bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Study between Radiofrequency Sinus Excision and Open Excision in Sacro-Coccygeal Pilonidal Sinus Disease
Authors: Gupta Pravin J.
Published: March 2006

Aim: Evaluation of outcome of pilonidal sinus excision using a radiofrequency device and comparing its results with excision and open granulation procedure. Methods: Patients with sacro-coccygeal pilonidal sinus disease (n = 44) were randomly assigned to undergo either a wide excision and healing by open granulation procedure [WEG] (n = 23) or a radiofrequency sinus excision [RSE] (n = 21). An Ellman radiofrequency generator was used for RSE. Intra- and postoperative events and outcome data were evaluated and analyzed by Student’s unpaired t test and χ2 test. Results: The significant differences in the two groups WEG and RSE were as follows: mean hospital stay (47 vs. 10 h, p < 0.05), period off work (29 vs. 8 days, p < 0.05), mean analgesic requirement (39 vs. 15 tablets, p < 0.05), time for complete wound healing (84 vs. 49 days, p < 0.05). At the mean follow-up of 30 months, 2 patients from the wide excision and open granulation group and one patient from the radiofrequency sinus excision group developed recurrence. Conclusion: These findings suggest that sinus excision with radiofrequency is a simple and swift procedure. It needs a short hospital stay and is associated with less postoperative pain and early resumption to work. As compared to excision and healing by granulation technique, the radiofrequency sinus excision procedure achieves faster wound healing and a better outcome.
Distal Cholangiocarcinoma Associated with Papillitis with Viral CMV Inclusions
Authors: Ruiz-Tovar Jaime , Martín-Pérez Elena , Gamallo-Amat Carlos
Published: March 2006

Cytomegalovirus (CMV) infections are usually described in immunodeficient patients. In immunocompetent patients active infection is uncommon, consisting usually of a mononucleosis-like syndrome. Numerous reports show that CMV is a potential pathogen in the gastrointestinal tract, even in immunocompetent patients, where it can produce lesions from the mouth to the anus. We report herein an uncommon association of chronic inflammation of the papilla and viral CMV inclusions with distal cholangiocarcinoma in a 72-year-old woman who presented jaundice, choluria, acholia and generalized pruritus. At laparotomy, dilatation of the bile ducts and an enlarged head of the pancreas were found. Pancreatoduodenectomy was performed. Pathology revealed an enlarged papilla, due to chronic inflammation with CMV inclusions. Histological analysis revealed moderately differentiated ductal adenocarcinoma of the distal bile tract.
Molecular Cloning of cDNA, Recombinant Protein Expression and Characterization of a Buckwheat 16-kDa Major Allergen
Authors: Koyano Satoru , Takagi Kayoko , Teshima Reiko , Sawada Jun-ichi
Published: March 2006

Background: Buckwheat is a common food in Japan, Korea and other countries. A candidate major buckwheat allergen, a 16-kDa protein (BWp16), was previously characterized as a pepsin-resistant protein associated with immediate-type allergies to buckwheat. However, whether recombinant BWp16 can react with a patient’s IgE remains uncertain. Methods: The cDNA encoding BWp16 from Japanese buckwheat seeds was cloned based on the sequences obtained by the 5′-rapid amplification of cDNA ends (RACE) and 3′-RACE PCR. Recombinant BWp16 protein expressed in Escherichia coli was purified using affinity chromatography. Western blotting, ELISA and cross inhibition tests of the purified recombinant BWp16 were performed using sera from patients with positive IgE binding to buckwheat and controls. Pepsin digestion experiments were also performed. Results: The full-length cDNA encodes 149 amino acid residues with a calculated molecular mass of 16.9 kDa. The deduced amino acid sequence included a putative signal peptide sequence. BWp16 showed significant homologies to the buckwheat 8-kDa allergen and Ricinus communis (castor bean) 2S albumin. Sera from patients with positive IgE binding to buckwheat reacted with the purified BWp16. Cross inhibition tests revealed immunological equivalence of the purified recombinant and natu ral BWp16. The recombinant and natural BWp16 were comparably resistant to pepsin digestion. Conclusions: BWp16 belongs to the 2S albumin family and is a buckwheat allergen. This purified recombinant BWp16 could be used in the diagnosis of buckwheat allergy.
Fetal Macrosomia – A Continuing Obstetric Challenge
Authors: Heiskanen Nonna , Raatikainen Kaisa , Heinonen Seppo
Published: March 2006

Background: Macrosomic fetuses represent a continuing challenge in obstetrics. Objectives: We studied maternal risk factors of fetal macrosomia and maternal and infant outcome in such cases. Methods: A retrospective cohort study was carried out with a total of 26,961 singleton pregnancies between 1989 and 2001. Records of 886 mothers who gave birth to live born infants weighing ≧4,500 g were compared to those of 26,075 mothers with normal weight (<4,500 g) infants. Multiple regression analysis was used to identify independent reproductive risk factors. Perinatal complications were also assessed. Results: The incidence of fetal macrosomia was 3.4%. Diabetes, previous macrosomic birth, postdatism (>42 weeks of gestation), obesity (BMI > 25 before pregnancy), male infant, gestational diabetes mellitus, and non-smoking were independent risk factors of fetal macrosomia, with adjusted risks of 4.6, 3.1, 3.1, 2.0, 1.9, 1.6, 1.4, respectively. In the macrosomic group, birth and maternal traumas occurred significantly more often than in the control group. However, records of subsequent pregnancies (n = 250) after the study period showed that a previous uncomplicated birth appeared to decrease complication risks. Conclusions: Most cases of fetal macrosomia occur in low-risk pregnancies and evaluation of maternal risks cannot accurately predict which women will eventually give birth to an overweight newborn. After an uncomplicated birth of a macrosomic infant, vaginal delivery may be a safe option for the infant and mother.
Effect of Body Warming on Regional Blood Flow Distribution in Conscious Hypoxic One-Month-Old Rabbits
Authors: Seifert Erin L. , Sant Anna Guilherme M. , Rohlicek Charles V.
Published: March 2006

Background: Previous experiments have shown that warming hypoxic infants reduces total peripheral vascular resistance. This suggests that the usual vasoconstriction of less essential vascular beds during hypoxia may be reduced and that the normal redistribution of blood flow to more vital organs may be compromised. Objective:Evaluate the effect of body warming during hypoxia on the distribution of blood flow. Methods: The fluorescent microsphere technique was used to compare regional blood flow in 1-month-old rabbits during systemic hypoxia (10% inspired O2) with (n = 9) and without (n = 10) body warming. Blood flow was measured in brain, stomach, small intestine, hindlimb muscle, skin, and kidneys. Arterial blood pressure, whole-body O2 consumption, arterial blood O2 saturation and blood gases were also measured. Measurements and Main Results: In hypoxia all animals decreased body temperature (–2°C). With hypoxia blood flow increased to brain and hindlimb muscle; decreased to stomach, small intestine, and kidneys, and was unchanged in skin. The increase in brain-blood flow maintained O2 delivery at normoxic levels. Rewarming to the normoxic body temperature significantly changed blood flow in hypoxia. Brain blood flow increased by 102 ± 30% (mean ± SEM) thereby increasing O2 delivery by 50 ± 23% above normoxic values. Blood flow also increased to skin, stomach, and small intestine. However, O2 delivery to these tissues remained below normoxic levels. Conclusions: Warming during hypoxia may impose an additional cardiovascular demand. The changes in the pattern of blood flow distribution with mild warming during hypoxia support the hypothesis that warming represents a significant heat stress.
Intrauterine Inflammation and the Onset of Peri-Intraventricular Hemorrhage in Premature Infants
Authors: Babnik Janez , Stucin-Gantar Irena , Kornhauser-Cerar Lilijana , Sinkovec Jasna , Wraber Branka , Derganc Metka
Published: March 2006

Background: Peri-intraventricular hemorrhage (P/IVH) is a common neonatal morbidity among premature infants. The aim of the study was to examine the association between placental and/or fetal inflammation and the onset of P/IVH in premature infants. Methods: A prospective study included 125 infants with gestational age 23–29 weeks. Placentas were examined for the presence of chorioamnionitis and funisitis, cord blood was sampled for the measurement of cytokines (IL-6 and IL-8). Fetal inflammation was defined as levels of IL-6 higher than 7.6 pg/ml. P/IVH was defined as early if diagnosed within the 1st day after birth; thereafter P/IVH was defined as late. Results: Adjusted for the influence of gestational age, early-onset sepsis (OR 3.2, p = 0.045) and no or incomplete antenatal steroid course (OR 6.0, p = 0.001) significantly predicted early P/IVH. Funisitis (OR 1.6, p = 0.06) and fetal inflammation (OR 2.6, p = 0.06) were only partially associated with early hemorrhage. Contrary to that, respiratory distress syndrome (OR 3.4, p = 0.04), mechanical ventilation (OR 5.9, p = 0.008), low blood pressure (OR 3.5, p = 0.02), and vasopressors (OR 5.7, p = 0.002) were associated with late P/IVH. In multivariate analysis no or incomplete steroid course remained independent predictors for early and use of vasopressors for late P/IVH. The interaction of fetal inflammation and vaginal delivery with no or incomplete steroid course increased the risk of early P/IVH. Conclusions: These results indicate different risk factors for early and late P/IVH. Neither funisitis nor fetal inflammation independently predicts the onset of P/IVH. However, the interaction of fetal inflammation and vaginal delivery with no or incomplete antenatal steroid course increase the risk of early but not also late P/IVH.
Prediction Models for Insulin Resistance in Girls with Premature Adrenarche
Authors: Vuguin Patricia , Grinstein Gabriela , Freeman Katherine , Saenger Paul , DiMartino Nardi Joan
Published: March 2006

Aim: The purpose of this study was to develop an accurate regression model to predict insulin resistance in girls with premature adrenarche. Methods: The insulin sensitivity index was calculated from the frequently sampled intravenous glucose tolerance test with tolbutamide. Thirty-five prepubertal girls (23 Caribbean-Hispanic and 12 African-American; mean age 6.8 years) were studied. The insulin sensitivity index was compared to birth weight, body mass index (BMI), the presence of acanthosis nigricans (AN), insulin-like growth factor 1, insulin-like growth factor binding protein 1, sex hormone binding globulin, lipid profile, and adrenocorticotropic hormone stimulated androgens. Results: The best prediction models included birth weight, BMI, and AN (model 1: R2 = 0.78) and BMI, AN, and serum 17-OH pregnenolone (model 2: R2 = 0.76). When viewed as screening tests, a cutoff value <5.5 (premature adrenarche insulin resistance score) in both equations showed a sensitivity of 100% and a specificity of 85%. Conclusion: Born small for gestational age, premature adrenarche, obesity, AN, and higher serum 17-OH pregnenolone levels may confer negative, but independent, health risks.
Endothelium-Derived Hyperpolarizing Factor
Authors: Félétou Michel , Vanhoutte Paul M.
Published: March 2006

The endothelium controls vascular tone not only by releasing nitric oxide (NO) and prostacyclin but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the denomination endothelium-derived hyperpolarizing factor (EDHF). We know now that this acronym includes different mechanisms. In general, EDHF-mediated responses involve an increase in the intracellular calcium concentration, the opening of calcium-activated potassium channels of small and intermediate conductance and the hyperpolarization of the endothelial cells. This results in an endothelium-dependent hyperpolarization of the smooth muscle cells, which can be evoked by direct electrical coupling through myo-endothelial junctions and/or the accumulation of potassium ions in the intercellular space. Potassium ions hyperpolarize the smooth muscle cells by activating inward rectifying potassium channels and/or Na
+
/K
+
-ATPase. In some blood vessels, including large and small coronary arteries, the endothelium releases arachidonic acid metabolites derived from cytochrome P450 monooxygenases. The epoxyeicosatrienoic acids (EET) generated are not only intracellular messengers but also can diffuse and hyperpolarize the smooth muscle cells by activating large conductance calcium-activated potassium channels. Additionally, the endothelium can produce other factors such as lipoxygenases derivatives or hydrogen peroxide (H
2
O
2
). These different mechanisms are not necessarily exclusive and can occur simultaneously.
Nitric Oxide and Posttranslational Modification of the Vascular Proteome
Authors: Handy Diane E. , Loscalzo Joseph
Published: March 2006

Nitric oxide (NO·) is known to exert its effects via guanylyl cyclase and cyclic GMP- dependent pathways and by cyclic GMP-independent pathways, including the posttranslational modification of proteins. Much ongoing research is focused on defining the mechanisms of NO·-mediated protein modification, the identity and function of the modified proteins, and the significance of these changes in health and disease. S-nitrosation or thionitrite formation has only been found on a limited number of residues in a subset of proteins in in vitro and in vivo studies. Protein S-nitrosation also appears to be reversible. There are several theories about the in vivo S-nitrosating agent, and most suggest a role for oxidation products of NO· in this process. Flux in cellular S-nitrosoprotein pools appears to be regulated by NO· availability and is redox-sensitive. An analysis of S-nitrosation in candidate proteins has clarified the mechanism by which NO· regulates enzymatic and cellular functions. These findings suggest the utility of using proteomic methods to identify unique targets for protein S-nitrosation to understand further the molecular mechanisms of the effects of NO·.
Association of Transforming Growth Factor-β1 Gene Polymorphisms With Myocardial Infarction in Patients With Angiographically Proven Coronary Heart Disease
Authors: Koch Werner , Hoppmann Petra , Mueller Jakob C. , Schömig Albert , Kastrati Adnan
Published: March 2006

Objective—Transforming growth factor (TGF)-β1 (TGF-β1) is a multifunctional cytokine that exhibits vasculoprotective properties. Production and plasma levels of TGF-β1 are influenced by polymorphisms in the TGF-β1 gene (TGFB1). We investigated whether the −509C/T (rs1800469), 868T/C (rs1982073), 913G/C (rs1800471), and 11929C/T (rs1800472) polymorphisms ofTGFB1are associated with myocardial infarction.

Methods and Results—The study population consisted of 3657 patients with myocardial infarction (885 women and 2772 men) and 1211 control individuals (598 women and 613 men) with angiographically normal coronary arteries and without signs or symptoms of myocardial infarction. Polymorphism-related genotypes were determined with TaqMan assays and haplotypes were estimated from the genotype data. The −509C/T polymorphism and −509C/868T/913G/11929C (CTGC) haplotype were associated with myocardial infarction in men, independently from the potentially confounding factors age, arterial hypertension, hypercholesterolemia, cigarette smoking, and diabetes mellitus. Lower risks of myocardial infarction were observed among the carriers of the −509CC genotype (adjusted odds ratio [OR], 0.49; 95% confidence interval [CI], 0.27 to 0.87;P=0.014) and homozygous carriers of the CTGC haplotype (adjusted OR, 0.61; 95% CI, 0.38 to 0.98;P=0.042) than among the noncarriers of this genotype or haplotype. None of the genotypes (P≥0.37) or haplotypes (P≥0.35) was associated with myocardial infarction in women.

Conclusions—Positive association findings in this study suggest thatTGFB1is a susceptibility locus for myocardial infarction.
Human Lecithin:Cholesterol Acyltransferase Deficiency
Authors: Nishiwaki Masato , Ikewaki Katsunori , Bader Giovanni , Nazih Hassan , Hannuksela Minna , Remaley Alan T. , Shamburek Robert D. , Brewer H. Bryan
Published: March 2006

Objectives—

Lecithin:cholesterol acyltransferase deficiency (LCAT-def) is characterized by low levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) and the accumulation of lipoprotein-X (LpX). Despite the low HDL, atherosclerosis is uncommon in LCAT-def. The decreased LDL would be a possible explanation but the underlying mechanism is not clear. In addition, the mechanism(s) for LpX accumulation is not known. The aim of the present study is to elucidate the mechanism(s) responsible for the low LDL and determine the plasma kinetics of LpX in LCAT-def.

Methods and Results—

We conducted a radiotracer study in LCAT-def (n=2) and normal controls (n=10) and a stable isotope study in one patient and other controls (n=7). LCAT-def LDL was catabolized faster than control LDL in the control subjects as well as in LCAT-def patients. Control LDL was catabolized faster in LCAT-def patients than the controls. The production rate of LDL apolipoprotein B-100 was normal in LCAT-def. The increased LDL apoB-100 catabolism was confirmed by a stable isotope study. LpX was catabolized more slowly in LCAT-def.

Conclusions—

The decreased LDL in LCAT-def is attributable to an increased catabolism caused by a rapid catabolism of abnormal LDL and an upregulation of LDL receptor pathway. The decreased catabolism of LpX contributes to its accumulation in LCAT-def.
Mechanisms of Dysregulation of Low-Density Lipoprotein Receptor Expression in Vascular Smooth Muscle Cells by Inflammatory Cytokines
Authors: Ruan Xiong Z. , Moorhead John F. , Tao Jian L. , Ma Kun L. , Wheeler David C. , Powis Stephen H. , Varghese Zac
Published: March 2006

Objective—

Although inflammation is a recognized feature of atherosclerosis, the impact of inflammation on cellular cholesterol homeostasis is unclear. This study focuses on the molecular mechanisms by which inflammatory cytokines disrupt low-density lipoprotein (LDL) receptor regulation.

Methods and Results—

IL-1β enhanced transformation of vascular smooth muscle cells into foam cells by increasing uptake of unmodified LDL via LDL receptors and by enhancing cholesterol esterification as demonstrated by Oil Red O staining and direct assay of intracellular cholesterol concentrations. In the absence of IL-1β, a high concentration of LDL decreased LDL receptor promoter activity, mRNA synthesis and protein expression. However, IL-1β enhanced LDL receptor expression, overriding the suppression usually induced by a high concentration of LDL and inappropriately increasing LDL uptake. Exposure to IL-1β also caused overexpression of the sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP), and enhanced its translocation from the endoplasmic reticulum to the Golgi, where it is known to cleave SREBP, thereby enhancing LDL receptor gene expression.

Conclusions—

These observations demonstrate that IL-1β disrupts cholesterol-mediated LDL receptor feedback regulation, permitting intracellular accumulation of unmodified LDL and causing foam cell formation. The implication of these findings is that inflammatory cytokines may contribute to intracellular LDL accumulation without previous modification of the lipoprotein.
Adeno-Associated Virus-Mediated Transduction of VEGF165 Improves Cardiac Tissue Viability and Functional Recovery After Permanent Coronary Occlusion in Conscious Dogs
Authors: Ferrarini Matteo , Arsic Nikola , Recchia Fabio A. , Zentilin Lorena , Zacchigna Serena , Xu Xiaobin , Linke Axel , Giacca Mauro , Hintze Thomas H.
Published: March 2006

We have previously shown that VEGF165 gene delivery into ischemic skeletal muscle exerts not only proangiogenic, but also remarkable antiapoptotic and proregenerative activity. The aim of this study was to determine whether recombinant adeno-associated virus (rAAV)-mediated gene delivery of VEGF165 into cardiac muscle, during acute myocardial infarction, exerts a protective effect to promote long-term functional recovery. Acute infarction of the anterior LV wall was induced in 12 chronically instrumented dogs by permanent occlusion of the LAD coronary artery. Four hours after occlusion, rAAV-VEGF165 or rAAV-LacZ (n=6 each; 5×10
12
viral particles per animal) was directly injected with an echo-guided needle into the dysfunctional cardiac wall. LV and arterial pressure, dP/dt
max
, and ejection fraction were not significantly different between the two groups over time. In contrast, in the infarcted region, at four weeks after infarction, fractional shortening was 75±18% and −3±15% of baseline and length-pressure area was 54±15% and 0.8±15% of baseline in VEGF165 versus LacZ, respectively (
P
<0.05). Histological analysis of the border regions showed a marked increase in the number of α-SMA-positive arterioles (68±2.8 versus 100±3.8 vessels per microscopic field in LacZ and VEGF165 group, respectively;
P
<0.05). In both groups, the receptor VEGFR-2 was diffusely expressed on the surviving cardiomyocytes and, consistently, myocardial viability was significantly improved in the VEGF165-treated group, with several troponin T-expressing cardiomyocytes displaying nuclear positivity for the proliferation marker PCNA. Altogether, our results indicate that VEGF165 gene delivery exerts a marked beneficial action by enhancing both arteriologenesis and cardiomyocyte viability in infarcted myocardium.
Cardiomyocyte-Specific Deletion of the Coxsackievirus and Adenovirus Receptor Results in Hyperplasia of the Embryonic Left Ventricle and Abnormalities of Sinuatrial Valves
Authors: Chen Jin-Wen , Zhou Bin , Yu Qian-Chun , Shin Sangyoon J. , Jiao Kai , Schneider Michael D. , Baldwin H. Scott , Bergelson Jeffrey M.
Published: March 2006

The coxsackievirus and adenovirus receptor (CAR), which mediates infection by the viruses most commonly associated with myocarditis, is a transmembrane component of specialized intercellular junctions, including the myocardial intercalated disc; it is known to mediate cell–cell recognition, but its natural function is poorly understood. We used conditional gene targeting to investigate the possible functions of CAR during embryonic development, generating mice with both germline and tissue-specific defects in CAR expression. Homozygous germline deletion of CAR exon 2 or cardiomyocyte-specific gene deletion at embryonic day 10 (E10) mediated by Cre recombinase expressed under the control of the cardiac troponin T promoter resulted in death by E12.5; embryos showed marked cardiac abnormalities by E10.5, with hyperplasia of the left ventricular myocardium, distention of the cardinal veins, and abnormalities of sinuatrial valves. Within the hyperplastic left ventricle, increased numbers of proliferating cells were evident; persistent expression of N-myc in the hyperplastic myocardium and attenuated expression of the trabecular markers atrial natriuretic factor and bone morphogenic protein 10 indicated that proliferating cardiomyocytes had failed to differentiate and form normal trabeculae. In electron micrographs, individual CAR-deficient cardiomyocytes within the left ventricle appeared normal, but intercellular junctions were ill-formed or absent, consistent with the known function of CAR as a junctional molecule; myofibrils were also poorly organized. When cardiomyocyte-specific deletion occurred somewhat later (by E11, mediated by Cre under control of the α-myosin heavy chain promoter), animals survived to adulthood and did not have evident cardiac abnormalities. These results indicate that during a specific temporal window, CAR expression on cardiomyocytes is essential for normal cardiac development. In addition, the results suggest that CAR-mediated intercellular contacts may regulate proliferation and differentiation of cardiomyocytes within the embryonic left ventricular wall.
Cardiac Ischemia Activates Vascular Endothelial Cadherin Promoter in Both Preexisting Vascular Cells and Bone Marrow Cells Involved in Neovascularization
Authors: Kogata Naoko , Arai Yuji , Pearson James T. , Hashimoto Kazuaki , Hidaka Kyoko , Koyama Tatsuya , Somekawa Satoshi , Nakaoka Yoshikazu , Ogawa Minetaro , Adams Ralf H. , Okada Masato , Mochizuki Naoki
Published: March 2006

Vascular endothelial cadherin (VE-cadherin) is expressed on vascular endothelial cells, which are involved in developmental vessel formation. However, it remains elusive how VE-cadherin–expressing cells function in postnatal neovascularization. To trace VE-cadherin–expressing cells, we developed mice expressing either green fluorescent protein or LacZ driven by VE-cadherin promoter using Cre-loxP system. Although VE-cadherin promoter is less active after birth than during embryogenesis in blood vessels, it is reactivated on cardiac ischemia. Both types of reporter-positive cells are found in the vasculature and in the infarcted myocardium. Those found in the vasculature were pre-existing endothelial cells and incorporated endothelial progenitor cells derived from extracardiac tissue. In addition to the vasculature, VE-cadherin promoter-activated cells were positive for CD45 in the bone marrow cells of the infarcted mice. VE-cadherin promoter–reactivated CD45-positive leukocytes were also found in the infarcted area. In addition, VE-cadherin promoter was activated in the bone marrow vessels of the infarcted mice. Collectively, our findings reveal a new ischemia-induced neovascularization mechanism involving VE-cadherin; the re-expressed VE-cadherin–mediated cell adhesion between cells may be involved not only in homing of bone marrow–derived cells to ischemic area but also mobilization from bone marrow.
Sleep-Disordered Breathing and Acute Ischemic Stroke
Authors: Bassetti Claudio L. , Milanova Milena , Gugger Matthias
Published: March 2006

Background and Purpose—

Sleep-disordered breathing (SDB) is frequent in stroke patients. Risk factors, treatment response, short-term and long-term outcome of SDB in stroke patients are poorly known.

Methods—

We prospectively studied 152 patients (mean age 56±13 years) with acute ischemic stroke. Cardiovascular risk factors, Epworth sleepiness score (ESS), stroke severity/etiology, and time of stroke onset were assessed. The apnea-hypopnea index (AHI) was determined 3±2 days after stroke onset and 6 months later (subacute phase). Continuous positive airway pressure (CPAP) treatment was started acutely in patients with SDB (AHI ≥15 or AHI ≥10+ESS >10). CPAP compliance, incidence of vascular events, and stroke outcome were assessed 60±16 months later (chronic phase).

Results—

Initial AHI was 18±16 (≥10 in 58%, ≥30 in 17% of patients) and decreased in the subacute phase (
P
<0.001). Age, diabetes, and nighttime stroke onset were independent predictors of AHI (
r
2
=0.34). In patients with AHI ≥30, age, male gender, body mass index, diabetes, hypertension, coronary heart disease, ESS, and macroangiopathic etiology of stroke were significantly higher/more common than in patients with AHI <10. Long-term incidence of vascular events and stroke outcome were similar in both groups. CPAP was started in 51% and continued chronically in 15% of SDB pts. Long-term stroke mortality was associated with initial AHI, age, hypertension, diabetes, and coronary heart disease.

Conclusions—

SDB is common particularly in elderly stroke male patients with diabetes, nighttime stroke onset, and macroangiopathy as cause of stroke; it improves after the acute phase, is associated with an increased poststroke mortality, and can be treated with CPAP in a small percentage of patients.
Individual and Familial Stressors Among Rural Nebraskan, Bilingual, Paraprofessional Educators
Authors: Dalla Rochelle L. , Lopez William E. , Jones Vicky O. , Xia Yan
Published: March 2006

Individual (e.g., depression, learning styles) and familial (e.g., social support) factors affecting the psychosocial well-being of bilingual, rural Nebraska, paraprofessional educators were examined. Of 26 participants, 15 were first and 5 were second generation Hispanic immigrants. All were currently ( n= 20) or formerly ( n= 6) involved in an online, distance education, bachelor's degree program in elementary education, with English as a second language certification. Results from data analyses are presented, as are suggestions for working with unique populations.
Profiles of Cognitive Developmental Performance in Gifted Children
Authors: Gonzalez Virginia
Published: March 2006

This quasiexperimental research studies the effect of socioeconomic status (SES), language learning, and culture on gifted Hispanic children's performance in an alternative developmental scale (Qualitative Use of English and Spanish Tasks) of cognitive ability for generating developmental profiles. Results showthe effect of SES and language learning across linguistic and cultural factors, revealing developmental continuities and discontinuities. Theoretical and practical educational implications are to include and generate developmentally appropriate assessments that uncover cultural-linguistic giftedness.
An Innovative Baccalaureate Degree
Authors: Arney Janna B. , Hardebeck Suzanne , Estrada Joselito , Permenter Vivian
Published: March 2006

The bachelor of applied arts and sciences (BAAS) degree is a baccalaureate program designed to meet the needs of nontraditional students by allowing technical hours to be transferred for credit to a baccalaureate degree. To determine if the university was positively serving the needs of its constituents, salaries of BAAS graduates were compared to salaries of graduates of the academic bachelor of business administration from 1995 to 2000. No statistical difference was found.
KSHV/HHV-8 infection of human hematopoietic progenitor (CD34+) cells: persistence of infection during hematopoiesis in vitro and in vivo
Authors: Wu William , Vieira Jeffrey , Fiore Nancy , Banerjee Prabal , Sieburg Michelle , Rochford Rosemary , Harrington William , Feuer Gerold
Published: March 2006

The cellular reservoir for Kaposi sarcoma-associated herpesvirus (KSHV) infection in the hematopoietic compartment and mechanisms governing latent infection and reactivation remain undefined. To determine susceptibility of human CD34+ hematopoietic progenitor cells (HPCs) to infection with KSHV, purified HPCs were exposed to KSHV, and cells were differentiated in vitro and in vivo. Clonogenic colony-forming activity was significantly suppressed in KSHV-infected CD34+ cells, and viral DNA was predominantly localized to granulocyte-macrophage colonies differentiated in vitro. rKSHV.219 is a recombinant KSHV construct that expresses green fluorescent protein from a cellular promoter active during latency and red fluorescent protein from a viral lytic promoter. Infection of CD34+ HPCs with rKSHV.219 showed similar patterns of infection, persistence, and hematopoietic suppression in vitro in comparison with KSHV. rKSHV.219 infection was detected in human CD14+ and CD19+ cells recovered from NOD/SCID mouse bone marrow and spleen following reconstitution with rKSHV.219-infected CD34+ HPCs. These results suggest that rKSHV.219 establishes persistent infection in NOD/SCID mice and that virus may be disseminated following differentiation of infected HPCs into the B-cell and monocyte lineages. CD34+ HPCs may be a reservoir for KSHV infection and may provide a continuous source of virally infected cells in vivo. (Blood. 2006;108:141-151)
FcγR-induced production of superoxide and inflammatory cytokines is differentially regulated by SHIP through its influence on PI3K and/or Ras/Erk pathways
Authors: Ganesan Latha P. , Joshi Trupti , Fang Huiqing , Kutala Vijay Kumar , Roda Julie , Trotta Rossana , Lehman Amy , Kuppusamy Periannan , Byrd John C. , Carson William E. , Caligiuri Michael A. , Tridandapani Susheela
Published: March 2006

Phagocytosis of IgG-coated particles via FcγR is accompanied by the generation of superoxide and inflammatory cytokines, which can cause collateral tissue damage in the absence of regulation. Molecular mechanisms regulating these phagocytosis-associated events are not known. SHIP is an inositol phosphatase that downregulates PI3K-mediated activation events. Here, we have examined the role of SHIP in FcγR-induced production of superoxide and inflammatory cytokines. We report that primary SHIP-deficient bone marrow macrophages produce elevated levels of superoxide upon FcγR clustering. Analysis of the molecular mechanism revealed that SHIP regulates upstream Rac-GTP binding, an obligatory event for superoxide production. Likewise, SHIP-deficient macrophages displayed enhanced IL-1β and IL-6 production in response to FcγR clustering. Interestingly, whereas IL-6 production required activation of both PI3K and Ras/Erk pathways, IL-1β production was dependent only on Ras/Erk activation, suggesting that SHIP may also regulate the Ras/Erk pathway in macrophages. Consistently, SHIP-deficient macrophages displayed enhanced activation of Erk upon FcγR clustering. Inhibition of Ras/Erk or PI3K suppressed the enhanced production of IL-6 in SHIP-deficient macrophages. In contrast, inhibition of Ras/Erk, but not PI3K, suppressed IL-1β production in these cells. Together, these data demonstrate that SHIP regulates phagocytosis-associated events through the inhibition of PI3K and Ras/Erk pathways.
Complex interaction of BCRP/ABCG2 and imatinib in BCR-ABL–expressing cells: BCRP-mediated resistance to imatinib is attenuated by imatinib-induced reduction of BCRP expression
Authors: Nakanishi Takeo , Shiozawa Ken , Hassel Bret A. , Ross Douglas D.
Published: March 2006

Imatinib, a potent tyrosine kinase inhibitor, is effluxed from cells by the breast cancer resistance protein (BCRP/ABCG2), yet published studies to date fail to demonstrate resistance to imatinib cytotoxicity in BCRP-overexpressing cells in vitro. We investigated cellular resistance to imatinib in BCR-ABL–expressing cells transduced and selected to overexpress BCRP (K562/BCRP-MX10). These cells exhibited a 2- to 3-fold increase in resistance to imatinib (P < .05) and a 7- to 12-fold increase in resistance to mitoxantrone, a known BCRP substrate. Resistance to imatinib was completely abolished by the specific BCRP inhibitor fumitremorgin C. Studies of the mechanism of the diminished resistance to imatinib compared with mitoxantrone revealed that imatinib decreased the expression of BCRP in K562/BCRP-MX10 cells without affecting mRNA levels. BCRP levels in cells that do not express BCR-ABL were not affected by imatinib. Loss of BCRP expression was accompanied by imatinib-induced reduction of phosphorylated Akt in the BCRP-expressing K562 cells. The phosphoinositol-3 kinase (PI3K) inhibitor LY294002 also decreased BCRP levels in K562/BCRP-MX10 cells. These studies show that BCRP causes measurable imatinib resistance, but this effect is attenuated by imatinib-mediated inhibition of BCR-ABL, which in turn downregulates overall BCRP levels posttranscriptionally via the PI3K-Akt pathway.
Immune deviation by mucosal antigen administration suppresses gene-transfer–induced inhibitor formation to factor IX
Authors: Cao Ou , Armstrong Elina , Schlachterman Alexander , Wang Lixin , Okita David K. , Conti-Fine Bianca , High Katherine A. , Herzog Roland W.
Published: March 2006

Formation of inhibitory antibodies is a serious complication of protein or gene replacement therapy for hemophilias, congenital X-linked bleeding disorders. In hemophilia B (coagulation factor IX [F.IX] deficiency), lack of endogenous F.IX antigen expression and other genetic factors may increase the risk of antibody formation to functional F.IX. Here, we developed a protocol for reducing inhibitor formation in gene therapy by prior mucosal (intranasal) administration of a peptide representing a human F.IX-specific CD4+ T-cell epitope in hemophilia B mice. C3H/HeJ mice with a F.IX gene deletion produced inhibitory IgG to human F.IX after hepatic gene transfer with an adeno-associated viral vector. These animals subsequently lost systemic F.IX expression. In contrast, repeated intranasal administration of the specific peptide resulted in reduced inhibitor formation, sustained circulating F.IX levels, and sustained partial correction of coagulation following hepatic gene transfer. This was achieved through immune deviation to a T-helper–cell response with increased IL-10 and TGF-β production and activation of regulatory CD4+CD25+ T cells.
Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia
Authors: Kojima Kensuke , Konopleva Marina , McQueen Teresa , O'Brien Susan , Plunkett William , Andreeff Michael
Published: March 2006

Although TP53 mutations are rare in B-cell chronic lymphocytic leukemia (CLL), Mdm2 overexpression has been reported as an alternative cause of p53 dysfunction. We investigated the potential therapeutic use of nongenotoxic p53 activation by a small-molecule antagonist of Mdm2, Nutlin-3a, in CLL. Nutlin-3a induced significant apoptosis in 30 (91%) of 33 samples from previously untreated patients with CLL; all resistant samples had TP53 mutations. Low levels of Atm (ataxia telangiectasia mutated) or high levels of Mdm2 (murine double minute 2) did not prevent Nutlin-3a from inducing apoptosis. Nutlin-3a used transcription-dependent and transcription-independent pathways to induce p53-mediated apoptosis. Predominant activation of the transcription-independent pathway induced more pronounced apoptosis than that of the transcription-dependent pathway, suggesting that activation of the transcription-independent pathway is sufficient to initiate p53-mediated apoptosis in CLL. Combination treatment of Nutlin-3a and fludarabine synergistically increased p53 levels, and induced conformational change of Bax and apoptosis in wild-type p53 cells but not in cells with mutant p53. The synergistic apoptotic effect was maintained in samples with low Atm that were fludarabine resistant. Results suggest that the nongenotoxic activation of p53 by targeting the Mdm2-p53 interaction provides a novel therapeutic strategy for CLL.
EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15
Authors: Sauce Delphine , Larsen Martin , Curnow S. John , Leese Alison M. , Moss Paul A. H. , Hislop Andrew D. , Salmon Michael , Rickinson Alan B.
Published: March 2006

In mice, interleukin-7 (IL-7) and IL-15 are involved in T-cell homeostasis and the maintenance of immunologic memory. Here, we follow virus-induced responses in infectious mononucleosis (IM) patients from primary Epstein-Barr virus (EBV) infection into long-term virus carriage, monitoring IL-7 and IL-15 receptor (IL-R) expression by antibody staining and cytokine responsiveness by STAT5 phosphorylation and in vitro proliferation. Expression of IL-7Rα was lost from all CD8+ T cells, including EBV epitope-specific populations, during acute IM. Thereafter, expression recovered quickly on total CD8+ cells but slowly and incompletely on EBV-specific memory cells. Expression of IL-15Rα was also lost in acute IM and remained undetectable thereafter not just on EBV-specific CD8+ populations but on the whole peripheral T- and natural killer (NK)-cell pool. This deficit, correlating with defective IL-15 responsiveness in vitro, was consistently observed in patients up to 14 years after IM but not in patients after cytomegalovirus (CMV)-associated mononucleosis, or in healthy EBV carriers with no history of IM, or in EBV-naive individuals. By permanently scarring the immune system, symptomatic primary EBV infection provides a unique cohort of patients through which to study the effects of impaired IL-15 signaling on human lymphocyte functions in vitro and in vivo. (Blood. 2006;108:11-18)
Spermatogenesis in long-term survivors after allogeneic hematopoietic stem cell transplantation is associated with age, time interval since transplantation, and apparently absence of chronic GvHD
Authors: Rovó Alicia , Tichelli André , Passweg Jakob R. , Heim Dominik , Meyer-Monard Sandrine , Holzgreve Wolfgang , Gratwohl Alois , De Geyter Christian
Published: March 2006

Factors associated with spermatogenesis after allogeneic hematopoietic stem cell transplantation (HSCT) were assessed in this prospective, single-center, cross-sectional study. All consecutive men aged 18 years or older and in complete remission 2 years or longer after HSCT were invited to participate. Seminal fluid analysis was performed on freshly collected samples according to World Health Organization guidelines. Between April 2003 and June 2004, 39 patients were included. The median age at semen analysis was 34 years (range, 20-59 years), and the median time interval between HSCT and sperm analysis 9 years (range, 2-20 years). Thirty-two patients (82%) underwent total body irradiation (TBI; ≥ 10 Gy) as part of their conditioning regimen. Eleven of 39 (28%) patients showed some spermatogenesis. Patients with detectable spermatozoa in the ejaculate were younger at HSCT (median age, 19 versus 28 years; P = .004), had a longer interval since HSCT (median time, 12 versus 7 years; P = .01), and were more often without chronic graft-versus-host disease (GvHD; 2 of 11 patients versus 16 of 28; P = .03). Nine of 16 patients (56%) undergoing transplantation when younger than age 25 years showed some degree of spermatogenesis. In conclusion, men who are long-term survivors, who were younger than 25 years at HSCT, and who apparently do not have chronic GvHD have a reasonable likelihood of spermatogenesis even when conditioned with standard-dose TBI.
The mutation rate in PIG-A is normal in patients with paroxysmal nocturnal hemoglobinuria (PNH)
Authors: Araten David J. , Luzzatto Lucio
Published: March 2006

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the presence in the patient's hematopoietic system of a large cell population with a mutation in the X-linked PIG-A gene. Although this abnormal cell population is often found to be monoclonal, it is not unusual that 2 or even several PIG-A mutant clones coexist in the same patient. Therefore, it has been suggested that the PIG-A gene may be hypermutable in PNH. By a method we have recently developed for measuring the intrinsic rate of somatic mutations (μ) in humans, in which PIG-A itself is used as a sentinel gene, we have found that in 5 patients with PNH, μ ranged from 1.24 × 10–7 to 11.2 × 10–7, against a normal range of 2.4 × 10–7 to 29.6 × 10–7 mutations per cell division. We conclude that genetic instability of the PIG-A gene is not a factor in the pathogenesis of PNH.
Role of urease in megasome formation and Helicobacter pylori survival in macrophages
Authors: Schwartz Justin T , Allen Lee-Ann H
Published: March 2006

Previous studies have demonstrated that Helicobacter pylori (Hp) delays its entry into macrophages and persists inside megasomes, which are poorly acidified and accumulate early endosome autoantigen 1. Herein, we explored the role of Hp urease in bacterial survival in murine peritoneal macrophages and J774 cells. Plasmid-free mutagenesis was used to replace ureA and ureB with cat in Hp Strains 11637 and 11916. ureAB null Hp lacked detectable urease activity and did not express UreA or UreB as judged by immunoblotting. Deletion of ureAB had no effect on Hp binding to macrophages or the rate or extent of phagocytosis. However, intracellular survival of mutant organisms was impaired significantly. Immunofluorescence microscopy demonstrated that (in contrast to parental organisms) mutant Hp resided in single phagosomes, which were acidic and accumulated the lysosome marker lysosome-associated membrane protein-1 but not early endosome autoantigen 1. A similar phenotype was observed for spontaneous urease mutants derived from Hp Strain 60190. Treatment of macrophages with bafilomycin A1, NH4Cl, or chloroquine prevented acidification of phagosomes containing mutant Hp. However, only ammonium chloride enhanced bacterial viability significantly. Rescue of ureAB null organisms was also achieved by surface adsorption of active urease. Altogether, our data indicate a role for urease and urease-derived ammonia in megasome formation and Hp survival.
Aggregated IgG inhibits the differentiation of human fibrocytes
Authors: Pilling Darrell , Tucker Nancy M , Gomer Richard H
Published: March 2006

Fibrocytes are fibroblast-like cells, which appear to participate in wound healing and are present in pathological lesions associated with asthma, pulmonary fibrosis, and scleroderma. Fibrocytes differentiate from CD14+ peripheral blood monocytes, and the presence of serum delays this process dramatically. We previously purified the factor in serum, which inhibits fibrocyte differentiation, and identified it as serum amyloid P (SAP). As SAP binds to Fc receptors for immunoglobulin G (IgG; FcγRs), FcγR activation may be an inhibitory signal for fibrocyte differentiation. FcγR are activated by aggregated IgG, and we find aggregated but not monomeric, human IgG inhibits human fibrocyte differentiation. Monoclonal antibodies that bind to FcγRI (CD64) or FcγRII (CD32) also inhibit fibrocyte differentiation. Aggregated IgG lacking Fc domains or aggregated IgA, IgE, or IgM do not inhibit fibrocyte differentiation. Incubation of monocytes with SAP or aggregated IgG inhibited fibrocyte differentiation. Using inhibitors of protein kinase enzymes, we show that Syk- and Src-related tyrosine kinases participate in the inhibition of fibrocyte differentiation. These observations suggest that fibrocyte differentiation can occur in situations where SAP and aggregated IgG levels are low, such as the resolution phase of inflammation.
Regulation of Insulin Gene Transcription by the Immediate-Early Growth Response Gene Egr-1
Authors: Eto Kazuhiro , Kaur Varinderpal , Thomas Melissa K.
Published: March 2006

Changes in extracellular glucose levels regulate the expression of the immediate-early response gene and zinc finger transcription factor early growth response-1 (Egr-1) in insulin-producing pancreatic β-cells, but key target genes of Egr-1 in the endocrine pancreas have not been identified. We found that overexpression of Egr-1 in clonal (INS-1) β-cells increased transcriptional activation of the rat insulin I promoter. In contrast, reductions in Egr-1 expression levels or function with the introduction of either small interfering RNA targeted to Egr-1 (siEgr-1) or a dominant-negative form of Egr-1 decreased insulin promoter activation, and siEgr-1 suppressed insulin gene expression. Egr-1 did not directly interact with insulin promoter sequences, and mutagenesis of a potential G box recognition sequence for Egr-1 did not impair the Egr-1 responsiveness of the insulin promoter, suggesting that regulation of insulin gene expression by Egr-1 is probably mediated through additional transcription factors. Overexpression of Egr-1 increased, and reduction of Egr-1 expression decreased, transcriptional activation of the glucose-responsive FarFlat minienhancer within the rat insulin I promoter despite the absence of demonstrable Egr-1-binding activity to FarFlat sequences. Notably, augmenting Egr-1 expression levels in insulin-producing cells increased the mRNA and protein expression levels of pancreas duodenum homeobox-1 (PDX-1), a major transcriptional regulator of glucose-responsive activation of the insulin gene. Increasing Egr-1 expression levels enhanced PDX-1 binding to insulin promoter sequences, whereas mutagenesis of PDX-1-binding sites reduced the capacity of Egr-1 to activate the insulin promoter. We propose that changes in Egr-1 expression levels in response to extracellular signals, including glucose, can regulate PDX-1 expression and insulin production in pancreatic β-cells.