We prospectively monitored the course of ICAD with repeated ultrasound in hospital. Unexpectedly, delayed ICA occlusion was noted in 5 patients under treatment. One of these developed a watershed infarct. We then analyzed the aPTT ratios over the first 6 days after diagnosis. Patients with delayed occlusion had significantly higher aPTT ratios (2.6 ± 0.4 vs. 2.0 ± 0.5, p < 0.05). Within the limits of a partially retrospective design, our study seems to support the notion that unfractionated heparin can increase the intramural hematoma. Our findings further justify a randomized clinical trial to resolve the anticoagulant/antiplatelet debate.
A Case of Adenomyosis per se with a Uterine Weight of 475 g
Authors: Harmanli Ozgur H. , Shen Ting , Zhu Shaobo , Chatwani Ashwin J.
Published: August 2004

Background: Adenomyosis alone usually does not cause significant uterine enlargement. Case: A 49-year-old woman underwent vaginal hysterectomy and pelvic reconstructive surgery for pelvic organ prolapse. Incidentally, she was found to have adenomyosis with a 475-gram uterus without any other uterine histopathologic finding. To our knowledge, this is the largest uterus with adenomyosis alone ever reported. Conclusion: Extreme enlargement of the uterus is possible due to adenomyosis alone.
Serum Leptin Levels in Marasmic Children and the Relationship between Leptin and Lipid Profile
Authors: Isik Yasemin , Kalyoncu Mukaddes , Okten Aysenur
Published: August 2004

Background and Aims: Leptin and dyslipidemia are risk factors for cardiovascular disease. We measured leptin and lipid levels, and examined whether there is an effect of leptin on lipid profile in marasmic children. Methods: Fifty children (25 marasmic, 25 healthy) aged between 0.3 and 2.5 years were evaluated. Leptin levels were compared with lipid profile in marasmic and healthy children. The relationships between leptin and sex, body mass index and lipid profile were investigated in marasmic children. Results: In the marasmic group, body mass index, leptin, total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol levels were lower (p < 0.0001, p < 0.0001, p < 0.0001, p = 0.01, respectively), and triglyceride levels higher than in the control group. In females, leptin was correlated positively with high-density lipoprotein cholesterol (p = 0.002), and inversely correlated with the triglyceride level (p = 0.003). In males, a positive correlation was found between leptin and low-density lipoprotein cholesterol (p = 0.026). In female patients, body mass index, leptin and high-density lipoprotein cholesterol levels were lower (p < 0.0001, for all) when compared to their female controls. In male patients, body mass index, leptin, high-density lipoprotein and low-density lipoprotein cholesterol levels were lower (p < 0.0001, p = 0.031, p = 0.002, p = 0.017, respectively) than those in their male controls. Conclusion: As a result, we found low leptin (an independent cardiovascular risk factor) levels, but dyslipidemia in our marasmic patients. Dyslipidemia may be a risk factor for cardiovascular complications in marasmic children in the future.
Regulation of Low-Density Lipoprotein Receptor Activity by Estrogens and Phytoestrogens in a HepG2 Cell Model
Authors: Owen Alice J. , Roach Paul D. , Abbey Mavis
Published: August 2004

Background/Aims: Estrogen treatment is thought to lower low-density lipoprotein (LDL) cholesterol levels by increasing clearance through hepatic LDL receptors. This study aimed to determine the effect of estrogens and phytoestrogens on LDL receptor activity in a human hepatoma cell line, HepG2. Methods: HepG2 cells in culture were incubated for 24 h with estrogen or phytoestrogen and LDL receptor activity was measured by examining the cellular binding of colloidal gold-labelled LDL. Results: 17β-Estradiol significantly increased LDL receptor activity whereas estriol had negligible effects. Incubation with the isoflavonoids, formononetin, biochanin A and daidzein, caused significant elevations in receptor activity at concentrations above 40 µM. Coumestrol, a coumestan with a high level of estrogenic activity, caused a 3-fold increase in receptor activity at a concentration of 50 µM. Of the phytoestrogenic mammalian lignans enterolactone and enterodiol, only enterolactone displayed the ability to significantly upregulate LDL receptor activity at 50 µM. Conclusion: This study suggests that the LDL receptor-stimulating effect of natural estrogens is mainly due to estradiol and that the cholesterol-lowering effect of diets high in phytoestrogens may be due in part to their ability to increase hepatic LDL receptor activity.
Ethanol Stimulates Glycogenolysis and Inhibits both Glycogenesis via Gluconeogenesis and from Exogenous Glucose in Perfused Rat Liver
Authors: Mokuda O. , Tanaka H. , Hayashi T. , Ooka H. , Okazaki R. , Sakamoto Y.
Published: August 2004

Aims: Although it is commonly recognized that ethanol suppresses gluconeogenesis, the influence of alcohol intake on blood glucose levels remains controversial. Ethanol may act on both glucose production and glucose consumption in the liver. Thus, we studied each effect of ethanol on glucose oxidation, gluconeogenesis, glycogenesis and glycogenolysis in the liver. Methods: The rat liver was isolated and cyclically perfused with a medium containing 50 mmol/l ethanol. Results: Ethanol enhanced 14C-glucose oxidation in the liver from 1.09 ± 0.11 to 1.41 ± 0.14 µmol for 20 min (p < 0.05). Gluconeogenesis from 14C-lactate was markedly reduced by ethanol from 8.0 ± 1.3 to 1.5 ± 0.6 µmol for 12 min (p < 0.01). Ethanol increased glycogenolysis (net hepatic glucose output, 0.47 ± 0.10 vs. 0.22 ± 0.04 mmol/30 min, p < 0.01), and then decreased hepatic glycogen content (179 ± 38 vs. 273 ± 39 mg in the presence of 1 mU/ml insulin after 30 min of perfusion, p < 0.05). Ethanol decreased the direct glycogenesis from 14C-glucose from 0.55 ± 0.08 to 0.33 ± 0.05 µmol per 100 mg glycogen for 30 min (p < 0.01). Ethanol inhibited the indirect glycogenesis from 14C-lactate from 0.21 ± 0.04 to 0.09 ± 0.01 µmol per 100 mg glycogen for 30 min (p < 0.01). Discussion: The influence of ethanol on the blood glucose regulation by the liver seems to be different between fasted and fed states. Namely, ethanol has both the hypoglycemic effects through decreased gluconeogenesis and increased glucose oxidation and the hyperglycemic effects through decreased glycogenesis and increased glycogenolysis.
Hyplip2
, a New Gene for Combined Hyperlipidemia and Increased Atherosclerosis
Authors: Wang Xuping , Gargalovic Peter , Wong Jack , Gu Jennifer L. , Wu Xiaohui , Qi Hongxiu , Wen Pingzi , Xi Li , Tan Bing , Gogliotti Rocky , Castellani Lawrence W. , Chatterjee Aurobindo , Lusis Aldons J.
Published: August 2004

Objective—

We previously reported the mapping of a quantitative trait locus (QTL) on chromosome 15 contributing to hyperlipidemia in a cross between inbred strains MRL/MpJ (MRL) and BALB/cJ (BALB). Using marker-assisted breeding, we constructed a congenic strain in which chromosome 15 interval from MRL is placed on the genetic background of BALB. The congenic allowed us to confirm the QTL result and to further characterize the properties and location of the underlying gene.

Methods and Results—

On chow and high-fat (atherogenic) diets, the congenic mice exhibited higher levels of plasma triglycerides and cholesterol than BALB mice. In response to the atherogenic diet, the congenic mice but not BALB mice exhibited a dramatic ≈30-fold increase in atherogenic lesions accompanied by ≈2-fold decrease in high-density lipoprotein cholesterol levels. With respect to atherosclerotic lesions and some lipid parameters, this chromosome 15 gene, designated
Hyplip2
, exhibited dominant inheritance. Expression array analyses suggested that
Hyplip2
may influence inflammatory and bile acid synthesis pathways. Finally, we demonstrated the usefulness of subcongenic strains to narrow the locus (50 Mbp) with the goal of positionally cloning
Hyplip2
.

Conclusions—

Our data demonstrate that the
Hyplip2
gene significantly contributes to combined hyperlipidemia and increased atherosclerosis in mice.
Gender Differences in Experimental Aortic Aneurysm Formation
Authors: Ailawadi Gorav , Eliason Jonathan L. , Roelofs Karen J. , Sinha Indranil , Hannawa Kevin K. , Kaldjian Eric P. , Lu Guanyi , Henke Peter K. , Stanley James C. , Weiss Stephen J. , Thompson Robert W. , Upchurch Gilbert R.
Published: August 2004

Objective—

It is hypothesized that a male predominance, similar to that in humans, persists in a rodent model of experimental abdominal aortic aneurysm (AAA) via alterations in matrix metalloproteinases (MMPs).

Methods and Results—

Group I experiments were as follows: elastase perfusion of the infrarenal aorta was performed in male (M) and female (F) rats. At 14 days, aortas were harvested for immunohistochemistry, real-time polymerase chain reaction (PCR), and zymography. Group II experiments were the following: abdominal aorta was transplanted from F or M donors into F or M recipients. At 14 days, rodents that had undergone transplantation underwent elastase perfusion. In group III, male rats were given estradiol or sham 5 days before elastase perfusion. In group I, M rats had larger AAAs with higher frequency than did F rats. M rat aortas had more significant macrophage infiltrates and increased matrix metalloproteinase (MMP)-9 production and activity. In group II, M-to-M aortic transplants uniformly developed aneurysms after elastase perfusion, whereas F-to-F aortic transplants remained resistant to aneurysm formation. F aortas transplanted into M recipients, however, lost aneurysm resistance. In group III, estradiol-treated rats demonstrated smaller aneurysms and less macrophage infiltrate and MMP-9 compared with M controls after elastase.

Conclusions—

These data provide evidence of gender-related differences in AAA development, which may reflect an estrogen-mediated reduction in macrophage MMP-9 production.
Hypochlorous Acid Impairs Endothelium-Derived Nitric Oxide Bioactivity Through a Superoxide-Dependent Mechanism
Authors: Stocker Roland , Huang Annong , Jeranian Erin , Hou Jing Yun , Wu Tina T. , Thomas Shane R. , Keaney John F.
Published: August 2004

Objective—

To determine how hypochlorous acid (HOCl), the principal product of myeloperoxidase, modulates vascular function.

Methods and Results—

Rabbit arterial rings exposed to HOCl (0 to 500 μmol/L) exhibited dose- and time-dependent impairment of endothelium-dependent arterial relaxation to acetylcholine and A23187, but not the NO donor, diethylamine NONOate, suggesting that HOCl targets the endothelium. This effect was not because of cytotoxicity, as HOCl treatment produced no significant change in endothelial cell morphology or lactate dehydrogenase release. We observed HOCl-mediated endothelial cell protein oxidation by immunoreactivity to HOP-1, a monoclonal antibody specific for HOCl-oxidized protein. In support of this notion, known HOCl scavengers, such as methionine and
N
-acetylcysteine, partially preserved endothelium-derived NO bioactivity in response to HOCl. In an unanticipated observation, HOCl-mediated impairment of NO bioactivity was prevented by manganese superoxide dismutase in a manner dependent on its enzymatic activity. Finally, we found that HOCl reduced endothelial nitric oxide synthase dimer stability, an effect that was also inhibited by superoxide dismutase.

Conclusions—

Taken together, these data indicate that HOCl imparts a defect in endothelial NO production due to a superoxide-dependent reduction in endothelial nitric oxide synthase dimer stability. These data provide another mechanism whereby myeloperoxidase-derived oxidants can contribute to the impairment of NO bioactivity that is characteristic of atherosclerosis.
ATP-Binding Cassette Transporter G8 Gene As a Determinant of Apolipoprotein B-100 Kinetics in Overweight Men
Authors: Chan D.C. , Watts G.F. , Barrett P.H.R. , Whitfield A.J. , van Bockxmeer F.M.
Published: August 2004

Objective—

We examined the influence of genetic variation of the ATP-binding cassette (ABC) transporter G8 on apolipoprotein B (apoB) kinetics in overweight/obese men.

Methods and Results—

Very low–density lipoprotein (VLDL) and low-density lipoprotein (LDL) apoB kinetics were determined in 47 men (body mass index 32±3 kg/m
2
) using stable isotope and multicompartmental modeling to estimate production rate (PR), fractional catabolic rate (FCR), and VLDL to LDL–apoB conversion. Relative to the wild-type (400TT), subjects carrying the ABCG8 400K allele had significantly decreased plasma concentrations of triglycerides, sitosterol, and campesterol, lower PR of VLDL–apoB, and higher VLDL to LDL–apoB conversion (
P
<0.05). The PR and FCR of LDL–apoB were also significantly higher with 400K allele (
P
<0.05). No association was found with ABCG8 D19H. Compared with APOE2 or APOE3, APOE4 carriers had significantly higher plasma LDL-cholesterol concentrations and lower LDL–apoB FCR. During multiple regression analysis including age, homeostasis model assessment score, plasma concentrations of sitosterol, and lathosterol, ABCG8 and apoE genotypes were independent determinants of VLDL–apoB PR and LDL–apoB FCR, respectively (
P
<0.05).

Conclusions—

Variation in the ABC transporter G8 appears to independently influence the metabolism of apoB-containing lipoproteins in overweight/obese subjects. This may have therapeutic implications for the management of dyslipidemia in these subjects.
Tissue Resident Cells Play a Dominant Role in Arteriogenesis and Concomitant Macrophage Accumulation
Authors: Khmelewski Eugen , Becker Aileen , Meinertz Thomas , Ito Wulf D.
Published: August 2004

Collateral growth is characterized by macrophage accumulation, suggesting an important role of circulating cells. To study origin and function of macrophages during arteriogenesis, we related the extent of macrophage accumulation to vascular proliferation and investigated the fate of fluorescently (CMFDA) labeled blood cells that were injected at the time of femoral artery occlusion. The effect of bone marrow depletion via cyclophosphamide before femoral artery occlusion on collateral proliferation and macrophage accumulation was studied, and we looked for the presence of bone marrow-derived stem cells in the vicinity of growing collateral vessels. Finally, we investigated the arteriogenic effect of macrophage activation via MCP-1 in bone marrow-depleted animals. Maximal macrophage accumulation occurred during the first 3 days after femoral artery occlusion and paralleled the extent of vascular proliferation. Fluorescently labeled leukocytes homed to spleen and wound but they were absent in proliferating collateral arteries during maximal macrophage accumulation. Depletion of circulating cells did neither affect macrophage accumulation nor collateral growth. Staining of monocyte-depleted animals for BrdUrd and ED2, αSMA, or VE-Cadherin demonstrated local proliferation of macrophages and vascular cells, whereas C-Kit, SSEA1, or Thy1-positive bone marrow-derived stem cells were not detectable. Enhancement of macrophage accumulation via MCP-1 was independent of circulating monocytes and promoted arteriogenesis in the absence of direct effects on vascular cells. We propose that the initial phase of vascular growth is characterized by local proliferation of tissue resident precursors rather than by migration of blood born cells. The full text of this article is available online at http://circres.ahajournals.org.
Combined Anticoagulant–Antiplatelet Use and Major Bleeding Events in Elderly Atrial Fibrillation Patients
Authors: Shireman Theresa I. , Howard Patricia A. , Kresowik Timothy F. , Ellerbeck Edward F.
Published: August 2004

Background and Purpose—

Bleeding risks from combined antiplatelet-warfarin therapy have not been well-described in clinical practice. We examined antiplatelet therapy among warfarin users and the impact on major bleeding rates.

Methods—

Retrospective cohort analysis of persons discharged on warfarin after an atrial fibrillation admission using data from Medicare’s National Stroke Project. Data included Medicare claims, enrollment information, and medical record abstracted data. Logistic regression and Cox proportional hazards models were used to predict concurrent antiplatelet use and hospitalization with a major acute bleed within 90 days after discharge from the index AF admission.

Results—

10 093 warfarin patients met inclusion criteria with a mean age of 77 years; 19.4% received antiplatelet therapy. Antiplatelet use was less common among women, older persons, and persons with cancer, terminal diagnoses, dementia, and bleeding history. Persons with coronary disease were more likely to receive an antiplatelet agent. Antiplatelets increased major bleeding rates from 1.3% to 1.9% (
P
=0.052). In the multivariate analysis, factors associated with bleeding events included age (OR, 1.03; 95% CI, 1.002 to 1.05), anemia (OR, 2.52; 95% CI, 1.64 to 3.88), a history of bleeding (OR, 2.40; 95% CI, 1.71 to 3.38), and concurrent antiplatelet therapy (OR, 1.53; 95% CI, 1.05 to 2.22).

Conclusions—

Although concerns about increased bleeding risk with combined warfarin-antiplatelet therapy are not unfounded, the risk of bleeding is moderately increased. The decision to use concurrent antiplatelet therapy appears to be tempered by cardiac and bleeding risk factors.
Hourly Blood Pressure Monitoring After Intravenous Tissue Plasminogen Activator for Ischemic Stroke
Authors: Aiyagari Venkatesh , Gujjar Arunodaya , Zazulia Allyson R. , Diringer Michael N.
Published: August 2004

Background and Purpose—

Blood pressure (BP) control is considered essential in patients treated with tissue plasminogen activator (tPA) for ischemic stroke, and it is recommended that BP be monitored every 15 minutes to 1 hour for 24 hours in these patients. We postulated that patients whose BP is not initially elevated are unlikely to have elevated BP later and, therefore, may not need prolonged BP monitoring.

Methods—

We performed a retrospective chart review of patients treated with intravenous tPA for ischemic stroke over a 3-year period. Patients with incomplete records were excluded.

Results—

Seventy-nine patients (35 male, age 68.8±14.3 years) were studied. Before tPA treatment, 16 patients (20%) had hypertension (systolic BP ≥185 or diastolic BP ≥110 mm Hg). All 16 patients had subsequent hypertension over the next 24 hours. Of the remaining 63, 27 patients (43%) had hypertension (systolic BP ≥180 or diastolic BP ≥105 mm Hg) within the first 6 hours. An additional 4 had minor transient systolic elevations (≤182 mm Hg) after 6 hours that normalized without treatment. Neurological worsening, seen in 13 patients (17%), was not associated with the presence of hypertension (initial or subsequent).

Conclusions—

In patients receiving tPA for stroke, absence of hypertension at presentation does not preclude subsequent increase in blood pressure. However, if blood pressure is not elevated during the first 6 hours, subsequent hypertension over the next 18 hours is unlikely. This study is small and retrospective, and needs to be repeated in a larger prospective cohort. However, our results provide preliminary evidence to suggest that where resources are scarce, these patients may be discharged from the intensive care unit earlier than the recommended 24 hours, provided that they are not at high risk for neurological deterioration.
Quality of Life After Stroke
Authors: Sturm Jonathan W. , Donnan Geoffrey A. , Dewey Helen M. , Macdonell Richard A. L. , Gilligan Amanda K. , Srikanth Velandai , Thrift Amanda G.
Published: August 2004

Background and Purpose—

Health-related quality of life (HRQoL) data are scarce from unselected populations. The aims were to assess HRQoL at 2 years poststroke, to identify determinants of HRQoL in stroke survivors, and to identify predictors at stroke onset of subsequent HRQoL.

Methods—

All first-ever cases of stroke in a population of 306 631 over a 1-year period were assessed. Stroke severity, comorbidity, and demographic information were recorded. Two-year poststroke HRQoL was assessed using the Assessment of Quality of Life (AQoL) instrument (deceased patients score=0). Handicap, disability, physical impairment, depression, anxiety, living arrangements, and recurrent stroke at 2 years were documented. If necessary, proxy assessments were obtained, except for mood. Linear regression analyses were performed to identify factors independently associated with HRQoL.

Results—

Of 266 incident cases alive at 2 years, 225 (85%) were assessed. The mean AQoL utility score for all survivors was 0.47 (95% CI, 0.42 to 0.52). Almost 25% of survivors had a score of ≤0.1. The independent determinants of HRQoL in survivors were handicap, physical impairment, anxiety and depression, disability, institutionalization, dementia, and age. The factors present at stroke onset that independently predicted HRQoL at 2 years poststroke were age, female sex, initial NIHSS score, neglect, and low socioeconomic status.

Conclusions—

A substantial proportion of stroke survivors have very poor HRQoL. Interventions targeting handicap and mood have the potential to improve HRQoL independently of physical impairment and disability.
The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT–dependent apoptosis in diffuse large B-cell lymphoma
Authors: Smith Peter G. , Wang Fengfei , Wilkinson Kathryn N. , Savage Kerry J. , Klein Ulf , Neuberg Donna S. , Bollag Gideon , Shipp Margaret A. , Aguiar Ricardo C. T.
Published: August 2004

Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Advances in the treatment of this disease will require the identification of novel therapeutic targets. We previously defined an expression signature of outcome in DLBCL and found that the phosphodiesterase PDE4B was overexpressed in fatal/refractory tumors. Phosphodiesterase 4B (PDE4B) inactivates the second messenger cyclic adenosine 3′,5′ monophosphate (cAMP) and abrogates its inhibitory effects in B lymphocytes. Hence, DLBCLs that express high PDE4B levels may be resistant to cAMP-induced apoptosis, contributing to their less favorable outcome. Herein, we confirmed the risk-related expression of PDE4B in an independent series of primary DLBCLs and defined the enzyme's role in modulating cAMP-induced apoptosis in parental DLBCL cell lines or those reconstituted with wild-type or mutant PDE4B. The cAMP-mediated apoptosis of DLBCLs was largely independent of the previously described cAMP effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), but associated with inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The central role of AKT in this process was confirmed by expressing constitutively active mutants of this kinase in DLBCL cells. Our findings highlight the important role of cAMP signaling in DLBCL and suggest that clinically relevant PDE4 and PI3K/AKT inhibitors might be useful in the treatment of DLBCL and additional B-lymphoid malignancies with increased PDE4B expression. (Blood. 2005;105:308-316)
Mycoplasma fermentans infection promotes immortalization of human peripheral blood mononuclear cells in culture
Authors: Zhang Shimin , Tsai Shien , Wu Timothy T. , Li Bingjie , Shih James W.-K. , Lo Shyh-Ching
Published: August 2004

Chronic infection or colonization by mycoplasma(s) could gradually and significantly alter many biologic properties of mammalian host cells in culture, including induction of malignant transformation. We examined effects of Mycoplasma fermentans infection on the continuing survival and immortality of human peripheral blood mononuclear cells (PBMCs) from healthy blood donors. Without specific supplemental growth factors, human PBMCs normally die rapidly, with few cells other than macrophages/monocytes surviving after 2 weeks in cultures. Only occasional Epstein-Barr virus (EBV)–positive B lymphocytes would continue to proliferate and undergo spontaneous immortalization. Our present study revealed that infection of human PBMCs in culture with the incognitus and PG18 strains of M fermentans, but surprisingly not with some other strains tested in parallel, markedly enhanced the rate of EBV-positive B lymphocytes to undergo immortalization (74% vs 17%). Compared with spontaneously immortalized PBMCs, the PBMCs immortalized in cultures infected with the mycoplasmas often had prominent karyotype changes with chromosomal loss, gain, or translocations. Furthermore, many of these immortalized B lymphocytes were found to be monoclonal in nature. The in vitro findings would be of relevance to lymphoproliferative disorders that occurred in patients with immune suppression. The mycoplasma-mediated promotional effect in cell immortalization and its potential clinical implications warrant further study.
Intracellular kinetics of iron in reticulocytes: evidence for endosome involvement in iron targeting to mitochondria
Authors: Zhang An-Sheng , Sheftel Alex D. , Ponka Prem
Published: August 2004

In erythroid cells the vast majority of iron (Fe) released from endosomes must cross both the outer and the inner mitochondrial membranes to reach ferrochelatase that inserts Fe into protoporphyrin IX. In the present study, we developed a method whereby a cohort of 59Fe-transferrin (Tf)-laden endosomal vesicles were generated, from which we could evaluate the transfer of 59Fe into mitochondria. Iron chelators, dipyridyl or salicylaldehyde isonicotinoyl hydrazone (SIH), were able to bind the 59Fe when they were present during a 37°C incubation; however, addition of these agents only during lysis at 4°C chelated virtually no 59Fe. Bafilomycin A1 (which prevents endosome acidification) and succinylacetone (an inhibitor of 5-aminolevulinate dehydratase) prevented endosomal 59Fe incorporation into heme. Importantly, both the myosin light chain kinase inhibitor wortmannin and the calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), caused significant inhibition of 59Fe incorporation from 59Fe-Tf-labeled endosomes into heme, suggesting that myosin is required for Tf-vesicle movement. Our results reaffirm the astonishing efficiency of Tf-derived Fe utilization in hemoglobin (Hb)-producing cells and demonstrate that very little of this Fe is present in a chelatable pool. Collectively, these results are congruent with our hypothesis that a transient endosome-mitochondrion interaction mediates iron transfer between these organelles. (Blood. 2005;105:368-375)
HLA DR phenotypic frequencies and genetic risk of Type 1 diabetes in west region of Algeria, Tlemcen
Authors: Aribi Mourad , Moulessehoul Soraya , Benabadji Ahmed-Bakir , Kendoucitani Mohammed
Published: August 2004

Background

The main genomic region controlling the predisposition to type 1 diabetes is the Human Leukocyte Antigens (HLA) class II of the major histocompatibility complex. Association with different HLA types depends also on the studied populations. In our investigation, we tried to measure the phenotypic HLA class II association frequencies of DR3 and/or DR4 antigens, using a serologic method called microlymphocytotoxicity analysis, in diabetic and nondiabetic (ND) subjects originating from the west-Algerian region of Tlemcen. The aim of the present study was to determine which HLA DR antigens represent a high susceptibility to develop the disease in this area. Using a case-control retrospective study design, we randomly recruited ninety-one related subjects, 39 type 1 diabetics and 52 ND as controls, at the Internal Medicine Board of Medical Centre University of Tlemcen.

Results

DR3 antigen frequencies were comparable between the type 1 diabetics and the ND subjects and showed no association with the disease (p = 1.000, OR = 0.95), whereas DR4 and DR3DR4 antigens were associated with susceptibility to develop type 1 diabetes (DR4; OR = 2.10, DR3DR4; OR = 1.30). Also, no incidence for DR3 (p = 0.2646) or DR3DR4 (p = 0.0699) antigen frequencies was related to the sex ratio. However, significant differences in HLA DR4 frequencies between type 1 diabetics and ND were found to be related to sex (p = 0.0085).

Conclusion

Taken together, our investigation showed that the strongest association with type 1 diabetes was noticed in the presence of HLA DR4 antigens followed by DR3DR4 antigens. This study highlighted a characteristic of Tlemcen population; a history of consanguineous marriages. Association studies between the disease and genetic polymorphisms should be undertaken in a population where consanguinity is more limited to reduce confounding in result interpretations.
Durable cytotoxic immune responses against gp120 elicited by recombinant SV40 vectors encoding HIV-1 gp120 ± IL-15
Authors: McKee Hayley J , T'sao Patricia Y , Vera Maria , Fortes Puri , Strayer David S
Published: August 2004

Background

A vaccine that elicits durable, powerful anti-HIV immunity remains an elusive goal. In these studies we tested whether multiple treatments with viral vector-delivered HIV envelope antigen (gp120), with and without IL-15, could help to approach that goal. For this purpose, we used recombinant Tag-deleted SV40-derived vectors (rSV40s), since they do not elicit neutralizing antibody responses, and so can be given multiply without loss of transduction efficiency.

Methods

SV(gp120) carried the coding sequences for HIV-1NL4-3 Env, and SV(mIL-15) carried the cDNA for mouse IL-15. Singly, and in combination, these two vectors were given monthly to BALB/cJ mice. Cytotoxic immunity and cytotoxic memory were tested in direct cytotoxicity assays using unselected effector cells. Antibody vs. gp120 was measured in a binding assay. In both cases, targets were P815 cells that were stably transfected with gp120.

Results

Multiple injections of SV(gp120) elicited powerful anti-gp120 cytolytic activity (>70% specific lysis) by unselected spleen cells. Cells from multiply-immunized mice that were rested 1 year after their last injections still showed >60% gp120-specific lysis. Anti-gp120 antibody was first detected after 2 monthly injections of SV(gp120) and remained elevated thereafter. Adding SV(mIL-15) to the immunization regimen dramatically accelerated the development of memory cytolytic responses, with ≥ 50% specific lysis seen 1 month after two treatments. IL-15 did not alter the development of antibody responses.

Conclusions

Thus, rSV40s encoding antigens and immunostimulatory cytokines may be useful tools for priming and/or boosting immune responses against HIV.
Capacity of myeloid and plasmacytoid dendritic cells especially at mature stage to express and secrete HLA-G molecules
Authors: Le Friec Gaëlle , Gros Frédéric , Sebti Yasmine , Guilloux Valérie , Pangault Céline , Fauchet Renée , Amiot Laurence
Published: August 2004

Human leukocyte antigen (HLA-G), a class Ib major histocompatibility complex molecule, is potentially relevant in the immune response through its various immune cell functions. Its expression noticed in some malignancies has also been shown on macrophages and dendritic cells (DC) in tumoral and inflammatory diseases. As DC constitute a key component in the immune response, this work aimed at assessing the expression of HLA-G at transcriptional and proteic levels during differentiation and maturation of the different DC subsets. We show that HLA-G transcription was induced during CD34+-derived DC differentiation and is associated with a cell-surface expression in half of cases and with a substantial secretion of soluble HLA-G in all cases. Results were very similar for monocyte-derived DC, but there was still a weak HLA-G cell-surface expression and a lower level of secretion. On the contrary, HLA-G transcription was weak in plasmacytoid DC without any HLA-G cell-surface expression and with a basal level of secretion. The mechanisms involved in HLA-G expression appear transcriptional and post-transcriptional. However, the amount of HLA-G transcripts and the expression of the protein are not related. HLA-G expression or secretion by DC may have negative consequences on the function of effective immune cells and also on DC themselves via the interaction with inhibitory receptors expressed by these cells. The capacity of DC to express or secrete HLA-G should be studied in the context of cellular therapy using DC in addition to its suppressive action in immune response.
Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms
Authors: Chen Guoqian , Li Jianhua , Ochani Mahendar , Rendon-Mitchell Beatriz , Qiang Xiaoling , Susarla Seenu , Ulloa Luis , Yang Huan , Fan Saijun , Goyert Sanna M , Wang Ping , Tracey Kevin J , Sama Andrew E , Wang Haichao
Published: August 2004

Bacterial endotoxin [lipopolysaccharide (LPS)] stimulates macrophages to sequentially release early [tumor necrosis factor (TNF)] and late [high mobility group box 1 (HMGB1)] proinflammatory cytokines. The requirement of CD14 and mitogen-activated protein kinases [MAPK; e.g., p38 and extracellular signal-regulated kinase (ERK)1/2] for endotoxin-induced TNF production has been demonstrated previously, but little is known about their involvement in endotoxin-mediated HMGB1 release. Here, we demonstrated that genetic disruption of CD14 expression abrogated LPS-induced TNF production but only partially attenuated LPS-induced HMGB1 release in cultures of primary murine peritoneal macrophages. Pharmacological suppression of p38 or ERK1/2 MAPK with specific inhibitors (SB203580, SB202190, U0126, or PD98059) significantly attenuated LPS-induced TNF production but failed to inhibit LPS-induced HMGB1 release. Consistently, an endogenous, immunosuppressive molecule, spermine, failed to inhibit LPS-induced activation of p38 MAPK and yet, still significantly attenuated LPS-mediated HMGB1 release. Direct suppression of TNF activity with neutralizing antibodies or genetic disruption of TNF expression partially attenuated HMGB1 release from macrophages induced by LPS at lower concentrations (e.g., 10 ng/ml). Taken together, these data suggest that LPS stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms.
Constitutive membrane expression of proteinase 3 (PR3) and neutrophil activation by anti-PR3 antibodies
Authors: van Rossum André P , Rarok Agnieszka A , Huitema Minke G , Fassina Giorgio , Limburg Pieter C , Kallenberg Cees G M
Published: August 2004

Antineutrophil cytoplasm autoantibodies with specificity for proteinase 3 (PR3) are thought to play a major role in the pathogenesis of Wegener's granulomatosis (WG), presumably by their potential to activate neutrophils. In patients with WG, high expression of PR3 on the surface of nonprimed neutrophils is associated with an increased incidence and rate of relapse. In this study, we analyzed the functional significance of constitutive PR3 expression for neutrophil activation as induced by anti-PR3 antibody. Therefore, primed and nonprimed neutrophils were stimulated with the monoclonal anti-PR3 antibody PR3G-3. Activation was measured as actin polymerization by the phalloidin assay as an early, detectable activation event and oxidative burst by the dihydrorhodamine assay, as a late, detectable activation event. In contrast to the oxidative burst, we found that anti-PR3 antibody-induced actin polymerization could be triggered in neutrophils without priming with tumor necrosis factor α (TNF-α). In addition, a correlation was found between the level of PR3 expression on the surface of these nonprimed neutrophils and the degree of actin polymerization. However, after priming with TNF-α, no correlation was found between membrane expression of PR3 and the level of actin polymerization or respiratory burst as induced by anti-PR3 antibody. These data suggest that the presence of PR3 on the surface of nonprimed neutrophils has consequences for their susceptibility to the initial activation step by anti-PR3 antibodies. These data may be relevant in view of the observed relation between membrane expression of PR3 on nonprimed neutrophils of patients with WG and their susceptibility for relapses.
Minireview: RET: Normal and Abnormal Functions
Authors: Santoro Massimo , Melillo Rosa Marina , Carlomagno Francesca , Vecchio Giancarlo , Fusco Alfredo
Published: August 2004

The RET gene encodes a single-pass transmembrane receptor tyrosine kinase. RET is the oncogene that causes papillary thyroid carcinoma and medullary thyroid carcinoma. The latter may arise as a component of multiple endocrine neoplasia type 2 syndromes; germline mutations in RET are responsible for multiple endocrine neoplasia type 2 inheritance. In this report we review data on the mechanisms leading to RET oncogenic conversion and on RET targeting as a strategy in thyroid cancer treatment.
Down-Regulation of Inositol 1,4,5-Trisphosphate Receptor in Cells Stably Expressing the Constitutively Active Angiotensin II N111G-AT1 Receptor
Authors: Auger-Messier Mannix , Arguin Guillaume , Chaloux Benoit , Leduc Richard , Escher Emanuel , Guillemette Gaetan
Published: August 2004

The diverse cellular changes brought about by the expression of a constitutively active receptor are poorly understood. QBI-human embryonic kidney 293A cells stably expressing the constitutively active N111G-AT1 receptor (N111G cells) showed elevated levels of inositol phosphates and frequent spontaneous intracellular Ca2+ oscillations. Interestingly, Ca2+ transients triggered with maximal doses of angiotensin II were much weaker in N111G cells than in wild-type cells. These blunted responses were observed independently of the presence or absence of extracellular Ca2+ and were also obtained when endogenous muscarinic and purinergic receptors were activated, revealing a heterologous desensitization process. The desensitized component of the Ca2+ signaling cascade was neither the G protein Gq nor phospholipase C. The intracellular Ca2+ store of N111G cells and their mechanism of Ca2+ entry also appeared to be intact. The most striking adaptive response of N111G cells was a down-regulation of their inositol 1,4,5-trisphosphate receptor (IP3R) as revealed by reduced IP3-induced Ca2+ release, lowered [3H]IP3 binding capacity, diminished IP3R immunoreactivity, and accelerated IP3R degradation involving the lysosomal pathway. Treatment with the inverse agonist EXP3174 reversed the desensitized phenotype of N111G cells. Down-regulation of IP3R represents a reversible adaptive response to protect cells against the adverse effects of constitutively active Ca2+-mobilizing receptors.
A Novel Cell Type-Specific Mechanism for Thyroid Hormone-Dependent Negative Regulation of the Human Type 1 Deiodinase Gene
Authors: Kim Sung-Woo , Hong Seong-June , Kim Kyung Min , Ho Sung-Chul , So Edward C. , Harney John W. , Larsen P. Reed
Published: August 2004

We have identified a cell type-specific, negative thyroid hormone-responsive element in the human type 1 iodothyronine deiodinase (hdio1) gene. This fragment, termed a JEG response element, bound tightly to a JEG-cell nuclear protein [JEG cell-specific transcription factor (JTF)] also present in placenta but not in COS-7, HeLa, or human embryonic kidney-293 cells. In JEG-3 cells, three copies of the JEG response element conferred a more than 40-fold transcriptional stimulation to the heterologous rat GH promoter which was further increased 2-fold by apo-thyroid hormone receptor (TR) and reduced 3-fold by T3. Dimethyl sulfide footprinting showed overlapping contact sites for the high-affinity interaction of JTF and low-affinity binding of TR-retinoid X receptor. Expression of the same construct was unaffected by TR or T3 in COS cells, indicating JTF was required for negative regulation by T3-TR. Mutations of the critical thyroid hormone responsive element binding P box amino acids EG to GS in TRα1 or TRβ2 eliminated the apo-TR and T3-TR effects. These studies identify a novel mechanism for cell type-specific, promoter-independent negative regulation by T3.