bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunomodulation and Safety of Topical Calcineurin Inhibitors for the Treatment of Atopic Dermatitis
Authors: Hultsch Thomas , Kapp Alexander , Spergel Jonathan
Published: August 2005

Atopic dermatitis (AD) is a chronic or chronically relapsing inflammatory skin condition that primarily affects children. Topical corticosteroids have been the mainstay of treatment since the late 1950s. While providing excellent short-term efficacy, topical corticosteroid usage is limited by potential adverse effects, including impairment of the function and viability of Langerhans cells/dendritic cells. The recently introduced topical calcineurin inhibitors pimecrolimus cream 1% (Elidel®) and tacrolimus ointment 0.03 and 0.1% (Protopic®) exhibit a more selective mechanism of action and do not affect Langerhans cells/dendritic cells. For the immune system of young children ‘learning’ to mount a balanced Th1/Th2 response, this selective effect has particular benefits. In clinical experience, topical calcineurin inhibitors have been shown to be a safe and effective alternative to topical corticosteroids in almost 7 million patients (>5 million on pimecrolimus; >1.7 million on tacrolimus). Topical pimecrolimus is primarily used in children with mild and moderate AD, whereas tacrolimus is used preferentially in more severe cases. None of the topical calcineurin inhibitors have been associated with systemic immunosuppression-related malignancies known to occur following long-term sustained systemic immunosuppression with oral immunosuppressants (e.g., tacrolimus, cyclosporine A, and corticosteroids) in transplant patients. Preclinical and clinical data suggest a greater skin selectivity and larger safety margin for topical pimecrolimus.
Usefulness of in vitro 1H Magnetic Resonance Spectroscopy for the Characterization of Primary Brain Tumors: Report of Two Cases
Authors: Sabatier Jean , Robert Olivier , Delisle Marie-Bernadette , Malet-Martino Myriam
Published: August 2005

Pathological diagnosis of brain tumors provides an index of brain disease severity and guides clinical practice in their treatment. Diagnoses are often made from biopsy material obtained using stereotactic techniques with the difficulty of making a histological diagnosis in small samples. In our experience, the estimation of the degree of malignancy on the basis of in vitro1H magnetic resonance spectroscopy (1H MRS) appears to well correlate with histology and clinical evolution. We report two cases with a discordance between the diagnoses on the basis of histology examination and in vitro 1H MRS whose evolution seems to correlate better with the data of1H MRS.
Determinants of Prestroke Cognitive Impairment in Stroke Associated with Small Vessel Disease
Authors: Mok V. , Wong A. , Tang Wai Kwong , Lam W.W.M. , Fan Yu Hua , Richards Polly S. , Wong K.T. , Ahuja A.T. , Wong Ka Sing
Published: August 2005

Understanding the determinants of prestroke cognitive impairment (PCI) in stroke associated with small vessel disease (SVD) may shed light on how to prevent further cognitive deterioration after stroke. We administered the Informant Questionnaire on Cognitive Decline (IQCODE) to close informants of 78 consecutive stroke patients who had SVD. PCI, as defined by an average score of IQCODE ≧3.4 was found in 19 (24%) patients. Regression analyses were performed on the following risk factors for PCI: age, years of education, gender, previous stroke, volume of white matter changes, measures of silent lacunes, cerebral atrophy index, medial temporal lobe atrophy and frontal lobe atrophy. Multivariate regression analyses revealed that only cerebral atrophy index (OR 1.5, CI 1.2–1.9, p < 0.001) predicted PCI among patients with SVD.
Incidence, Clinical Features and Subtypes of Delirium in Elderly Patients Treated for Hip Fractures
Authors: Santana Santos Franklin , Wahlund Lars Olof , Varli Ferid , Tadeu Velasco Irineu , Eriksdotter Jönhagen Maria
Published: August 2005

Objective: To describe the incidence, risk factors and clinical features (subtypes) of delirium during the postoperative period after hip fracture surgery in elderly patients. Design: Prospective study. Methods: Thirty-four consecutive patients (9 men and 25 women) were included in this study between June 16 to July 14, 2003. All patients underwent surgery for a fractured neck of femur and were pre- and postoperatively cared for at a combined geriatric/orthopedic ward. Assessment: The diagnosis of delirium was based on the criteria of the DSM-IV and the Confusion Assessment Method Scale. Subtypes of delirium were classified according to the criteria proposed by Lipowski: hyperactive-hyperalert (or agitated), hypoactive-hypoalert (somnolent) and mixed delirium. Results: Fifty-five percent (n = 19) of the 34 patients developed delirium after surgery. The development of delirium was associated with the medication midazolam taken perioperatively. Nine (47%) of the delirious patients had a hyperactive type of delirium; 5 (26%) developed a hypoactive delirium, and 5 (26%) had a mixed type. We did not find any association among subtypes of delirium and clinical features. Conclusions: Delirium is a common complication in the postoperative period of elderly patients treated for hip fractures. The use of midazolam in the perioperative period increased the risk of developing postoperative delirium. Thehyperactive type of delirium was the most common subtype of delirium.
Early Androgen Deficiency in Infants and Young Boys with 47,XXY Klinefelter Syndrome
Authors: Ross Judith L. , Samango-Sprouse Carole , Lahlou Najiba , Kowal Karen , Elder Frederick F. , Zinn Andrew
Published: August 2005

Background/Aims: Klinefelter syndrome (KS) is characterized by the karyotype 47,XXY. In this study, we evaluated the physical and testicular failure phenotypes of infants and young boys with KS. Methods: The evaluation included auxologic measurements, biologic indices of testicular function, and clinical assessment of muscle tone in 22 infants and young boys with KS, ages 1–23 months. Results: Mean length, weight, and head circumference in SDS were generally within the normal range at –0.3 ± 1.0, –0.1 ± 1.4, and 0.0 ± 1.5, respectively. Mean penile length and testicular volume SDS were –0.9 ± 0.8 and –1.1 ± 0.8, indicating significantly reduced penile and testicular size. Mean testosterone levels for the boys ≤6 and >6–23 months were 128 ± 131 (4.4 ± 4.5 nmol/l) and 9.5 ± 7.2 ng/dl (0.3 ± 0.2 nmol/l), respectively. High-arched palate was observed in 6/17 boys and clinodactyly (5th finger) was observed in 15/16 boys. Hypotonia was evaluated clinically and was noted to be present in 12/17 boys. Conclusion: The physical phenotype in infants and young boys with KS (1–23 months old) includes normal auxologic measurements and early evidence of testicular failure. Muscle tone was decreased in most of the boys. Testicular volume and penile length were diminished, indicating early androgen deficiency. The neonatal surge in testosterone was attenuated in our KS population. Thus, infants and young boys with KS have evidence of early testicular failure. The etiology of this failure and the clinical role of early androgen replacement require further study.
Decreased Production of Collagen Type III in Cultured Smooth Muscle Cells from Varicose Vein Patients Is due to a Degradation by MMPs: Possible Implication of MMP-3
Authors: Sansilvestri-Morel Patricia , Rupin Alain , Jullien Nicolas D. , Lembrez Nathalie , Mestries-Dubois Patricia , Fabiani Jean Noël , Verbeuren Tony J.
Published: August 2005

An alteration of extracellular matrix is involved in varicose veins. We have previously shown that collagen III production, but not its mRNA expression, is decreased in cultured smooth muscle cells (SMC) from varicose veins, involving an over-production of collagen I. In this study, the mechanisms involved in this collagen III reduction are explored. Steady state levels of collagen III mRNA and its ability to translate a protein were evaluated. Neither stability nor functionality of the α1(III) coding mRNA were affected in cells from varicose veins. Potential intracellular degradations of collagen III were investigated with inhibitors of intracellular proteases but the production was unaffected. The level of N-terminal propeptides of collagen III in the extracellular medium was determined and was similar in SMC from control and varicose veins. The stability of collagen III was determined by time-course experiments and a degradation of the protein was observed in cells from varicose veins. The production of collagen III was partially restored in cells from varicose veins in the presence of Marimastat, a matrix metalloproteinase (MMP) inhibitor. The mRNA expression and protein production of MMP3 were increased in cells from varicose veins. Fibronectin, a potential substrate of MMP3, was decreased in SMC from varicose veins. In conclusion, collagen III, and probably fibronectin, are degraded extracellularly in SMC from varicose veins by a mechanism involving MMPs, and maybe MMP3 by a direct or an indirect pathway. The degradation of collagen III and fibronectin may have repercussions for the mechanical properties of the venous wall.
In vivo Observation of Papillae of the Human Tongue Using Confocal Laser Scanning Microscopy
Authors: Just Tino , Stave Joachim , Pau Hans Wilhelm , Guthoff Rudolf
Published: August 2005

The aim of this investigation was to visualize the epithelial structures of the tongue using confocal laser scanning microscopy (LSM). The human tongue epithelium of 28 healthy subjects, aged 21–67 years, mean age 38 years, 14 women and 14 men, was examined in vivo by LSM. Using LSM, a combination of the Heidelberg Retina Tomograph HRT II and the Rostock Cornea Module, up to 800-fold magnifications were obtained. On the tongue surface both filiform and fungiform papillae and their taste pores were easily identified. The epithelium of the tongue with its subcellular structures could be observed up to a depth of 50 µm, cellular structures up to 150 µm and subepithelial vessels up to 300 µm. Additionally the papillary crests and blood flow were visible. Confocal LSM seems suitable for noninvasive in vivo examination of the tongue. The hydraulic z scan, the manual start setting and the measurement of the depth allow a clear classification of the observed structures.
Lack of Adult-Type Salivary Cortisol Circadian Rhythm in Hospitalized Preterm Infants
Authors: Kidd Susan , Midgley Paula , Nicol Mary , Smith John , McIntosh Neil
Published: August 2005

Background/Aims: Knowledge of the presence or absence of cortisol (F) circadian rhythm in preterm infants is important for the interpretation of F measurements made in samples taken for both clinical and research purposes. Little is known about its emergence in very preterm infants. This study examines circadian rhythm in F secretion in hospitalized infants born before 30 weeks’ gestation. Methods: Design: Prospective longitudinal observational study. Subjects: 11 infants admitted consecutively and born before 30 completed weeks of gestation. Measurements: F was measured by highly specific radioimmunoassay on morning and evening saliva samples gathered at weekly intervals until discharged home. Circadian rhythm was defined as ≧40% reduction from morning to evening level. Results: For all data, the median salivary F was 10.3 nmol/l (range <0.5–372.8). F levels were highest in the first 3 weeks of life. No infants displayed classical circadian rhythm for 4 weeks or more prior to being discharged from hospital. The other infants showed randomly distributed morning and evening F values with a trend in 4 infants towards periods of consistently higher evening than morning values. Conclusion: Adult-type F circadian rhythm is rarely evident in hospitalized preterm infants born before 30 weeks’ gestation.
Effects of Polyunsaturated/Saturated Fatty Acid Ratio and Antioxidant Supplementation on Hepatic TBARS and Enzyme Activities under the Maintenance of Dietary Peroxidizability Index Value in Young and Adult Rats
Authors: Kang Min Jeong , Ahn Hae Sun , Lee Sang Sun
Published: August 2005

Aims: To investigate the effects of the polyunsaturated/saturated fatty acid (P/S) ratio and antioxidant supplementation on hepatic lipid peroxidation and enzyme activities under the control of the dietary peroxidizability index (PI) value in young and adult rats. Methods: We measured thiobarbituric acid-reactive substance (TBARS) concentration and enzyme activities in liver tissue. Female Sprague-Dawley rats aged 3 and 16 weeks were used. Dietary P/S ratios were 0.38 and 4.81 (LP and HP) when the PI value was 81.22. The diets were supplemented with vitamin E 1,000 mg/kg diet and selenium 2.5 mg/kg diet (LPS and HPS). Results: The hepatic TBARS concentration was higher in LP and LPS than in HP and HPS. In reducing TBARS concentration, antioxidant supplementation was more effective in adult rats than in young rats. Glutathione peroxidase and glutathione-S-transferase activities were lower in young rats than in adult rats. Conclusion: We conclude that dietary fats and antioxidant supplementation play an important role in the change of hepatic TBARS concentration when the dietary PI value is maintained at the same level. However, with the exception of glutathione reductase, no effects of the P/S ratio and antioxidant supplementation on hepatic enzyme activities were detected. This may be due to the invisible effects of fixed PI value in diets.
A Volumetric Magnetic Resonance Imaging Study of the Amygdala in Frontotemporal Lobar Degeneration and Alzheimer’s Disease
Authors: Whitwell Jennifer L. , Sampson Elizabeth L. , Watt Hilary C. , Harvey Richard J. , Rossor Martin N. , Fox Nick C.
Published: August 2005

The amygdala is severely atrophied at post-mortem in frontotemporal lobar degeneration (FTLD), and may contribute to the prominent behavioural changes that are early features of FTLD. The aim of this study was to assess amygdala atrophy using MRI in the main syndromic variants of FTLD and Alzheimer’s disease (AD). Brain and amygdala volumes, adjusted for intracranial volume, were measured on 46 clinically diagnosed FTLD patients [22 frontal variant FTD (FTD), 14 semantic dementia (SD), 10 progressive non-fluent aphasia (PNFA)], 20 AD patients, and 17 controls. While severe amygdala atrophy was present in both FTLD (41% smaller than controls on the left; 33% on the right) and in AD (22% on the left; 19% on the right), the FTLD group had significantly greater amygdala atrophy (z = 3.21, p = 0.001 left, z = 2.50, p = 0.01 right) and left/right asymmetry (z = 2.03, p = 0.04) than AD. Amygdala atrophy was greater in SD than FTD, PNFA and AD (p < 0.02 for all). Highly asymmetrical atrophy was present in SD, greater on the left (z = 3.23, p = 0.001), and to a lesser extent in PNFA. Despite an overlap between clinical and radiological features of FTLD and AD, marked amygdala atrophy points towards a diagnosis of FTLD, with left greater than right atrophy suggestive of one of the language variants.
A Guinea Pig Strain with Recessive Heredity of Deafness, Producing Normal-Hearing Heterozygotes with Resistance to Noise Trauma
Authors: Skjönsberg Åsa , Herrlin Petra , Duan Maoli , Johnson Ann-Christin , Ulfendahl Mats
Published: August 2005

A new strain of waltzing guinea pigs arose spontaneously in a guinea pig breeding facility in Germany in 1996. In addition to obvious vestibular dysfunction, the waltzing animals appear deaf already at birth. Histological analysis revealed that the waltzers lack an open scala media due to the collapse of Reissner’s membrane onto the surface of the hearing organ. Subsequent breeding has shown that this strain has a recessive mode of inheritance. The homozygotes are deaf and display a waltzing behaviour throughout their lives while the heterozygotes show no significant signs of inner ear injury despite being carriers of this specific mutated gene of hearing impairment. However, the heterozygous animals offer the opportunity to study how hereditary factors interact with auditory stress. In the present study, the susceptibility of the carriers to noise was investigated. Auditory brainstem responses were obtained prior to and after noise exposure (4 kHz, 110 dB, 6 h). The carriers were significantly less affected by the noise as compared to control animals. This difference was still significant at 4 weeks following noise exposure. It is suggested that the heterozygous animals have an endogenous resistance to auditory stress.
Circulating Endothelial Progenitor Cells and Coronary Collaterals in Patients with Non-ST Segment Elevation Myocardial Infarction
Authors: Lev Eli I. , Kleiman Neal S. , Birnbaum Yochai , Harris David , Korbling Martin , Estrov Zeev
Published: August 2005

Background: Endothelial progenitor cells (EPCs) are bone marrow-derived cells that are augmented in response to ischemia and incorporated into neovascularization sites. We sought to determine whether circulating EPCs are related to collateral formation following non-ST segment elevation myocardial infarction (NSTEMI). Methods: Twenty patients who underwent percutaneous coronary intervention (PCI) within a week of NSTEMI were divided into two groups: patients without collaterals (coll–, n = 10) and patients with Rentrop grade 3–4 collaterals (coll+, n = 10). Blood samples were drawn before PCI and 24 ± 2 h after PCI. EPC colonies were grown from peripheral blood mononuclear cells, characterized, and counted. Using flow cytometry the percentage of cells coexpressing vascular endothelial growth factor receptor-2 and CD133 was determined. Results: The coll+ group had higher degree of culprit vessel stenosis and lower initial thrombolysis in myocardial infarction flow grade. The relative number of EPCs before PCI was significantly higher in the coll+ group than in the coll– group (1.49 ± 0.9% vs. 0.77 ± 0.4%, p = 0.045). There were no significant intergroup differences in the number of EPC colony-forming cells. The number of EPC colonies increased in the coll– group after PCI (9.5 ± 4.8 to 14.0 ± 5.9/106 cells, p = 0.01). Conclusions: This study supports an association between circulating EPC levels and collateral formation in patients with an NSTEMI.
Sarco/Endoplasmic Reticulum Ca
2+
-ATPase Gene Transfer Reduces Vascular Smooth Muscle Cell Proliferation and Neointima Formation in the Rat
Authors: Lipskaia Larissa , del Monte Federica , Capiod Thierry , Yacoubi Sabrina , Hadri Lahouaria , Hours Michel , Hajjar Roger J. , Lompré Anne-Marie
Published: August 2005

Proliferation of vascular smooth muscle cells (VSMC) is a primary cause of vascular disorders and is associated with major alterations in Ca
2+
handling supported by loss of the sarco/endoplasmic reticulum calcium ATPase, SERCA2a. To determine the importance of SERCA2a in neointima formation, we have prevented loss of its expression by adenoviral gene transfer in a model of balloon injury of the rat carotid artery. Two weeks after injury, the intima/media ratio was significantly lower in SERCA2a-infected than in injured noninfected or injured β-galactosidase–infected carotids (0.29±0.04 versus 0.89±0.19 and 0.72±0.14, respectively;
P
<0.05), and was comparable to that observed in control carotids (0.21±0.03). The pathways leading to proliferation were analyzed in serum-stimulated VSMC. Forced expression of SERCA2a arrested cell cycle at the G1 phase and prevented apoptosis. SERCA2a inhibits proliferation through inactivation of calcineurin (PP2B) and its target transcription factor NFAT (nuclear factor of activated T-cells) resulting in lowering of cyclin D1 and pRb levels. By using NFAT-competing peptide VIVIT, we showed that NFAT activity is strongly required to promote VSMC proliferation. In conclusion, we provide the first evidence that increasing SERCA2a activity inhibits VSMC proliferation and balloon injury–induced neointima formation.
Cigarette Smoking Among Spouses
Authors: Qureshi Adnan I. , Fareed M. , Suri K. , Kirmani Jawad F. , Divani Afshin A.
Published: August 2005

Background and Purpose—

It is well known that passive exposure to cigarette smoking increases the risk of coronary events, but the effect on the risk of stroke is not well defined. We performed this study to determine the effect of cigarette smoking among spouses on the risk of developing stroke and ischemic stroke among a nationally representative sample of women.

Methods—

We examined the association between history of smoking among spouses with the incidence of stroke in a national cohort of 5379 women who participated in the First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study.

Results—

During a mean follow-up of 8.5 years, the risk was significantly increased for all strokes (relative risk, 5.7; 95% CI, 1.4 to 24) and ischemic stroke (relative risk, 4.8; 95% CI, 1.2 to 20) among cigarette-smoking women with a cigarette-smoking spouse compared with those with a nonsmoking spouse after adjusting for other cardiovascular risk factors.

Conclusion—

The study provides new evidence linking spousal smoking to stroke.
Chagas Disease Is an Independent Risk Factor for Stroke
Authors: Oliveira-Filho Jamary , Viana Leila C. , Vieira-de-Melo Rodrigo M. , Faiçal Frederico , Torreão Jorge A. , Villar Flávio A.G.A. , Reis Francisco J.F.B.
Published: August 2005

Background and Purpose—

Chagas disease (CD) is frequently associated with cardioembolic stroke in South America. Our objective was to identify the predictors of stroke in a region where CD is endemic.

Methods—

We screened 305 consecutive cardiopathy patients. Significant predictors of stroke in univariable analyses were included in a multivariable model.

Results—

Stroke was more frequent in CD (15.0%) compared with other cardiopathies (6.3%;
P
=0.015). Other predictors of stroke in univariable analyses were previous diabetes or cardioversion and use of amiodarone, antiplatelet agents, and warfarin. In multivariable analysis, remaining predictors of stroke were CD (odds ratio [OR], 1.09; 95% CI, 1.02 to 1.17), cardioversion (OR, 1.07; 95% CI, 1.02 to 1.13), and diabetes (OR, 1.12; 95% CI, 1.01 to 1.24).

Conclusions—

In conclusion, CD is a risk factor for stroke, independent of systolic dysfunction or presence of cardiac arrhythmias.
Optimizing Cutoff Scores for the Barthel Index and the Modified Rankin Scale for Defining Outcome in Acute Stroke Trials
Authors: Uyttenboogaart Maarten , Stewart Roy E. , Vroomen Patrick C.A.J. , De Keyser Jacques , Luijckx Gert-Jan
Published: August 2005

Background and Purpose—

There is little agreement on how to assess outcome in acute stroke trials. Cutoff scores for the Barthel Index (BI) and modified Rankin Scale (mRS) are frequently arbitrarily chosen to dichotomize favorable and unfavorable outcome. We investigated sensitivity and specificity of BI cutoff scores in relation to the mRS to obtain the optimal corresponding BI and mRS scores.

Methods—

BI and mRS scores were collected from 1034 ischemic stroke patients. Sensitivity and specificity were calculated for BI cutoff scores from 45 to 100 in mRS score 1, 2, and 3 and were plotted in receiver operator characteristic (ROC) curves.

Results—

The cutoff scores for the BI with the highest sum of sensitivity and specificity were 95 (sensitivity 85.6%; specificity 91.7%), 90 (sensitivity 90.7%; specificity 88.1%), and 75 (sensitivity 95.7%; specificity, 88.5%) for, respectively, mRS 1, 2, and 3. The area under the ROC curve was 0.933 in mRS 1, 0.960 in mRS 2, and 0.979 in mRS 3.

Conclusions—

The optimal cutoff scores for the BI were 95 for mRS 1, 90 for mRS 2, and 75 for mRS 3. For future acute stroke trials that assess stroke outcome with the BI and mRS, we recommend the use of these BI cutoff score(s) with the corresponding mRS cutoff score(s), to ensure the use of consistent and uniform end points.
Baroclinic Instabilities of the Two-Layer Quasigeostrophic Alpha Model
Authors: Holm Darryl D. , Wingate Beth A.
Published: August 2005

The class of alpha models for turbulence may be derived by applying Lagrangian averaging to the exact fluid equations and then making a closure approximation based on Taylor’s hypothesis of frozen-in fluctuations. This derivation provides a closed expression for the unknown pseudomomentum in the generalized Lagrangian mean theory of Andrews and McIntyre. In the current study, the mean effects of turbulence on baroclinic instability are explored, as determined by the two-layer quasigeostrophic-alpha model in quasigeostrophic (QG) balance. The QG-alpha model is found to lower the critical wavenumber, reduce the bandwidth of instability, and preserve the value of forcing at onset in the baroclinic case. It also preserves the fundamental dependence of baroclinic instability on the gradient of the potential vorticity. These results encourage using the alpha-model approach—based on combining Lagrangian averaging with Taylor’s hypothesis closure approximations—in simulations of global ocean circulation, because this class of turbulence closure models allows Lagrangian-averaged effects of baroclinic instability to be simulated on a coarse mesh.
Water Mass Export from Drake Passage to the Atlantic, Indian, and Pacific Oceans: A Lagrangian Model Analysis
Authors: Friocourt Yann , Drijfhout Sybren , Blanke Bruno , Speich Sabrina
Published: August 2005

The northward export of intermediate water from Drake Passage is investigated in two global ocean general circulation models (GCMs) by means of quantitative particle tracing diagnostics. This study shows that a total of about 23 Sv (Sv ≡ 106 m3 s−1) is exported from Drake Passage to the equator. The Atlantic and Pacific Oceans are the main catchment basins with 7 and 15 Sv, respectively. Only 1–2 Sv of the water exported to the Atlantic equator follow the direct cold route from Drake Passage without entering the Indian Ocean. The remainder loops first into the Indian Ocean subtropical gyre and flows eventually into the Atlantic Ocean by Agulhas leakage. The authors assess the robustness of a theory that relates the export from Drake Passage to the equator to the wind stress over the Southern Ocean. Our GCM results are in reasonable agreement with the theory that predicts the total export. However, the theory cannot be applied to individual basins because of interocean exchanges through the “supergyre” mechanism and other nonlinear processes such as the Agulhas rings. The export of water from Drake Passage starts mainly as an Ekman flow just northward of the latitude band of the Antarctic Circumpolar Current south of South America. Waters quickly subduct and are transferred to the ocean interior as they travel equatorward. They flow along the eastern boundaries in the Sverdrup interior and cross the southern basins northwestward to reach the equator within the western boundary current systems.
Sensitivity of Coastal Currents near Point Conception to Forcing by Three Different Winds: ECMWF, COAMPS, and Blended SSM/I–ECMWF–Buoy Winds
Authors: Dong Changming , Oey Lie-Yauw
Published: August 2005

Previous observational and modeling studies have indicated the importance of finescale winds in determining the circulation near Point Conception in the Santa Maria Basin (SMB) and the Santa Barbara Channel (SBC), California. There has not been a systematic attempt, however, to analyze and quantify the sensitivity of the near-surface circulation to different wind data. Here, a regional circulation model of the SMB and SBC is driven using three wind datasets: the European Centre for Medium-Range Weather Forecasts (ECMWF; ≈ 110 km × 110 km horizontal grid), the Coupled Ocean–Atmosphere Mesoscale Prediction System (COAMPS; 9 km × 9 km horizontal grid), and a blended wind product that combines Special Sensor Microwave Imager (SSM/I), ECMWF, and buoy and coastal wind data and that is referred to as SEB. A springtime period (March–May 1999) in which equatorward wind dominates and wind stress curls are strong is chosen for the study. Two groups of experiments are conducted: with and without assimilating moored temperature observations. The focus is on long time scales of greater than weeks and on mean currents. Comparisons between these experiments and between model and observation show that the circulation driven by the ECMWF wind is much weaker than that by the other two winds. On the other hand, the SEB dataset shows locally intensified wind stress curls behind capes and coastal bends, whereas these wind stress curls are weak in COAMPS. It is found that these small-scale variations in the wind field force alongshore inhomogeneous pressure gradients that in turn can significantly affect the near-coast currents. The result is that modeled currents forced by SEB agree better with observations than do those produced by COAMPS. Empirical orthogonal function analyses were conducted on the near-surface currents, sea level, wind, and wind stress curl. The mode-1 current (≈40%) is unidirectional (i.e., generally equatorward or poleward) and correlates well with the mode-1 wind (≈90%). The mode-2 current (≈20%) is cyclonic in the SBC and poleward inshore and equatorward offshore in the SMB; it correlates well with mode-1 sea level (≈70%), which suggests that mode-2 currents are driven by the pressure gradient. It is significant that neither mode-2 current nor mode-1 sea level correlates well with mode-1 wind stress curl (≈70%); rather, they correlate well with the time integral of the mode-1 wind stress curl. These conclusions support a previous theoretical idea that cyclonic circulation in the SBC and the inshore currents of the SMB are both driven by alongshore pressure setup induced by the time integral of the wind stress curl, rather than by the wind stress curl itself. This idea of a pressure setup is consistent with the differences found between the currents driven by COAMPS and SEB winds.
A redox signature score identifies diffuse large B-cell lymphoma patients with a poor prognosis
Authors: Tome Margaret E. , Johnson David B. F. , Rimsza Lisa M. , Roberts Robin A. , Grogan Thomas M. , Miller Thomas P. , Oberley Larry W. , Briehl Margaret M.
Published: August 2005

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease in which approximately 40% of the patients respond well to current chemotherapy, but the prognosis for the other 60% is poor. The Leukemia/Lymphoma Molecular Profiling Project (LLMPP) used microarray technology to define a molecular profile for each of 240 patients with DLBCL and develop a molecular outcome predictor score that accurately predicted patient survival. Data from our laboratory and others suggest that alterations in antioxidant defense enzyme levels and redox environment can be oncogenic and affect the response to glucocorticoid treatment, one of the components of combination chemotherapy regimens for lymphoma. The goal of the current study was to reanalyze the LLMPP microarray data to determine whether the levels of antioxidant defense enzymes and redox proteins were correlated with prognosis in DLBCL. We found that patients with DLBCL with the worst prognosis, according to the outcome predictor score, had decreased expression of catalase, glutathione peroxidase, manganese superoxide dismutase, and VDUP1, a protein that inhibits thioredoxin activity. The data suggest that the patients with the worst prognosis combine a decrease in antioxidant defense enzyme expression with an increase in thioredoxin system function (the redox signature score).
Heterogeneity of engrafted bone-lining cells after systemic and local transplantation
Authors: Wang Liping , Liu Yaling , Kalajzic Zana , Jiang Xi , Rowe David W.
Published: August 2005

The outcome of various osteoprogenitor-cell transplantation protocols was assessed using Col1a1-GFP reporter transgenic mice. The model requires the recipient mice to undergo lethal total body irradiation (TBI) followed by rescue with whole bone marrow. When the mice are rescued with total bone marrow from a Col1a1-GFP transgenic mouse, green fluorescence protein (GFP)-positive donor cells can be observed on most endosteal and trabecular bone surfaces. Although the cells express an osteoblast-restricted GFP, they fail to progress to osteocytes, do not form a mineralized matrix, and do not generate bone nodules in vitro. However when calvarial progenitor cells derived from the same transgenic mice are injected into the bone marrow space, osteogenesis by the donor cells is observed. Using different GFP colors that distinguish the donor and recipient osteoblasts, commingling of the 2 cells types is observed along the mineralizing osteoblast surface as well as within the osteocyte population of the endosteal bone. Despite the ability of the injected progenitor cells to produce bone within the injected bone, they lack the ability to form mineralized bone nodules when explanted to primary osteoblast culture. These reagents and imaging protocols will be useful in evaluating other cells having a better progenitor potential than calvarial-derived stromal cells.
The Ig-ITIM superfamily member PECAM-1 regulates the “outside-in” signaling properties of integrin αIIbβ3 in platelets
Authors: Wee Janet L. , Jackson Denise E.
Published: August 2005

Previous studies have implicated the immunoglobulin (Ig)–immunoreceptor tyrosine–based inhibitory motif (ITIM) superfamily member platelet endothelial cell adhesion molecule-1 (PECAM-1) in the regulation of integrin function. While PECAM-1 has been demonstrated to play a role as an inhibitory coreceptor of immunoreceptor tyrosine–based activation motif (ITAM)–associated Fcγ receptor IIa (FcγRIIa) and glycoprotein VI (GPVI)/FcR γ-chain signaling pathways in platelets, its physiologic role in integrin αIIbβ3–mediated platelet function is unclear. In this study, we investigate the functional importance of PECAM-1 in murine platelets. Using PECAM-1–deficient mice, we show that the platelets have impaired “outside-in” integrin αIIbβ3 signaling with impaired platelet spreading on fibrinogen, failure to retract fibrin clots in vitro, and reduced tyrosine phosphorylation of focal adhesion kinase p125 (125FAK) following integrin αIIbβ3–mediated platelet aggregation. This functional integrin αIIbβ3 defect could not be attributed to altered expression of integrin αIIbβ3. PECAM-1–/– platelets displayed normal platelet alpha granule secretion, normal platelet aggregation to protease-activated receptor-4 (PAR-4), adenosine diphosphate (ADP), and calcium ionophore, and static platelet adhesion. In addition, PECAM-1–/– platelets displayed normal “inside-out” integrin αIIbβ3 signaling properties as demonstrated by normal agonist-induced binding of soluble fluoroscein isothiocyanate (FITC)–fibrinogen, JON/A antibody binding, and increases in cytosolic-free calcium and inositol (1,4,5)P3 triphosphate (IP3) levels. This study provides direct evidence that PECAM-1 is essential for normal integrin αIIbβ3–mediated platelet function and that disruption of PECAM-1 induced a moderate “outsidein” integrin αIIbβ3 signaling defect.
Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma
Authors: Stühmer Thorsten , Chatterjee Manik , Hildebrandt Martin , Herrmann Pia , Gollasch Hella , Gerecke Christian , Theurich Sebastian , Cigliano Luisa , Manz Rudolf A. , Daniel Peter T. , Bommert Kurt , Vassilev Lyubomir T. , Bargou Ralf C.
Published: August 2005

Mutation of p53 is a rare event in multiple myeloma, but it is unknown if p53 signaling is functional in myeloma cells, and if targeted nongenotoxic activation of the p53 pathway is sufficient to kill tumor cells. Here, we demonstrate that treatment of primary tumor samples with a small-molecule inhibitor of the p53–murine double minute 2 (MDM2) interaction increases the level of p53 and induces p53 targets and apoptotic cell death. Significantly, given the importance of the bone marrow microenvironment for the support and drug resistance of myeloma cells, tumor cells undergo effective apoptosis also in the presence of stromal cells, which themselves appear to tolerate exposure to nutlin-3. The in vitro toxicity of nutlin-3 was similar to that of the genotoxic drug melphalan. Because nutlin-mediated p53 activation is not dependent on DNA damage, MDM2 antagonists may help to avoid or reduce the severe genotoxic side effects of chemotherapeutic agents currently used to treat multiple myeloma. Therefore, MDM2 antagonists may offer a new treatment option for this disease.
MEK kinase 1 activity is required for definitive erythropoiesis in the mouse fetal liver
Authors: Bonnesen Barbara , Orskov Cathrine , Rasmussen Susanne , Holst Peter Johannes , Christensen Jan Pravsgaard , Eriksen Karsten Wessel , Qvortrup Klaus , Odum Niels , Labuda Tord
Published: August 2005

Mitogen-activated protein kinase/extracellular signal to regulated kinase (MEK) kinase 1 (MEKK1) is a c-Jun N-terminal kinase (JNK) activating kinase known to be implicated in proinflammatory responses and cell motility. Using mice deficient for MEKK1 kinase activity (Mekk1ΔKD) we show a role for MEKK1 in definitive mouse erythropoiesis. Although Mekk1ΔKD mice are alive and fertile on a 129 × C57/BL6 background, the frequency of Mekk1ΔKD embryos that develop past embryonic day (E) 14.5 is dramatically reduced when backcrossed into the C57/BL6 background. At E13.5, Mekk1ΔKD embryos have normal morphology but are anemic due to failure of definitive erythropoiesis. When Mekk1ΔKD fetal liver cells were transferred to lethally irradiated wild-type hosts, mature red blood cells were generated from the mutant cells, suggesting that MEKK1 functions in a non–cell-autonomous manner. Based on immunohistochemical and hemoglobin chain transcription analysis, we propose that the failure of definitive erythropoiesis is due to a deficiency in enucleation activity caused by insufficient macrophage-mediated nuclear DNA destruction.
Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2
Authors: Kralovics Robert , Teo Soon-Siong , Buser Andreas S. , Brutsche Martin , Tiedt Ralph , Tichelli Andre , Passamonti Francesco , Pietra Daniela , Cazzola Mario , Skoda Radek C.
Published: August 2005

We identified 13 new gene expression markers that were elevated and one marker, ANKRD15, that was down-regulated in patients with polycythemia vera (PV). These 14 markers, as well as the previously described PRV1 and NF-E2, exhibited the same gene expression alterations also in patients with exogenously activated granulocytes due to sepsis or granulocyte colony-stimulating factor (G-CSF) treatment. The recently described V617F mutation in the Janus kinase 2 (JAK2) gene allows defining subclasses of patients with myeloproliferative disorders based on the JAK2 genotype. Patients with PV who were homozygous or heterozygous for JAK2-V617F exhibited higher levels of expression of the 13 new markers, PRV1, and NF-E2 than patients without JAK2-V617F, whereas ANKRD15 was down-regulated in these patients. Our results suggest that the alterations in expression of the markers studied are due to the activation of the Jak/signal transducer and activator of transcription (STAT) pathway through exogenous stimuli (sepsis or G-CSF treatment), or endogenously through the JAK2-V617F mutation.
Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin
Authors: Delaby Constance , Pilard Nathalie , Gonçalves Ana Sofia , Beaumont Carole , Canonne-Hergaux François
Published: August 2005

Ferroportin, the only mammalian iron exporter identified to date, is highly expressed in duodenal enterocytes and in macrophages. Several lines of evidence indicate that in enterocytes the iron export mediated by ferroportin occurs and is regulated at the basolateral cell surface, where the transporter is strongly expressed. By contrast, in macrophages, ferroportin has been shown in intracellular vesicles. We used a high-affinity antibody to specify the localization of endogenous ferroportin expressed in primary culture of bone marrow–derived macrophages, in both basal and induced conditions. Our observations indicate that ferroportin is expressed in vesicular compartments that can reach the plasma membrane of macrophages. Of importance, when ferroportin expression was up-regulated through iron treatment or erythrophagocytosis, ferroportin expression was strongly enhanced at the plasma membrane of macrophages. Moreover, hepcidin dramatically reduced macrophage ferroportin protein levels. At the subcellular level, hepcidin was shown to induce rapid internalization and degradation of the macrophage iron exporter. These data are consistent with a direct iron export by ferroportin through the plasma membrane of macrophages and strongly support an efficient posttranscriptional down-regulation of ferroportin by hepcidin in these cells.
Archazolid and apicularen: Novel specific V-ATPase inhibitors
Authors: Huss Markus , Sasse Florenz , Kunze Brigitte , Jansen Rolf , Steinmetz Heinrich , Ingenhorst Gudrun , Zeeck Axel , Wieczorek Helmut
Published: August 2005

Background

V-ATPases constitute a ubiquitous family of heteromultimeric, proton translocating proteins. According to their localization in a multitude of eukaryotic membranes, they energize many different transport processes. Since their malfunction is correlated with various diseases in humans, the elucidation of the properties of this enzyme for the development of selective inhibitors and drugs is one of the challenges in V-ATPase research.

Results

Archazolid A and B, two recently discovered cytotoxic macrolactones produced by the myxobacterium Archangium gephyra, and apicularen A and B, two novel benzolactone enamides produced by different species of the myxobacterium Chondromyces, exerted a similar inhibitory efficacy on a wide range of mammalian cell lines as the well established plecomacrolidic type V-ATPase inhibitors concanamycin and bafilomycin. Like the plecomacrolides both new macrolides also prevented the lysosomal acidification in cells and inhibited the V-ATPase purified from the midgut of the tobacco hornworm, Manduca sexta, with IC50 values of 20–60 nM. However, they did not influence the activity of mitochondrial F-ATPase or that of the Na+/K+-ATPase. To define the binding sites of these new inhibitors we used a semi-synthetic radioactively labelled derivative of concanamycin which exclusively binds to the membrane Vo subunit c. Whereas archazolid A prevented, like the plecomacrolides concanamycin A, bafilomycin A1 and B1, labelling of subunit c by the radioactive I-concanolide A, the benzolactone enamide apicularen A did not compete with the plecomacrolide derivative.

Conclusion

The myxobacterial antibiotics archazolid and apicularen are highly efficient and specific novel inhibitors of V-ATPases. While archazolid at least partly shares a common binding site with the plecomacrolides bafilomycin and concanamycin, apicularen adheres to an independent binding site.
FIGENIX: Intelligent automation of genomic annotation: expertise integration in a new software platform
Authors: Gouret Philippe , Vitiello Vérane , Balandraud Nathalie , Gilles André , Pontarotti Pierre , Danchin Etienne GJ
Published: August 2005

Background

Two of the main objectives of the genomic and post-genomic era are to structurally and functionally annotate genomes which consists of detecting genes' position and structure, and inferring their function (as well as of other features of genomes). Structural and functional annotation both require the complex chaining of numerous different software, algorithms and methods under the supervision of a biologist. The automation of these pipelines is necessary to manage huge amounts of data released by sequencing projects. Several pipelines already automate some of these complex chaining but still necessitate an important contribution of biologists for supervising and controlling the results at various steps.

Results

Here we propose an innovative automated platform, FIGENIX, which includes an expert system capable to substitute to human expertise at several key steps. FIGENIX currently automates complex pipelines of structural and functional annotation under the supervision of the expert system (which allows for example to make key decisions, check intermediate results or refine the dataset). The quality of the results produced by FIGENIX is comparable to those obtained by expert biologists with a drastic gain in terms of time costs and avoidance of errors due to the human manipulation of data.

Conclusion

The core engine and expert system of the FIGENIX platform currently handle complex annotation processes of broad interest for the genomic community. They could be easily adapted to new, or more specialized pipelines, such as for example the annotation of miRNAs, the classification of complex multigenic families, annotation of regulatory elements and other genomic features of interest.
Folate system correlations in DNA microarray data
Authors: Radivoyevitch Tomas
Published: August 2005

Background

Gene expression data is abundantly available from the Gene Expression Omnibus (GEO) and various websites. Pathway specific analyses of gene-gene correlations across these datasets remain relatively unexplored, though they could be informative.

Methods

Folate gene expression data is explored here in two ways: (1) directly, using gene-gene scatter plots and gene expression time course plots; and (2) indirectly, using de novo purine synthesis (DNPS) and de novo thymidylate synthesis (DNTS) flux predictions of a folate model perturbed by relative gene expression modulations of its Vmax parameters.

Results

Positive correlations within and between the DNPS and DNTS folate cycles are observed in the folate gene expression data. For steady state measurements across childhood leukemia patients, positive correlations between DNPS and DNTS are consistent with higher proliferative fractions requiring higher levels of both fluxes. For cells exposed to ionizing radiation, transient increases in both pathways are consistent with DNA damage driven dNTP demand, and a steadily decreasing backdrop is consistent with radiation induced cell cycle arrest. By and large, folate model based flux predictions paralleled these findings, the main differences being a gain of correlation information for the TEL-AML1 leukemia data, and the loss of one interesting inference, namely, that RNA repair driven DNPS precedes DNA repair driven DNTS after a 10 gray dose of ionizing radiation.

Conclusion

Pathway focused correlation analyses of DNA microarray data can be informative, with or without a mathematical model. Conceptual models are essential. Mathematical model based analyses should supplement, but should not replace, direct data analyses.
Novel curcumin- and emodin-related compounds identified by in silico 2D/3D conformer screening induce apoptosis in tumor cells
Authors: Füllbeck Melanie , Huang Xiaohua , Dumdey Renate , Frommel Cornelius , Dubiel Wolfgang , Preissner Robert
Published: August 2005

Background

Inhibition of the COP9 signalosome (CSN) associated kinases CK2 and PKD by curcumin causes stabilization of the tumor suppressor p53. It has been shown that curcumin induces tumor cell death and apoptosis. Curcumin and emodin block the CSN-directed c-Jun signaling pathway, which results in diminished c-Jun steady state levels in HeLa cells. The aim of this work was to search for new CSN kinase inhibitors analogue to curcumin and emodin by means of an in silico screening method.

Methods

Here we present a novel method to identify efficient inhibitors of CSN-associated kinases. Using curcumin and emodin as lead structures an in silico screening with our in-house database containing more than 106 structures was carried out. Thirty-five compounds were identified and further evaluated by the Lipinski's rule-of-five. Two groups of compounds can be clearly discriminated according to their structures: the curcumin-group and the emodin-group. The compounds were evaluated in in vitro kinase assays and in cell culture experiments.

Results

The data revealed 3 compounds of the curcumin-group (e.g. piceatannol) and 4 of the emodin-group (e.g. anthrachinone) as potent inhibitors of CSN-associated kinases. Identified agents increased p53 levels and induced apoptosis in tumor cells as determined by annexin V-FITC binding, DNA fragmentation and caspase activity assays.

Conclusion

Our data demonstrate that the new in silico screening method is highly efficient for identifying potential anti-tumor drugs.